Immunology Flashcards
1
Q
What are the characteristics of innate immunity?
A
- Present at birth
- Rapid
- Relies on pattern recognition
- Not specific
- No memory
- Primarily mediated by neutrophils
2
Q
What are the characteristics of adaptive immunity?
A
- Slow (on first exposure)
- Diverse
- Adapts to antigen (not pre-formed)
- Highly specific
- Generates memory and improved immunity w/ repeated antigen exposure
3
Q
What is specificity?
A
The ability to distinguish between different substances
4
Q
Describe specificity with regards to innate immunity
A
Proteins that recognize common patterns of infectious organisms
Not very specific
5
Q
Describe specificity with regards to adaptive immunity
A
Surface protein recognizes unique molecules
Highly specific
6
Q
What is passive immunity?
Describe the characteristics of passive immunity
A
Transfer of pre-formed antibody from one person or animal to another
Rapid
Short-lived
7
Q
What are examples of passive immunity?
A
- Antitoxins for botulinum toxins
- Antibodies to rabies virus
- Maternal IgG antibodies crossing the placenta
- Maternal IgA antibodies in breast milk
8
Q
What is active immunity?
Describe the characteristics of active immunity
A
Induction of an immune response (exposure to antigen)
Slow
Memory (long-lived)
9
Q
What is an example of active immunity?
A
An immunization
10
Q
Patient AJ is planning to travel internationally in 3 days to a region endemic for Hepatitis A. She will be there for one year. What is the best type of immunity-based therapy to offer her to prevent infection?
A
Immunization against Hepatitis A with Ig and the inactivated virus
11
Q
Which immunoglobulin do nursing infants have?
A
Maternal IgA
12
Q
Which immunoglobulin do all very young infants (under 6 weeks) have?
A
Maternal IgG
(And Maternal IgA if they are nursing)
13
Q
Which sort of immune response are infants under the age unable to generate?
A
Infants under 2 years old cannot generate an effective T-cell independent B cell response
(such as to a polysaccharide capsule)
14
Q
Which sort of immune response do older adults have a decreased ability to generate?
A
T-cell independent B cell response
15
Q
Which two groups cannot generate / generated reduced T-cell independent B cell responses?
A
- Infants under age of two
- Older adults
Struggle w/ encapsulated bacteria
Have greater frequency and severity of infections
16
Q
Why are encapsulated bacteria particularly dangerous to infants under the age of two?
A
Infants under two cannot generate an effective T-cell independent B cell response
17
Q
Why are encapsulated bacteria particularly dangerous to older adults?
A
Older adults have decreased ability to generate an effective T-cell independent B cell response
18
Q
What must pneumoccal vaccines consisting of polysaccharides be conjugated to in order for children under the age of 2 to allow for a protective immune response?
A
Proteins
19
Q
What are cytokines?
A
Small proteins that are produced by cells and have effects on cells
Include chemokines, interleukins, lymphokines, tumor necrosis factors, interferons
20
Q
What is the function of IL-2?
A
Promotes T cell growth and activation
21
Q
What is “clusters of differentiation”?
A
Nomenclature system for the proteins used to identify cells
22
Q
What does a CD refer to?
A
A protein expressed by cells
23
Q
On which cells is CD3 expressed?
A
All T cells
24
Q
On which cells is CD4 expressed?
What does CD4 bind to?
A
Helper T cells
Binds to MHC class II
25
On which cells is CD8 expressed?
What does CD8 bind to?
Cytotoxic T cells
Binds to MHC class I
26
On which cells is CD19 expressed?
All B cells
27
On which cells is CD56 expressed?
NK cells
28
What is CD28?
What does it bind to?
Co-stimulatory protein on T cells (2nd signal)
Binds to B7 on APCs
29
A 33 year old woman is planning to travel internationally in 3 days to a region endemic for Hepatitis A. What is the best type of immunity-based therapy to offer her to prevent infection?
Due to short time before her potential exposure to Hepatitis A, she should receive immune globulin (Ig), which is passive immunization, since the antibody is preformed and the protection is rapid.
This protection is short-lived, so she should also receive inactive Hepatitis A vaccine, which provides longer protection.
Ideally, she would also have a booster in 6 months for much longer protection.
30
What protein must antigen-presenting cells express on their surface to present a peptide to CD4+ T helper cells?
MHC II
31
Would exposure to only the polysaccharide capsule of bacteria lead to a T cell mediated immune response?
Could there still be an immune response?
No, if there is no protein present, there will not be a T cell-mediated immune response
There could be a T cell independent immune response driven by B cells
32
How do pathogens prevent being destroyed by innate immunity?
* Evade immune system
* Use elements of immune system for their own advantage
33
How does Bordetella pertusis evade the immune system?
Has proteins that bind to ciliated respiratory cells to enable infection
34
What is innate immunity?
Part of immune response that exists at birth and is present in all multicellular organisms
Rapid, relies on pattern recognition to identify pathogens, has no specificity, shows no memory or improvement in immunity with time or repeated antigen exposure
35
Which white blood cells are involved in the innate immune response?
* Neutrophils
* Monocytes/macrophages
* Basophils
* Mast cells
* NK cells
36
What is the role of neutrophils in innate immunity?
Neutrophils (granulocytes, PMNs)
* First responders
* Rapidly migrate from bone marrow to blood to tissue (peripheral blood neutrophilia)
* Engulf/kill pathogens
* Release additional pro-inflammatory cytokines
* Major cell of acute inflammatory response
* Do not present antigen on MHC class II
37
What is neutropenia?
What causes it?
What does it lead to?
Too few neutrophils
Often caused by chemotherapy
Leads to significantly increased susceptibility to infection
38
What is the role of monocytes in the blood / tissue macrophages in innate immunity?
Tissue macrophages
* Recognize pathogens through pattern recognition
* Release cytokines to recruit neutrophils
* Macrophages phagocytose organisms
* Antigen-presenting cells (express MHC class II)
39
Where are mast cells present?
What are mast cells activated by?
What do mast cells release?
Mast cells
* Present throughout connective tissue
* Activated by trauma, complement proteins (C3a and CD5a), and cross-linking of IgE (which is bound by IgE Fc freceptor)
* Express-tole like receptors that recognize bacteria and viruses
* Release histamine and other mediators of inflammation
40
Where are basophils present?
What are basophils activated by?
What do basophils release?
Basophils
* Present in blood
* Activated by trauma, complement proteins (C3a and CD5a), and cross-linking of IgE (which is bound by IgE Fc freceptor)
* Express-tole like receptors that recognize bacteria and viruses
* Release histamine and other mediators of inflammation
41
What is the role of NK cells in innate immunity?
NK cells (CD56+ and CD16+)
* Directly kill infected cells
* Recognize virus-infected cells and tumor cells via lack of MHC class I on those cells and by binding Fc (constant region) of antibody bound to those cells (antibody-dependent cellular cytotoxicity)
* Produce and secrete cytotoxic granules such as perforin and granzyme B
* Do not express specific antigen receptors
42
What are complement proteins?
\>20 plasma proteins that augment inflammation
43
What do complement proteins circulate as?
Inactive precursors
44
How are complement proteins activated?
Activated in a cascade of cleavage reactions that allow proteins and immune complexes to be destroyed or eliminated
45
What are the functions of complement?
* Direct lysis of cells
* Generation of mediators of inflammation
* Opsonization (enhancement of phagocytosis)
46
Why is regulation of complement essential?
To prevent tissue damage
47
What do the three mechanisms of complement activation converge on?
C3 convertase
48
What does C3 convertase do?
Acts on C3 to make C3a and C3b
49
What does C3b do?
Acts on C5 to make C5a and C5b
50
What does C5b do?
Inserts into cell membrane of pathogen and is bound by C6, C7, C8, and C9 to make the membrane attack complex
51
What does the membrane attack complex do?
Which bacteria are particularly susceptible?
Forms a hole in the membrane causing the pathogen to lyse
Gram-negative bacteria are particularly susceptible
52
Describe the classic pathway of complement activation
C1 binds to the constant fragment of IgG or IgM (antigen-antibody complex)
53
Describe the alternative pathway of complement activation
Microbial products directly activate complement
54
Describe the lectin pathway of complement activation
Mannose-binding lectin (serum protein) binds carbohydrate antigens on the surface of micro-organisms (such as encapsulated bacteria)
55
What is the function of C1?
Recognizes antigen-antibody complexes in the classical pathway of complement activation
56
What is the function of C3 convertase?
Associates with pathogen cell membrane and cleaves/activates other complement proteins
57
What is the function of C3a?
Triggers mast cells to degranulate and release histamine (anaphylatoxins)
58
What are the functions of C5a?
* Triggers mast cells to degranulate and release histamine (anaphylatoxins)
* Chemotactic for neutrophils
59
What is the function of C3b?
Opsonin for phagocytosis (iC3b and C3d are breakdown products of C3b)
60
What do C5b, C6, C7, C8, and C9 form?
The membrane attack complex
61
What is the function of C1 esterase inhibitor?
Inhibits the formation of C3
62
What is the function of decay accelerating factor (CD55)?
Inhibits the formation of C3
63
What condition does a deficiency in C1 esterase inhibitor cause?
What is the biomolecular cause of the condition?
What are the symptoms?
Hereditary angiodema
Uncontrolled generation of bradykinins
Persistent swelling in extremities, face, lips, genitals, and GI tract
64
What do deficiencies in the membrane attack complex (C5b, C6, C7, C8, C9) lead to?
Predispose to infections with Neisseria
65
What does C1 bind to initiate the classical complement pathway?
IgG bound to antigen
66
What are defensins?
Where are defensins found?
Small cationic peptides that bind to and create pores in microbes
Alpha definsins are in the GI tract
Beta defensins are in the respiratory tract
67
What are interferons (alpha and beta)?
Anti-viral proteins that bind to the cell surface and induce an anti-viral state in cells
Inhibit viral replication
Produced by lymphocytes and macrophages
68
How do bacterial capsules reduce the effectiveness of the complement system?
* Prevents complement activation
* Decreases C3b binding
(Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae)
69
How are monocytes/macrophages involved in inflammation?
1. Monocytes and macrophages express pattern recognition proteins
2. Recognize PAMPs (ex: CD14/TLR4 recognizes LPS)
3. Release pro-inflammatory cytokines/mediators and stimulate acute phase reponse
Macrophages also release anti-inflammatory cytokines to control immune response
70
What do pro-inflammatory cytokines trigger?
What occurs?
Acute phase response
Increased synthesis of plasma proteins by the liver, including C-reactive protein, mannose-binding lectin, Factor XII
Contributes to sepsis
71
What is IL-1?
* Pro-inflammatory cytokine
* Endogenous pyrogen
* Induces acute phase response
72
What is IL-6?
* Pro-inflammatory cytokine
* Endogenous pyrogen
* Induces acute phase response
73
What is IL-8?
* Pro-inflammatory cytokine
* Recruits neutrophils (chemokine)
Clean up in aisle 8 (IL-8)
74
What is tumor necrosis factor alpha (TNFa)?
* Pro-inflammatory cytokine
* Numerous pro-inflammatory effects
* Stimulates cell growth and proliferation
* Recruits neutrophils
* Increases cyclooxygenase
75
What is the function of cyclooxygenase?
Acts on arachidonic acid from cell membrane to produce prostaglandins
Prostaglandins mediate vasodilation and increased vascular permeability, pain, and fever
76
What is IL-10?
* Anti-inflammatory cytokine
* Turns off immune response
77
What is transforming growth factor beta (TGFb)?
* Anti-inflammatory cytokine
* Turns off immune response
78
On which cells is CD14 expressed?
What is the function of CD14?
Monocytes/macrophages
Co-receptor for TLR4 that recognizes LPS
79
What elements of innate immunity might defend against infection by bacteria in the GI tract?
* Intact mucosal epithelium
* Mucous
* pH
* Microbial molecules such as defensins
* Macrophages
* Dendritic cells
80
The classic complement pathway is initiated by interaction of C1 with what?
IgG or IgM
81
What is the role of pattern recogniton in triggering inflammation?
Pattern recognition receptors (PRRs) such as TLRs on monocytes/macrophages, mast cells, and other cells of the immune system recognize the pathogen-associated molecular patterns (PAMPs)
The signal leads the cell to release pro-inflammatory cytokines
82
In a patient with a chronic inflammatory disease mediated by the release of pro-inflammatory cytokines, which cytokines could oppose the inflammation and tissue damage?
Anti-inflammatory cytokines such as IL-10 and TGF-beta
(However, anti-inflammatory cytokines can also contribute to tissue damage under certain circumstances)
83
What is acute inflammation? What are the cells involved?
Predominantly an innate immune response (rapid, not specific) mediated by fluid in the tissues (edema) and neutrophil migration into tissues
Macrophages arrive after neutrophils and release further cytokines
Can resolve (such as fibrosis or scar tissue) or progress to chronic inflammation
84
What is the role of neutrophils in acute inflammation?
* Drawn towards inflammatory mediators from macrophages and mast cells
* Phagocytose and destroy organisms
* Release further cytokines to draw additional neutrophils
85
What is chronic inflammation? Which cells are involved?
Predominantly an adaptive immune response (delayed, specific) mediated by lymphocytes, plasma cells, and monocytes/macrophages
86
What are the causes of chronic inflammation?
Persistent infection, prolonged exposure to a toxic agent, or autoimmunity
87
What is granulomatous inflammation?
What is a granuloma?
A subtype of chronic inflammation characterized by granuloma formation
A granuloma is a collection of macrophages, sometimes with giant cells (large macrophages with multiple nuclei) and surrounding lymphocytes
88
What is the difference between a caseating and non-caseating granuloma?
A caseating granuloma has central necrosis (TB, fungal infection)
A non-caseating granuloma lacks central necrosis (foreign material reaction, sarcoidosis, cat scratch disease)
89
What type of response to extracellular pathogens tend to give rise to?
Which cells/molecules are involved?
Pyogen (pus-producing) response
Neutrophils, antibodies, complement
90
What type of response do intracellular pathogens tend to give rise to?
Which cells/substances are involved?
Granulomatous response
Macrophages, CD4+ T cells
91
What are the basic steps in inflammation produced by the innate immune system?
1. Cells of the innate immune system recognize pathogens through PAMPs
2. These cells release pro-inflammatory cytokines
3. Cytokines acute phase response and releazse of numerous mediators of inflammation
92
What releases TNFa?
What is the function of TNFa?
Macrophages
Pro-inflammatory effects including increased cyclooxygenase
93
What does cyclooxygenase do?
Acts on arachidonic acid from the cell membrane to produce prostaglandins which mediate vasodilation and increased vascular permeability, pain, and fever
94
What does 5-lipooxygenase do?
Acts on arachidonic acid to produce leukotrienes (LTB4, LTC4, LTD4, LTE4) which attrachts neutrophuls and causes bronchospasm and increased vascular permeability
(contributes to anaphylaxis but is slower acting than histamine)
95
What are bradykinins produced from?
What do bradykinins do?
Bradykinins are produced from the kinin system (cleavage of high molecular weight kinogen/kalikrein)
Mediate vasodilation, increased vascular permeability, and pain
**Hint: Tom Brady = Brady-kinin**
- Dilates the defense and creates holes in it
- Causes pain to opponents
96
Which cell releases IL-1, IL-6, and IL-8?
Macrophage
97
Which cell releases histamine?
What does histamine do?
Mast cells (stimulated by binding of C3a and C5a complement)
Leads to vasodilation, endothelial cell contraction, and increased vascular permeability
98
What are the vascular components of inflammation?
* Vasodilation
* Increased vascular permeability
99
What does vasodilation lead to?
Increased blood flow
100
What causes increased vascular permeability?
What is the function of increased vascular permeability?
Caused by endothelial cell contraction and damage
Allows fluid and cells to reach areas of infection
101
Which molecules mediate vessel changes?
Histamine, prostaglandins, and leukotrienes
102
What are the basic stages of phagocytosis?
1. Recognitin and attachment
2. Engulfment
3. Destruction
4. Resolution
103
Describe the recognition and attachment stage of phagocytosis
Binding of IgG antibody or C3b complement to the bacteria improves recognition and attachment of the bacteria for engulfment by neutrophils (opsonization)
104
Which receptors are involved in the recognition and attachment stage of phagocytosis?
* Pattern recongnitionr receptors for PAMPs: TLRs, NOD, RIG-I
* Receptors for opsonins: complement C3b, IgG, IgM
105
What molecular compounds that neutrophils have allow them to opsonize bacteria in the recognition and attachment stage of phagocytosis?
Receptors for the IgG Fc (constant region) fragment and for C3b
106
What sort of bacteria is opsonization a critical part of phagocytosis for?
Encapsulated bacteria
107
cWhat effect do bacterial capsules have on phagocytosis?
Capsules decrease ability of neutrophils to phagocytose bacteria
108
What compounds are key to immunity against encapsulated bacteria?
Antibodies and complement
109
Describe the engulfment stage of phagocytosis
Neutrophils ingest bacteria by invagination of the cell membrane around the bacteria to form a vacuole (phagosome)
110
Describe the destruction phase of phagocytosis
Phagosomes containing bacteria merge with lysosomes (containing myeloperoxidase, lysozyme, and other degradative enzymes) to form phagolysosomes, where killing occurs
111
Is oxygen-dependent killing or oxygen-independent killing more effective?
Oxygen-dependent
112
What occurs in oxygen-dependent killing by neutrophils?
1. In the respiratory burst, NADPH oxidase forms the superoxide radical
2. Superoxide dismutase forms hydrogen peroxide
3. Myeloperoxidase in neutrophils catalyzes production of hypochlorite io
113
Which sort of bacteria is hydrogen peroxide not effective against?
Catalase-producing organisms (staphylococci)
114
What is the most effective mediator of the pathogen destruction?
Hypochlorite ion
115
Describe oxygen-independent killing
Involves other numerous enzymes and is not as effective as oxygen-dependent killing
116
Describe the resolution phase of phagocytosis
Neutrophils undergo rapid apoptosis after the inflammatory stimulus is removed
117
What is the cause of chronic granulomatous disease?
What do patients suffer from?
Caused by a defect in NAPDH oxidase and failure to produce hydrogen peroxide and kill bacteria
Patients have recurrent infections from catalase-producing organisms
118
What causes Chediak-Higashi syndrome?
What are its symptoms?
Caused by failure to form phagolysosomes
Leads to neutropenia, giant granules in the neutrophils and monocytes, albinism, and increased risk of pyogenic infections
119
What may occur if a patient has low numbers or suppressed neutrophils and monocytes/macrophages?
Patient may not show the same signs and symptoms of infection with pathogens as quickly as someone that has an intact immune system, masking a serious illness
120
What processes does inflammation resolution involve?
* Some tissues can regenerate
* Macrophages release anti-inflammatory TGF-beta
* Macrophages recruit fibroblasts and release vascularization factors (granulation tissue)
* If tissue architecture is lost, fibroblasts deposit collagen and ECM to form scars
121
What are the two types of healing of cutaneous wounds?
* Healing by first intention (primary union)
* Healing by second intention (secondary union)
122
When does healing by first intention (primary union) occur?
When the injury involves only the epithelial layer and the wound edges are approximated (i.e. clean surgical incision approximated by sutures)
123
What is the principal mechanism of repair in healing by first intention?
Epithelial regeneration
124
What are the stages of repair in healing by first intention?
1. Hemorrhage and formation of a blood clot
2. Acute inflammation
3. Proliferation of the epithelial cells
4. Organization of the wound
5. A scar composed of connective tissue w/ scant inflammatory cells
125
What occurs in the first stage of healing by first intention?
Hemorrhage and formation of a blood clot involving activation of the coagulation cascade, platelets, and fibrin
126
What occurs in the second stage of healing by first intention?
Acute inflamamtion occurs initially with neutrophils and then macrophages (24-48) hours
The tissue is edematous with increased fluid and necrotic debris
Dehydration of the external surface of the clot and the overlying necrotic material forms a scab over the wound
127
What occurs in the third stage of healing by first intention?
Proliferation of the epithelial cells where the basal cells at the edge of the epidermis proliferate and migrate along the dermis
The epithelial cells meet in the middle to close the wound and form and intact layer under the scab
Neutrophils regress and granulation tissue invades the wound space with macrophages, fibroblasts, and new blood vessels
128
What occurs in the fourth stage of healing by first intention?
Organization of the wound occurs over weeks to months and involves collagen accumulation and fibroblast proliferation with decreased inflammation and regression of the vessels
129
What occurs in the fifth stage of healing by first intention?
A scar composed of connective tissue with scant inflammatory cells
The epidermis is fairly normal and dermal appendeges are absent
Maximum strength slowly increases but never reaches the same level as before the wound
130
When does healing by secondary intention (secondary union) occur?
When tissue loss is extensive and the wound edges cannot be brought together (e.g. ulcer)
131
What are the similarities and differences between healing by secondary intention to healing by first intention?
In healing by secondary intention,
* The clot is larger
* Inflammation is more intense
* There is more granulation tissue with greater likelihood of complications
* Wound contraction occurs due to myofibroblasts
132
Which cells are involved in wound contraction in healing by secondary intention?
Myofibroblasts
133
What is fibrosis?
A similar process to wound healing that occurs in parenchymal organs with excessive deposition of collagen and other extracellular matrix components in the tissue in response to injurious stimuli
134
What can continued/extensive fibrosis lead to?
Loss of organ function
135
What is the major cytokine involved in fibrosis?
TGF-beta
136
Why does a child with leukocyte adhesion deficiency, a defect in integrin (CD18 subunit) have increased peripheral blood neutrophils?
Integrins are required for adhesion of the neutrophils to the endothelium
Without adhesion to endothelium, neutrophils cannot cross the endothelium to exit in peripheral blood and other tissues
The number of neutrophils in peripheral blood will increase because the neutrophils cannot leave the peripheral blood
137
What is the role of myeloperoxidase in neutrophils?
Myeloperoxidase catalyzes formation of hypochlorite ion, which is the most effective mediator of pathogen destruction
138
What type of infections occur in patients with neutropenia?
Severe bacterial and fungal infections
Organisms that are typically not harmful or have low virulence can be fatal (opportunistic infections)
The bacterial infections include a wide range of bacteria (such as coagulase negative staph, other Gram positive, and Gram negative bacteria)
Sepsis is a major concern
Fungal infections can be invasive (Candida and Aspergillus) and can also involve the blood
139
What is the function of prostaglandins?
Mediate vasodilation and icnreased vasculafr permeability, pain, and fever
140
What do leukotrienes do?
Attrach neutrophils, mediate bronchospasm, and increased vascular permeability
141
What is the function of the vascular component of inflammation?
Allows fluid, proteins, and cells to reach pathogen or tissue damage
142
What are the mediators of endothelial cell contraction?
* Prostaglandins
* Leukotrienes
* Bradykinins
* Histamines
* Others
143
What are the soluble mediators of inflammation?
* Proinflammatory cytokines
* Arachidonic acid products
* Bradykinins
* Histamines
144
What are the cellular mediators of inflammation?
* Neutrophils and monocytes first
* Then monocytes, lymphocytes, and plasma cells
145
How do catalase producing organisms such as Staphylococci evade oxygen-dependent destruction?
Catalase breaks down hydrogen peroxide
This decreases the formation of hypochlorite by myeloperoxidase
146
A 4 yo pt has recurrent infections, currently with Staph aureus pneumonia. Her peripheral blood neutrophil count is low and testing shows neutrophil NADPH oxidase function is normal. Which disease does she likely have?
Chediak-Higashi syndrome
147
What are antibodies?
Proteins produced by B-cells and plasma cells that are **composed of two heavy chains and two light chains**
They play a major role in providing protection against infection
Antibody = immunoglobulin
148
A light chain of an antibody can have which components?
Lambda
Kappa
149
A heavy chain of an antibody can have which components?
Mu (IgM)
Delta (IgD)
Gamma (IgG)
Alpha (IgA)
Epsilon (IgE)
150
What two parts do each heavy chain and light chain have?
Constant region
Variable region
151
Which isotype/cass of antibody is a B cell receptor?
B cell receptor is surface IgM or IgD
152
Which region of a chain on an antibody determines class/isotype?
Constant region
153
What is the B cell receptor?
An antibody (IgM and IgD in naive B cells) on the surface of B cells that has a transmembrane domain and is associated with Ig-alpha (CD79a) and Ig-beta (CD79b)
Also has CD19
154
Describe the specificity of a BCR on a B cell
Each B cell has a BCR specific for one antigen
155
Which two genes are involved in the VJD recombinase?
RAG1
RAG2
156
Which segments does a variable region of heavy chain have?
V, J, and D
157
Which segments does a light chain of a variable region have?
V and J segments
158
Apart from VDJ recombinase, what are RAG 1 and RAG 2 involved in?
TCR gene rearrangement
159
Mutations in RAG1 or RAG2 can cause which immune disorder?
SCID
160
What two types of diversity do B cell receptors have?
Combinatorial diversity
Junctional diversity
161
What is combinatorial diversity?
Somatic recombination of the V and J gene regions occurs for antibody light chain variable regions and V, D, and J antibody regions for the heavy chain variable regions
Mediated by VDJ recombinase
162
What are the characteristics of junctional diversity?
* Nucleotides are added and removed during recombination
* Occurs at the joining ends of the gene segments
* Significantly increases diversity of the VDJ and VJ regions
* Known as hypervariable regions
163
What regions does junctional diversity affect?
Hypervariable regions
164
Describe the "steps" in isotype determination of an antibody
Isotype of antibody is determined by constant region of heavy chain
* Constant region genes join to variable region genes
* IgM is produced first
* Successful gene rearrangement and protein production leads to B cell development
165
What are the stages in B cell development with regards to the B cell receptor?
1. Pro-B cell has no heavy chains
2. Pre-B cell has cytoplasmic mu heavy chains and is pre-BCR, successful gene rearrangement of mu heavy chain
3. Immature B cell has IgM surface BCR, successful gene rearrangement of the light chain (kappa or lambda)
4. Naive B cell has IgM, IgD surface BCR
166
How does the pro-B cell to pre-B cell transition occur?
Successful gene rearrangement of the mu heavy chain
167
How does the pre-B cell to immature B cell transition occur?
Successful gene rearrangement of the light chain (kappa or lambda) which allows for expression of an IgM BCR
168
What is Bruton's tyrosine kinase?
A signal transduction protein required for pre-B cells to differentiate to B cells
169
What causes X-linked agammaglobulinemia?
What does a patient with X-linked agammaglobulinemia experience?
Mutation in Bruton's tyrosine kinase (cannot go from pre-B cell to immature B cell)
Markedly decreased B cells, low antibodies of all types, no tonsils
170
What type of infections would patients with X-linked agammaglobulinemia be most susceptible to?
Pyogenic infections
(No antibodies -\> decreased opsonization -\> trouble w/ extracellular bacteria especially ones with capsules -\> get a neutrophil pus-producing response)
171
What two things are critical for increased antibody affinity for antigen?
* Germinal centers
* CD40L: CD40 interactions
172
What are the steps of antigen recognition and B cell activation?
1. Antibody variable region of the IgM component of the BCR recognizes and binds a specific antigen
2. Binding leads to receptor cross-linking in association with Ig-alpha/Ig-beta (CD79a/CD79b) and phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs)
3. ITAM phosphorylation triggers downstream signaling pathways
173
What does binding antigen signal through?
ITAMs
174
What is CD21 (CR2)?
A complement receptor expressed with CD19 on the B cell surface
175
How does CD21 serve as a second signal for B cells?
CD21 interacts with the C3d complement component bound to antigen (alternative complement pathway)
Enhances B cell activation ~1000 fold
176
Where does the B cell migrate after antigen binding?
Why?
Secondary lymphoid tissues
To interact with T cells, antigen-presenting cells, and follicular dendritic cells
177
What occurs in the germinal center of the lymphoid tissues to antigen activated B cells?
* Rapidly divide
* Antigen-specific B cells express antigenic peptides on MHC class II to CD4+ T helper cells
* Interact with antigen-specific T cells, APCs, and follicular dendritic cells
* Undergo isotype switching, somatic hypermutation, and affinity maturation
178
How do B7 and CD40 act as a second signal for B cells?
After binding of antigen, B cell upregulates costimulatory molecules (B7 and CD40)
CD40 interacts with CD40L on T cell
B7 interacts with CD28 on T cell
BCR takes up the antigen and expresses protein antigens on MHC class II protein
179
What does T cell express to provide a second signal?
T cell expresses CD40L which binds to CD40 on the B cell to provide a second signal
(also B7 of B cell which interacts with CD28 of T cell)
180
Production of which molecules leads to isotype/class switching?
Production of cytokines by the CD4+ T cells in the presence of CD40:CD40L interaction
181
What signal triggers B-cell isotype switching?
Certain cytokines in the setting of CD40 binding by CD40L
182
What occurs in B cell isotype switching?
B cells switch the heavy chain constant region from the IgM constant region to a downstream isotype (IgG, IgA, or IgE)
Antigen specificity (VJD) is not altered by isotype switching
183
Why do B cells undergo isotype switching?
Different antibody isotypes are specialized for different protective responses
Note: isotype switching does **not** alter antigen binding specificity
184
What is deleted during B cell isotype switching?
Intervening heavy chain DNA
B cells cannot revert back to expressing IgM antibodies after isotype switching
185
Describe the succession of isotype switching in B-Cells
Can the order ever change?
IgM -\> IgG -\> IgA -\> IgE
The order can never change; in order to switch isotypes, DNA is deleted (this is irreversible)
186
What are the functions of follicular dendritic cells?
* Capture complement/antigen complexes on the cell surface
* Present antigen complexes to B cells and allow selection for B cells with higher affinity/avidity antibodies
187
What does T cell co-stimulation cause B cells to undergo?
What occurs in this process?
Somatic hypermutation in the germinal center
Antibody variable regions are subject to random point mutations (activation-induced cytidine deaminase [AID])
Some of the mutations give rise to higher affinity/avidity antibodies which are selected for by FDCs and T cell interactions
188
What is affinity maturation?
The process of selection for increased affinity/avidity in B cells in the germinal center
This occurs after B cells have undergone somatic hypermutation in the germinal center
189
What do B cells undergo in the germinal center?
B cells are antigen-selected
* Antigen-specific B cells interact with antigen-specific CD4+ T cells, antigen-presenting cells, and follicular dendritic cells
* B cells mutate the antibody genes to improve binding to antigen
* B cells that are highly antigen-specific differentiate into plasma cells and memory B cells
190
In the germinal center, what is the fate of B cells that are highly specific for antigen??
* They differentiate into Antibody-producing plasma cells
* Some may become long-lived memory B cells
191
Describe the antibodies that plasma cells produce
Antibodies are highly specific for an antigen
This makes sense, because these plasma cells came from the B-cells with the highest affinity for a specific antigen (they were selected in affinity maturation)
192
What proteins do plasma cells express?
CD38, CD138, and cytoplasmic immunoglobulins
193
Where is CD19 expressed?
Expressed on B cell surface
Component of BCR
194
What are CD79a and CD79b?
B cell receptor associated proteins (Ig-alpha, Ig-beta) involved in signal transduction after antigen crosslinking
Their activation leads to phosphorylation of ITAMs to trigger downstream signaling pathways
195
Where is CD20 expressed?
B cell surface
196
What is CD21?
CD21 = Complement receptor (CR2)
It binds to the complement component C3d (on the antigen) when the antigen binds to the antibody on the B-cell.
This dramatically enhances the B-cell response
197
What is CD40?
CCD40 is a co-stimulatory molecule expressed on B cell surface. It binds to CD40L on helper T cells to provide a second signal to B cells.
Critical for class switching, affinity maturation, and differentiation
198
Where are CD38 and CD138 expressed?
Plasma cell surface
199
On an individual naive B cell expressing both IgM and IgD surface antibody, which regions of the surface IgM antibodies are identical to the surface IgD antibody?
Variable regions of both heavy and light chains are identical between the IgM and IgD antibody
B cells only express one heavy chain variable region and one light chain variable region, even when the constant regions differ
200
On an individual naive B cell expressing both IgM and IgD surface antibody...
which regions of the surface IgM antibodies are different from the surface IgD antibody?
The constant region of the heavy chain
IgM has a Mu heavy chain
IgD has a Delta heavy chain
201
What is the role of follicular dendritic cells in the adaptive immune response?
FDCs are present in the germinal center and trap complement/antigen complexes on their surface to present to B cells
B cells recognize and bind to the antigen on the surface of FDC
FDCs select for the B cells with antibodies on their surface (BCRs) that bind with high affinity/avidity to the antigen on the surface of the FDCs
202
Can class switching occur in the absence of T cells?
Why?
Yes, but it is very limited
T cells express CD40L, which binds to CD40 on B cells. This is critical in the formation of an effective germinal center response which gives rise to isotype switching and somatic hypermutation
203
What might happen if the immune system cannot recognize "self" component?
Autoimmunity
204
What might happen if the immune system fails to recognize "non-self"?
No protection from infection
205
What is humoral immunity?
What does it protect us from?
What mediates it?
Part of adaptive immunity
* Antibody-mediated
* Protects us from **extracellular** bacteria, viruses, toxins
* Mediated by B-cells and plasma cells
206
What are the roles of B-cells and plasma cells in adaptive immunity?
Mediate humoral immunity
* Neutralize toxins and viruses
* Opsonize pathogens
* Makes them tastier to macrophages :)
207
What is cell-mediated immunity?
What does it protect us from?
What mediates it?
* The cell-mediated arm of adaptive immunity
* Protects us from **intracellular** bacteria, viruses, fungi, parasites
* Mediated by T-cells and macrophages
208
What are the roles of T-cells and macrophages in adaptive immunity?
Mediate cell-mediated immunity
* Directly kill virus-infected cells
209
Which immune cells would respond to the presence of a bacterial polysaccharide capsule in the body?
B-Cells; B-cell receptors can recognize and respond to almost anything, including proteins, carbohydrates, drugs, etc.
(T-cells can only recognize peptides in the context of MHC)
210
What is the difference between an antibody and a B-cell receptor?
* An **antibody** is secreted by B-cells
* A **B-cell receptor** remains attached to the B-cell membrane
Antibodies and B-cells have similar structures and can bind similar molecules
211
**T-Cell independent immune response**
1. Which type of immunity?
2. What mediates it?
3. What does it do?
**T-Cell independent immune response**
1. Highly specific, humoral (antibody-mediated) arm of adaptive immunity
2. Mediated by B-cells
3. Produces IgM in response to multivalent non-proteins (ex: polysaccharide capsule)
212
What kinds of molecules would activate the T-cell independent response?
Multivalent non-proteins
Example: polysaccharide capsule, other non-protein non-self molecules
213
**Antibody-driven immune response**
1. Which type of immunity?
2. What mediates it?
3. What does it do?
**Antibody-driven immune response**
1. Highly specific, humoral arm of adaptive immunity
2. Mediated by CD 4+ helper T-cells and B-Cells
3. MHC II presents peptides to CD4+ helper T-cells
* The helper T-cells **help out** by secreting molecules that activate B-cells to produce antibodies
* The antibodies activate CD8+ cytotoxic T-cells to attack and destroy virus-infected cells
214
What is the difference between an immunogen and an antigen?
* An antigen is any molecule that reacts with an antibody
* Almost anything can react with an antibody
* An immunogen is any molecule that **induces an immune response**
* Not all antigens are immunogens
215
What do antibodies do?
* Neutralize toxins and viruses
* Opsonize bacteria (enhance phagocytosis)
216
What kinds of molecules will T-Cell receptors recognize?
T-cell receptors (TCRs) will ony recognize **proteins**
All T-cells require the activation of the TCR **and** co-receptor: CD4+ and CD 8+ co-receptors only recognize **linear peptides presented by MHC**
* CD4+ Helper T-cells recognize peptides presented by **MHC II**
* CD8+ Cytotoxic T-cells recognize peptides presented by **MHC I**
217
Which cells express MHC Class I?
**All nucleated cells** in the human body have MHC class I and can present antigen to CD8+ Cytotoxic T-Cells
218
Which cells express MHC class II?
**Professional antigen-presenting cells** have MHC class II. They present antigen to CD4+ Helper T-cells
219
In the most general sense, what is required for B-cell and T-cell activation?
2 signals
1. Recognition of antigen
2. Costimulatory signal
220
In general, what is required for B-cell activation?
2 signals
1. Antigen recognition by a **surface antibody** (B-cell receptor)
2. From T cells through...
a) Costimulatory molecules in T-cell **dependent** immune response
b) complement in T-cell **indepenent** immune response
221
In general, what is required for CD4+ Helper T-cell activation?
2 signals
1. TCR and co-receptor CD4 recognize and bind the peptide bound to MHC II on the APC
2. The APC also expresses B7, a protein that binds to CD28 on the T-cell
Activation -\> Cytokine production
222
In general, what is required for CD8+ cytotoxic T-cell activation?
2 signals
1. TCR and coreceptor CD8 recognize and bind to the peptide bound to MHC I, presented by an APC
2. Cytokines secreted from CD4+ cells
223
How do CD8+ Cytotoxic T-cells kill their prey?
2 methods
1. Production of cytotoxic molecules like perforin or granzyme
2. Expresion of FasL (induces apoptosis when binding to the Fas protein)
224
Which cytokine promotes T-cells growth and differentiation?
IL-2
225
List the physical and physiological barriers that prevent infection
1. Skin and mucous membranes
2. Ciliated cells in the respiratory tract
3. Enzymes in saliva, other secretions
4. Low pH of skin and mucous
5. Defensins in GI tract and respiratory tract
6. Normal fluid flow
7. Normal flora
226
What physical/physiological barriers protect against bacterial infection in the respiratory tract?
Ciliated cells (The ciliary elevator)
Beta-defensin
227
What might cause damage to the ciliary elevator?
Alcohol, cigarettes, viral infections
228
Why are individuals with heart valve defects more susceptible to infection?
Stagnant fluid allows for infection by bacteria
(normally, fluid flow prevents colonization and infection)
229
Why are patients with extensive burns at increased risk of infection?
Skin is the first line of defense against invasion by pathogens
Multiple holes/defects in this defense leave the body susceptible to infection
230
How do normal flora protect us from infection by harmful bacteria?
**Normal flora prevent pathogen invasion**
Nobody really knows exactly how this works, but it it hypothesized that the normal flora occupies receptors that could be used by a pathogen to enter the body
Note: Normal flora in the wrong palce can be pathogenic
231
Which complement protein first recognizes antigen-antibody complexes in the classic pathway?
C1
(C**1** = the **#1** antigen-antibody recognizing protein)
232
Which complement proteins trigger mast cells to degranulate and release histamine?
C3a, C5a
233
Which complement protein is chemotactic to neutrophils?
What does this mean?
C5a
Chemotactic = ~attractive~
C5a recruits neutrophils
234
Which complement protein opsonizes bacteria?
C3b
235
Which complement proteins form the membrane attack complex?
C5a, C6, C7, C8, C9
-\> Direct microbe killing
236
Which complement proteins inhibit the formation of C3 convertase?
C1 esterase inhibitor
Decay accelarating factor (CD55)
237
What is a PAMP?
PAMP = Pathogen-associated molecular pattern
**Not** present on eukaryotic cells
Basically, a PAMP is the pattern that the **innate immune system** uses to recognize non-self and initiate an immune response
238
What is the pattern on pathogens that cells of our innate immune system recognize?
PAMPs (pathogen-associated molecular patterns)
239
What components of our immune system recognize extracellular pathogenic patterns?
Toll-Like Receptors (TLRs)
Mannose Receptors
240
1. What are TLRs?
2. Where are they found?
3. What do they do?
1. TLRs = Toll Like Receptors
- A family of 10 receptors
2. TLRs are found on the surfaces of macrophages, dendritic cells, mast cells, and B cells
- Cells that help connect the innate and adaptive immune systems
3. TLRs recognize microbial components (like PAMPs) and initiate the synthesis of cytokines
241
What is TLR4?
What does it do?
TLR4 = Toll-like receptor 4
Recognizes LPS on the surface of gram negative bacteria
(Works together with CD14 expressed by monocytes and macrophages to recognize LPS)
242
Which receptors participate in the recognition of LPS?
TLR 4
CD14
Both are expressed by monocytes and macrophages
243
1. What are Mannose receptors?
2. Where are they found?
3. What do they do?
1. Mannose receptors recognize mannose, a polysaccharide commonly found on the surface of bacterial and yeast cells
2. Mannose receptors are found on the surfaces of dendritic cells and macrophages
3. When the mannose receptor binds mannose on the bacterial cell, it **induces phagocytosis**
244
What components of our immune system recognize **intracellular** pathogens?
NOD receptors
RIG-1 helicase
245
1. What are NOD receptors?
2. Where are they found?
3. What do they do?
1. NOD receptors are pattern-recognition receptors that regognize pathogens within our cells
2. In the cytosol of immune-competent cells
3. NOD receptors recognize **peptidoglycan**
246
1. What is RIG-1 helicaase
2. Where is it found?
3. What does it do?
1. RIG-1 helicase is a pattern recognition protein that recognizes intracellular pathogens
2. RIG-1 helicase is found in cytoplasm of immune-competent cells
3. RIG-1 helicase recognizes nucleic acids of viruses
247
Which receptor is especially important in fighting a listeria infection in our bodies?
NOD receptors
Listeria is an intracellular pathogen; NOD receptors in the cytoplasm of immune-competent cells can recognize the pathogen and help mount an immune response
248
Which cytokine recruits neutrophils?
IL-8
A pro-inflammatory cytokine
249
Which cells link innate and adaptive immunity?
Antigen presenting cells (APCs): Macrophages and dendritic cells
250
How do antigen-presenting cells connect adaptive and innate immunity?
Innate
* APCs use pattern recognition to recognize pathogens
Link
* APCs digest pathogens and turn them into antigens that they **present to T-cells**
* APS produce **cytokines that activate the adaptive immune** response of T-Cells, B-Cells, and plasms cells
Adaptive
* activated T-Cells, B-Cells, and plasma cells carry out the adaptive immune response
251
Pattern recognition is part of the innate immune response.
Why then, do cells of the adaptive immune response also express TLRs?
TLRs are used to recognize patterns of invader cells; pattern recognition is the driver of the innate immune system
Macrophages are the mediators of the **adaptive** immune response, but they are also important for **connecting the innate and adaptive immune systems**
They use TLRs to recognize patterns of invader pathogens so they can initate the adaptive immune response
252
Define inflammation
The body's response to infection or tissue necrosis.
Inflammation allows inflammatory cells, plasma proteins, and fluid to enter the interstitial space.
253
Inflammation can cause extensive damage to our tissues.
Why then, does our body produce an inflammatory response?
The goal of inflammation is to eliminate pathogens and clear debris.
The process is not easy on our body, but failure to eliminate pathogens can lead to disease progression and death
254
Which mediators of inflammation mediate pain?
Prostaglandins
Bradykinin
255
What mediates a pyogenic response of our immune system?
Pyogenic (pus-forming) immune responses are due to the action of **neutrophils, antibodies, and complement** during **accute inflammation**.
Often triggered by **extracellular pathogens**
256
What is a giant cell?
Where can we find them?
A giant cell is a large macrophage with multiple nuclei
We typically find them surrounding granulomas
257
What kinds of pathogens are often associated with chronic inflammation?
Intracellular pathogens
Often triggers granulomatous response mediated by macrophages, CD4+ (helper) T cells
258
Which mediators of inflammation promote mediate vasodilation?
Prostaglandins
Bradykinins
Histamines
259
Which mediators of inflammation increase vascular permeability?
Prostaglandins
Leukotreines
Bradykinins
Histamines
260
Which interleukins are pyrogenic?
Pyrogenic = causes fever
IL-1, IL-6
261
In phagocytic cell recruitment and migration, what molecules direct neutrophils to the site of inflammation?
IL-8, C5a
These molecules are chemokines; they are chemotactic for neutrophils
This occurs after diapedesis (neutrophil escape from the blood vessel), when the neutrophil is in the tissue
262
Which cytokine increases cyclooxygenase?
TNF-alpha
263
What are the steps of phagocytic cell recruitment and migration into sites of inflammation?
1. Margination
2. Rolling
3. Adhesion
4. Diapedesis and Chemotaxis
264
Describe the **margination** step of phagocytic cell recruitment and migration
Margination includes...
* Vasodilation
* Increased vascular permeability
* Slowing of blood flow
* White blood cells moving to the periphery of flow
265
Describe the **rolling** step of phagocytic cell recruitment and migration
Sialyl Lewis X on neutrophils binds to P-selectin and E-selectin. This causes the neutrophil to roll slowly along the endothelium
Sialyl Lewis X is expressed constituitively on neutrophils
P-selectin and E selectin are induced by histamine, IL-1, and TNF-alpha
266
What is Sialyl Lewis X?
What process is it involved in?
Sialyl Lewis X is a protein expressed constituitively on the surface of neutrophils
It binds to P-selectin in E-selectin in the "rolling" step of phagocytic cell recruitment and migration
267
Which molecules induce P-selectin and E-selectin?
Where are P-selectin and E-selectin expressed?
Why is this important?
**Histamine, IL-1, and TNF-alpha** induce P-selectin and E-selectin expression **on the inner walls of blood vessel endothelium**
They are induced in response to inflammation; they are important in the **rolling** step of phagocytic cell recruitment and migration. Without P-selectin and E-selectin, neutrophils cannot reach the site of inflammation
268
Describe the **adhesion** step of phagocytic cell recruitment and migration
Integrins expressed on neutrophils bind to ICAM and VCAM, causing firm adhesion of the neutrophil to the endothelium
* Integrin expression is induced by C5a and leukotrine
* ICAM and VCAM are cellular adhesion molecules induced by TNF-alpha and IL-1
269
Which molecules induce integrin expression on neutrophils?
Why is this important?
C5a, leukotrine
Integrins are important because they bind to ICAM and VCAM in the **ahesion** step of phagocytic cell recruitment and migration.
Without integrins (and C5a and leukotrine), neutrophils would not be able to reach the site of inflammation
270
Which molecules induce ICAM and VCAM?
Where are ICAM and VCAM expressed?
Why is this important?
ICAM and VCAM are induced by **TNF-alpha and IL-1**
ICAM and VCAM are c**ellular adhesion molecules** expressed on the **inner endothelium of blood vessels**
ICAM and VCAM bind to integrins on neutrophils in the **adhesion** step of phagocytic cell recruitment and migration; without ICAM and VCAM, neutrophils would not reach the site of inflammation
271
Describe the **diapedesis and chemotaxis** step of phagocytic cell recruitment and migration
Diapedesis = neutrophil migrates through endothelium to escape from the blood vessel
Chemotaxis = neutrophil migrates through tissue toward chemokines IL-8 and C5a
272
*S. pyogenes* secretes C5a peptidase
Describe the effect of C5a peptidase on phagocytic cell recruitment and migration
C5a peptidase destroys C5a, which is a chemokine for neutrophils
Without C5a, neutrophils chemotaxis will be decreased; they won't be able to effectively move toward the site of inflammation
273
A patient has had multiple, recurrent bacterial infections without appropriate pus formation.
What might be the problem?
What evidence would support your diagnosis?
This patient might have Leukocyte Adhesion Deficeincy (LAD), due to a defect in the CD18 subunit of integrins. As a result, neutrophils cannot escape from blood vessels to get ot the tissue (Neutrophils can't adhere to endothelium = they can't undergo diapedesis)
Normal to high neutrophil count in the peripheral blood would support your diagnosis
274
A defect in the CD18 subunit if integrins causes...
Leukocyt adhesion deficiency (LAD)
Neutrophils can't adhere to the endothelium, which means they cannot migrate to the site of inflammation
275
A defect in NADPH oxidase leads to...
Chronic granulomatous disease
* Defective NADPH oxidase
* -\> Failure to produce hydrogen peroxide
* -\> Cannot make hypochlorite ion
* Cannot kill bacteria effectively
276
What destructive enzymes are contained in the lysosome?
Myeloperoxidase
Lysozyme
Other degradative enzymes
277
A patient has a history of recurrent infections from catalase (+) bacteria with the formaiton of multiple granulomas
What might be the problem?
Chronic granulomatous disease;
A defect in NADPH oxidase results in downstream failure to produce the hypochlorite ion from hydrogen peroxide;
Hydrogen peroxide alone is not effective at killing catalase (+) bacteria, because these bacteria can break down hydrogen peroxide.
278
Which inherited immune disorder prevents the formation of phagolysosomes?
What is the clinical presentation?
Chediak-higashi syndrome; a defect of organelle trafficking
The patient may also have:
* Neutropenia
* Giant granules in neutrophils and monocytes
* Albinism
* Increased risk of pyogenic and opportunistic infection
279
How might chronic inflammation cause cancer?
* Chronic inflammation means chronic complement activation
* This causes activated neutrophils to release free oxygen radicals in a nonspecific manner
* This is great for killing bacteria, but not great for our cells
* Persistent exposure to free oxygen radicals can cause **cell proliferation and DNA damage**
* This increases the risk of dysplastic or neoplastic changes in tissue
280
What type of infections occur in patients with neutropenia?
Neutropenia = fewer neutrophils than normal. The body is misisng the "first responders" to infection, which can result in more innocuous organisms taking hold and causing disease
* Infection by opportunistic pathogens
* Bacterial and fungal infections
* Even organisms with typically low virulence can cause disease
* Example: catalase (-) organisms
* Fungal infections may be invasive
* Increased risk for sepsis
281
What conditions might result in weakened accute inflammation?
Any condition that prevents an adequate number of neutrophils from reaching the site of infection/injury
Examples:
* Neutropenia (Chediak-higashi syndrome, chemotherapy)
* Failure of neutrophils to migrate to the site of infection (Leukocyte Adhesion deficiency)
282
What two chains are present in an antibody?
Heavy chain
Light chain
283
Which chain and region of an antibody determines the isotype?
Heavy chain constant region
284
What are the possibilities for the constant region of a heavy chain?
* Mu (IgM)
* Delta (IgD)
* Gamma (IgG)
* Alpha (IgA)
* Epsilon (IgE)
285
What are the possibilities for the constant region of a light chain?
* Kappa
* Lambda
286
What is light chain restriction?
All antibodies on a B cell must be either all kappa or all lambda
Cannot have two different light chains expressed on B cell or plasma cell
(light chain can be used to identify clonal B cells)
287
What does the Fc portion of an antibody for?
Fragment, crystallizable
288
Where is the complement binding region (IgM and IgG) of an antibody found?
Fc portion
289
When does the complement binding region become accessible?
Why?
When antigen binds
Only want complement active when immune response is necessary
290
What are the two parts of the Fc region of an antibody?
Complement binding region
Phagocyte binding region
291
What region does the Fc portion of the antibody contain?
Constant region
292
What sorts of cells have receptors that bind the Fc portion of antibodies?
Phagocytes
293
What are the two main functions of the Fc portion of an antibody?
* Enhances phagocytosis (opsonization)
* Mediates many effector functions
294
What does the Fab portion of an antibody stand for?
Fragment, antigen-binding
295
What two regions does the Fab portion of an antibody contain?
* Variable regions
* Complementarity-determining regions (CDRs)
296
Each B cell makes an antibody with a ____ variable region that binds to ____ antigen(s)
Each B cell makes an antibody with a unique variable region that binds to one antigen
297
What are the main points about the T cell dependent immune response?
* Surface IgM BCR recognizes a protein antigen
* B cells express peptides on MHC class II
* T cell-B cell interaction of CD40/CD40L leads to germinal center formation, class switching, and somatic hypermutation
* Antibodies produced are of high affinity
298
In the T cell dependent immune response, surface ____ BCR recognizes \_\_\_\_\_
In the T cell dependent immune response, surface IgM BCR recognizes a protein antigen
299
In the T cell dependent immune response, B cells express _____ on \_\_\_\_\_
In the T cell dependent immune response, B cells express peptides on MHC class II
300
In the T cell dependent immune response, T cell-B cell interaction of ___ leads to \_\_\_, \_\_\_\_\_, and \_\_\_\_\_
In the T cell dependent immune response, T cell-B cell interaction of CD40/CD40L leads to germinal center formation, class switching, and somatic hypermutation
301
In the T cell dependent immune response, antibodies produced have ____ affinity
In the T cell dependent immune response, antibodies produced have high affinity
302
What are the main points about the T cell independent immune response?
* B cells recognize a non-protein antigen (e.g. polysaccharide cell wall) which can crosslink surface IgM and activate the B cell
* Antigens often have repeated identical antigenic epitopes that cause crosslinking of the BCR complex
* This leads to production of secreted IgM (sometimes IgG and IgA) which is specific for the antigen
* Complement (through CD21) and TLR are involved in B cell activation
* Affinity generally lower
* Splenic B cells (marginal zone) and mucosal B cells (B1) are involved
303
In the T cell independent immune response, B cells recognize _____ antigen (e.g. polysaccharide cell wall) which can crosslink surface _____ and active the _____ cell
In the T cell independent immune response, B cells recognize a non-protein antigen (e.g. polysaccharide cell wall) which can crosslink surface IgM and activate the B cell
304
In the T cell independent immune response, antigens often have _____ \_\_\_\_\_\_ antigenic epitopes that causes crosslinking of the BCR complex
In the T cell independent immune response, TI antigens often have repeated identical antigenic epitopes that causes crosslinking of the BCR complex
305
In the T cell independent immune response, ____ (sometimes IgG and IgA) that is ____ for the antigen is secreted
In the T cell independent immune response, IgM (sometimes IgG and IgA) that is specific for the antigen is secreted
306
In the T cell independent antigen response, ____ (through CD21) and ___ are involved in B cell activation
In the T cell independent antigen response, complement (through CD21) and TLR are involved in B cell activation
307
In the T cell independent antigen response, antibodies have ____ affinity
In the T cell independent antigen response, antibodies have lower affinity
308
\_\_\_\_\_ B cells (marginal zone B cells) and ____ B cells (B1 B cells are involved in the T cell independent antigen response
Splenic B cells (marginal zone B cells) and mucosal B cells (B1 B cells) are involved in the T1 antigen response
309
Compare and contrast the T cell dependent and T cell independent responses in terms of chemical nature, isotype switching, affinity maturation, memory, and location
310
What is the chemical nature of the antigen for the T cell dependent immune response?
Protein
311
What is the chemical nature of the antigen for the T cell independent immune response?
Repetitive polymeric antigen (polysaccharide, glycolipid)
312
Describe isotype switching in T cell dependent immune response
IgG, IgE, and IgA
313
Describe isotype switching in T cell independent immune response
Limited (some IgG and IgA)
314
Does affinity maturation occur in the T cell dependent immune response?
Yes
315
Does affinity maturation occur in the T cell independent immune response?
No
316
Is there memory in the T cell dependent immune response?
Yes
317
Is there memory in the T cell independent immune response?
Limited
318
Where does the T cell dependent immune response occur?
Germinal center
319
Where does the T cell independent immune response occur?
Splenic marginal zone and mucosal regions
320
What are natural antibodies?
Some antibodies (namely IgM) present prior to exposure
321
What sort of response to natural antibodies promote? To what antigens?
T cell independent B cell response to environmental antigens
322
What is notable about cross-reactivity with regards to natural antibodies?
Some degree of cross-reactivity between similar antigen
323
What is the most clinically significant example of natural antibodies?
Natural antibodies against ABO glycoproteins on patient's RBCs that lack the A or B antigen
Antibodies present w/o prior exposure to foreign RBCs
324
An 82 yo male comes in to get a pneumoccocal vaccination. You explain he needs the vaccine that contains the diphtheria toxoid attached to pneumoccocal polysaccharide capsule (PCV13). For an effective antibody immune response to the capsule, what is essential?
Helper T cells recognize the diphtheria toxoid
325
There are ____ receptors on neutrophils that bind the IgG ___ portion
There are IgG receptors on neutrophils that bind the IgG Fc portion
326
327
A 3 yo boy has had multiple recurrent bacterial infections (pneumonia and ear infections) and diagnostic studies show his T cells do not express CD40L after activation. What finding would you expect upon evaluation of serum immunoglobulins?
Increased IgM and decreased IgG and IgA (hyper IgM syndrome)
328
What class of antibody is most effective at blocking bacteria from attaching to the mucosa in the stomach?
IgA antibodies
329
How can an effective vaccine be developed against a hapten (a molecule that does not elicit an immune response)?
Attaching a hapten to a protein will drive a B and T cell immune response, leading to the development of antibodies against the hapten
330
What is an example of an antigen that can induce a T cell independent immune response?
Polysaccharide capsule vaccine against pneumococcus (Pneumovax 23)
331
What three types of cells does the T cell dependent immune response involve?
* Antigen presenting cells (presenting antigen and producing cytokines)
* CD4+ helper T cells
* B cells
332
Which cell type does the T cell independent immune response involve?
B cells
333
Describe the antibody response to a T cell independent antigen in the marginal zone or mucosa
* Naive B cells (marginal zone, mucosal) recognize antigen through IgM BCR
* Co-stimulation occurs through complement receptors (CD21) and/or TLRs
* Antigen-specific B cells differentiate to short-lived plasma cells and produce predominantly IgM
* Limited isotype switch can occur (IgG, IgA)
* No effective affinity maturation
* Limited memory
334
Where are the naive B cells located that are involved in the antibody response to a T cell independent antigen?
* Marginal zone
* Mucosa
335
In the antibody response to a T cell independent antigen, naive B cells (marginal zone, mucosal) recognize _____ through ____ BCR
In the T cell indendent immune response, naive B cells (marginal zone, mucosal) recognize antigen through the IgM BCR
336
In the antibody response to a T cell independent antigen, ____ occurs through ____ (e.g. CD21) and/or \_\_\_\_
In the antibody response to a T cell indepdent antigen, co-stimulation occurs through complement receptors (e.g. CD21) and/or TLRs
337
In the antibody response to a T cell independent antigen, antigen-specific B cells differentiate to short-lived ____ cells and produce predominantly \_\_\_\_
In the antibody response to a T cell independent antigen, antigen-specific B cells differentiate to short-lived plasma cells and produce predominantly IgM
338
In the antibody response to a T cell independent antigen, there is ____ isotype switching (IgG, IgA), _____ affinity maturation, _____ memory
In the antibody response to T cell independent antigen, there is limited isotype switching (IgG, IgA), no effective affinity maturation, and limited memory
339
Describe the steps of the antibody response to a T cell depdent antigen for naive B cells outside of the germinal centers
* Recognize antigen through IgM BCR
* Internalize antigen on the IgM
* Degrade antigen to peptides to present on MHC class II
* Express CD40 and B7 (CD80/86)
* Can receive additional signals from complement, TLR, CD4+ T cells, and/or cytokines
* After binding antigen and activation, B cells migrate towards B cell-T cell zone border (secondary lymphoid tissues)
340
Where are the naive B cells in a T cell dependent antigen response located?
Outside of the germinal centers
341
In the antibody response to a T cell dependent antigen, naive B cells recognize ____ through the ____ BCR
In the antibody response to a T cell dependent antigen, naive B cells recognize antigen through the IgM BCR
342
In the antibody response to a T cell dependent antigen, naive B cells ____ the antigen on the IgM
In the antibody response to a T cell dependent antigen, naive B cells internalize the antigen on the IgM
343
In the antibody response to a T cell dependent antigen, naive B cells degrade antigen to peptides to present on \_\_\_\_\_\_\_\_
In the antibody response to a T cell dependent antigen, naive B cells degrade antigen to peptides to present on MHC class II
344
In the antibody response to a T cell dependent antigen, naive B cells express _____ and \_\_\_\_\_
In the antibody response to a T cell dependent antigen, naive B cells express CD40 and B7 (CD80/86)
345
In the antibody response to a T cell dependent antigen, naive B cells can receive additional signals from \_\_\_\_\_, \_\_\_\_\_, \_\_\_\_\_, and/or \_\_\_\_
In the antibody response to a T cell dependent antigen, naive B cells can receive additional signals from complement, TLR, CD4+ T cells, and/or cytokines
346
In the antibody response to a T cell dependent antigen, naive B cells migrate _______ (secondary lymphoid tissue) after binding ____ and \_\_\_\_
In the antibody response to a T cell dependent antigen, naive B cells migrate towards B cell-T cell zone border (secondary lymphoid tissue) after binding antigen and activartion
347
Describe the steps of the antibody response to a T cell dependent antigen for antigen-activated B cells in the B cell-T cell zone border outside germinal center
* Interact with antigen-activated CD4+ T helper cells
* Differentiate to short-lived plasma cells (plasmablasts)
* Produce and secrete IgM antibody
* Antibody is low affinity for antigen
348
Where does antibody response to a T cell dependent antigen by antigen-activated B cells occur?
B cell-T cell zone border outside germinal center then inside germinal center
349
In the antibody response to a T cell dependent antigen, antigen-activated B cells in the B cell-T cell zone border outside the germinal center interact with \_\_\_\_\_\_
In the antibody response to a T cell dependent antigen, antigen-activated B cells in the B cell-T cell zone border outside the germinal center interact with antigen-activated CD4+ T helper cells
350
In the antibody response to a T cell dependent antigen, antigen-activated B cells in the B cell-T cell zone border outside the germinal center differentiate into _____ cells that secrete _____ which has ___ affinity for antigen
In the antibody response to a T cell dependent antigen, antigen-activated B cells in the B cell-T cell zone border outside the germinal center differentiate into short-lived plasma cells (plasmablasts) that secrete IgM antibody which has low affinity for antigen
351
Describe the steps of the antibody response to a T cell dependent antigen by antigen-activated B cells inside the germinal centers
* Further interact with antigen-specific activated CD4+ T helper cells (mainly through CD40:CD40L)
* Rapidly proliferate
* Undergo isotype switching and somatic hypermutation
* Suppurted by IL-4 and IL-5 (TH2 CD4+ T helper cells)
* Interact with follicular dendritic cells and antigen-presenting cells to select for high affinity antibody
* Late germinal center
* B cells with high affinity antibodies differentiate into memory B cells or plasma cells
352
In the antibody response to a T cell dependent antigen, antigen-activated B cells inside the germinal centers further interact with \_\_\_\_\_\_, particularly through \_\_\_\_
In the antibody response to a T cell dependent antigen, antigen-activated B cells inside the germinal centers further interact with antigen-specific activated CD4+ T helper cells, particularly through CD40:CD40L
353
In the antibody response to a T cell dependent antigen, antigen-activated B cells inside the germinal centers rapidly \_\_\_\_\_
In the antibody response to a T cell dependent antigen, antigen-activated B cells inside the germinal centers rapidly proliferate
354
In the antibody response to a T cell dependent antigen, antigen-activated B cells inside the germinal centers undergo ____ and \_\_\_\_\_
In the antibody response to a T cell dependent antigen, antigen-activated B cells inside the germinal centers undergo isotype switching and somatic hypermutation
355
In the antibody response to a T cell dependent antigen, what molecules support isotype switching and somatic hypermutation of antigen-activated B cells inside germinal centers?
IL-4 and IL-5 (TH2 CD4+ T helper cells)
356
In the antibody response to a T cell dependent antigen, antigen-activated B cells inside the germinal centers interact with _____ and _____ to select for ____ antibody
In the antibody response to a T cell dependent antigen, antigen-activated B cells inside the germinal centers interact with follicular dendritic cells and antigen-presenting cells to select for high affinity antibody
357
In the antibody response to a T cell dependent antigen, antigen-activated B cells in the late germinal center with ____ antibodies differentiate into _____ cells or _____ cells
In the antibody response to a T cell dependent antigen, antigen-activated B cells in the late germinal center with high affinity antibodies differentiate into memory B cells or plasma cells
358
What is critical for generating a germinal center response?
CD40L and MHC class II
359
What do successive exposures to a T cell dependent antigen lead to?
Successive exposure to a T cell dependent antigen leads to increased affinity of the B cell receptor/antibody
360
After repeat T cell dependent antigen exposure, what two things occur?
* Antigen-specific memory B cells interact with the antigen-specific T cells in the germinal center
* Somatic mutations and selection lead to increasingly more specific antibodies
361
What do somatic mutations of Ig V genes lead to?
Selection of high-affinity B cells (high-affinity antibodies)
362
What is the purpose of a booster vaccine?
Increase affinity of antibodies against pathogens
(multiple T cell dependent antigen exposures increase affinity of the B cell receptor/antibody)
363
Why is feedback inhibition of humoral immunity necessary?
Antigen-antibody complexes can have harmful effects
364
Through which pathway do antigen-antibody complexes activate complement?
Classical pathway
365
Feedback inhibition is caused by the production of which antibody?
IgG
366
Describe the steps involved in feedback inhibition of humoral immunity
IgG production leads to feedback inhibition
* FcyRIIB on surface of B cells
* Binds Fc portion of IgG
* Signals through immunomodulatory tyrosine-based inhibition motif (ITIM)
* Terminates B cell response to antigen
367
What binds to the Fc portion of IgG for feedback inhibition of humoral immunity?
FcyRIIB on surface of B cells
368
What is used to signal after FcyRIIB binds the Fc portion of IgG in feedback inhibition of humoral immunity?
Immunomodulatory tyrosine-based inhibition motif (ITIM)
369
What is the major class of antibody produced after first exposure to antigen?
Can that class of antibody activate complement?
IgM is the first antibody produced afrer exposure to antigen in the primary immune response
IgM can activate complement
370
Does a T cell independent antigen (such as polysaccharide capsule of bacteria) give rise to a secondary immune response to second antigen exposure?
T cell independent antigens generate no memory or only very limited memory B cells
Typically no secondary immune response
Second antigen exposure would lead to immune response similar to the first exposure
371
A male patient presents with present but low levels of all classes of immunoglobulins at age 15. What types of infections is he at risk for?
Is it possible he has SCID?
He has CVID, so he is at risk for bacterial infections, Giardia, and enterovirus
He does not have SCID. SCID presents in infancy and is life-threatening without therapy. SCID involves an almost complete absence of the adaptive immune response and no immunoglobulins (and almost no B cells, no T cells +/- NK cells)
372
What does IL-7 do?
Enhances B-cell development
373
How are T cells selected in MHC restriction?
For their ability to bind weakly to self-MHC molecules
374
Which T cells survive MHC restriction?
T cells that bind MHC weakly survive
375
What do T cells recognize?
Peptide bound to a self-MHC molecule
376
What is the key factor in self vs. non-self discrimination and transplant tolerance?
MHC
377
What are the major proteins recognized as foreign in transplant rejection?
MHC
378
Where do T cells mature?
Thymus
379
What is the CD4/CD8 state of T cells in the cortex?
CD4-CD8- to CD4+CD8+
380
What kind of selection occurs on T cells in the cortex of the thymus?
Positive selection
381
What is the CD4/CD8 state of T cells in the medulla?
CD4+ or CD8+
382
What kind of selection occurs on T cells in the medulla of the thymus?
Negative selection
383
What sort of thymocyte exists in the cortex?
Double negative thymocyte
384
What are early T cell precursors called?
Thymocytes
385
When the T cell precursor transits from the bone marrow to the thymus, what is the state of CD3, CD4, and CD8 on its surface?
Negative for surface CD3, CD4, and CD8 molecules
386
What increases as thymocytes develop?
Surface CD3 expression
387
Where does the first step of thymic T cell selection occur?
Thymic cortex
388
What is the first stage of thymic T cell selection?
What is not expressed?
CD4-CD8- (double negative) stage
Does not express TCR
389
What does a TCR have on each chain?
A variable region and a constant region
390
What allows for TCR gene rearrangement?
RAG1/RAG2 gene expression
391
What does RAG1/RAG2 gene expression lead to in the beta chain of the TCR?
VDJ gene rearrangement
392
Which chain of the TCR does VDJ rearrangment occur in?
Beta chain
393
What does RAG1/RAG2 gene expression lead to in the alpha chain of the TCR?
VJ gene rearrangement
394
Which chain of the TCR does VJ rearrangment occur in?
Alpha chain
395
Does isotype switching occur in the TCR?
No
396
What does the expression of RAG1/RAG2 genes produce?
TCR with unique antigen specificity
397
Where does the second stage of thymic T cell selection occur?
Thymic cortex
398
What is the second stage of thymic T cell selection?
What is expressed with the TCR?
CD4+CD8+ (double positive) stage
Surface CD3 expressed with the TCR
399
What sort of selection occurs in the double positive stage of thymic T cell selection?
Positive selection
400
Describe positive selection in the double positive stage of thymic T cell selection
Cortical epithelial cells express MHC class I and class II molecules
A T cell will survive if the TCR with CD4 or CD8 binds weakly to the self-MHC molecules
(Occurs in cortex)
401
Where does the third stage of thymic T cell selection occur?
Thymic medulla
402
What is the third stage of thymic T cell selection?
CD4+ or CD8+ (single positive) stage
403
What sort of selection occurs in the single positive stage of thymic T cell selection?
Negative selection
404
Describe negative selection in the single positive stage of thymic T cell selection
* Cortical epithelial cells express MHC class I and II molecules
* Autoimmune regulator (AIRE) transcription factor synthesizes self proteins to be expressed in the MHC molecules
* Strong binding of the TCR to self-antigen/MHC molecules -\> cell death or becomes regulatory T cell
* Weak/no binding of the TCR to self-antigen/MHC molecule -\> survive and go to the periphery
405
In the single positive stage of thymic T cell selection, what occurs if the TCR binds strongly to the self-antigen/MHC molecule?
T cell death or becomes regulatory T cell
406
In the single positive stage of thymic T cell selection, what occurs if the TCR binds weakly/not at all to the self-antigen/MHC molecule?
T cell survives and goes to the periphery
407
Diagram the steps in T cell development
408
What tissue is this?
What are the correct labels for the two arrows?
Thymus
409
What is positive selection in thymic T cell selection?
Inclusive type of selection which checks all thymocytes for ability to recognize peptides on self-MHC
410
What is negative selection in thymic T cell selection?
Exclusive type of selection which eliminates potentially autoreactive T cells
411
What occurs in the negative selection portion in thymic selection of T cells?
* Positively selected thymocytes migrate into medulla of thymus
* Those that react w/ high affinity to self-peptides/MHC complexes will undergo apoptosis or become regulatory T cells
* Those that react with lower affinity are allowed to survive and leave the thymus as mature T cells
412
What produces self-peptides that are used in negative selection during thymic selection of T cells?
Autoimmune regulator (AIRE)
413
What organ fails to form normally in DiGeorge syndrome?
Thymus
(thymic aplasia due to developmental defect in third and fourth pharyngeal pouches)
414
What is deficient in people with DiGeorge syndrome?
Marked deficiency in T cells
415
What infections are people with DiGeorge syndrome susceptible to?
Severe viral, fungal, and protozoal infections
Some also have pyogenic infections
416
What lab finding do people with DiGeorge syndrome exhibit besides low T cell count?
Why?
Hypocalcemia
Due to lack of parathyroid glands
417
Some patients with DiGeorge syndrome (thymic aplasia) have decreased serum antibodies and recurrent pyogenic infections. Why might this occur if the B cells develop normally?
Lack of CD4+ T cells to support B cell antibody production
418
What do patients with mutations that eliminate the expression of RAG1 or RAG2 genes have?
Severe combined immunodeficiency
419
People with severe combined immunodeficiency have no expression of which genes?
RAG1 or RAG2
420
What cells do people with RAG deficiency lack?
Which cells do they have?
No B or T cells
Normal NK cells
421
Why do people with RAG deficiency lack B cells and T cells?
RAG1/RAG2 are required for VDJ recombination and successful development of both B cells and T cells
422
What syndrome do mutations that cause lower than normal but not eliminated RAG expression cause?
How does this syndrome present?
Ommen Syndrome
Autoimmune manifestations and immunodeficiency
423
What will occur to T cells that leave the thymus and react with antigen in the absence of co-stimulation?
These T cells will become anergic (non-responsive)
424
What is T cell anergy specific to?
Antigen-specific
425
What occurs when T cells repeatedly encounter high levels of self-antigen in the periphery?
Clonal deletion through apoptosis
(Tregs also participate in suppressing self-reactive T cells)
426
When does clonal deletion through apoptosis of T cells occur?
When T cells repeatedly encounter high levels of self-antigen in the periphery
427
How many signals does T cell activation require?
2
428
What is the first signal for CD4+ T cell activation?
Antigen recognition by the TCR via the MHC class II
429
Describe the steps involved in the first signal for CD4+ T cell activation
1. Antigen recognition in the context of the MHC by the TCR
2. Binding of antigen by TCR
3. ITAMs are phosphorylated
4. ZAP70 tyrosine kinase is recruited and activated
5. ZAP70 initiates a cascade of signaling
6. Increased expression of cytokines, cytokine receptors, and cell proliferation genes
The longer the antigen is bound, the more the ITAMs are phosphorylated
430
With regards to the first signal of CD4+ T cell activation, what does longer duration of antigen binding lead to?
More phosphorylation of ITAMs
431
What are the major components involved in the first signal of CD4+ T cell activation?
Antigen, TCR (MHC), ITAMs, ZAP70 tyrosine kinase
432
What is the second signal in CD4+ T cell activation?
Binding of activating co-stimulatory molecules (to CD28) or cytokines
433
What is the usual co-stimulatory receptor in the second signal of CD4+ T cell activation?
CD28
(cytokines binding to cytokine receptors can also provide second signal)
434
What is the first signal in activation of CD8+ cytotoxic T cells?
TCR and co-receptor CD8 recognize and bind the peptide in MHC class I
435
What is the second signal in activation of CD8+ cytotoxic T cells?
Cytokines (IL-2) secreted from CD4+ cells or co-stimulatory molecule engagement
436
When T cells are activated, what do T cells upregulate expression of?
* IL-2 (T cell growth factor)
* IL-2R
(Autocrine effect of IL-2 binding to IL-2 receptor allows clonal growth and proliferation of antigen-specific activated T cells)
437
What does the upregulation of IL-2 and IL-2R by activated T cells lead to?
Autocrine effect of IL-2 binding to IL-2 receptor allows clonal growth and proliferation of antigen-specific activated T cells
438
What is CD28?
Co-stimulatory molecule
439
What does co-stimulatory molecule CD28 expressed on T cells bind to?
B7 (CD80/CD86) on antigen-presenting cells
440
What occurs if a second signal is received after CD28 expressed on T cells binds B7 on the antigen-presenting cells?
T cell is activated
441
What occurs if a second signal is not received after CD28 expressed on T cells binds B7 on the antigen-presenting cells?
T cell becomes anergic
442
What are CTLA-4 and PD1?
Inhibitory molecules expressed on the surface of T cells that help control and downregulate the immune response
443
Where are CTLA-4 and PD1 expressed?
Surface of T cells
444
What are the inhibitory molecules expressed on the surface of T cells that help control and downregulate the immune response?
CTLA-4 and PD1
445
When are the T cell inhibitory molecules upregulated?
48-96 hours after initial T cell activation
446
How does CTLA-4 inhibit T cells?
Binds to B7 -\> blocks binding of B7 to CD28 -\> inhibits IL-2 synthesis
447
How does PD1 inhibit T cells?
PD1 interacts with its receptor PDL1 on APCs (macrophages and dendritic cells) -\> inhibits immune response
448
Why is PD1 a target for chemotherapy in cancer treatment?
Some cancer cells express PD1
449
How do superantigens evade the immune system?
Bind directly to TCR and MHC class II protein without internal processing
450
What are two examples of superantigens?
Staphylococcal enterotoxins
Toxic shock syndrome toxins
451
What is the effect of superantigen binding directly to TCR and MHC class II protein without internal processing?
Activates multiple T cells at once regardless of TCR antigen specificity
Uncontrolled release of cytokines from T cell and APC (IL-2, IL-1, and TNF)
Contributes to illness
452
What does superantigen activation of multiple T cells at once regardless of TCR antigen specificity lead to?
Uncontrolled release of cytokines from T cell and APC (IL-2, IL-1, and TNF)
453
What bacteria produces toxic shock syndrome toxin 1 ?
In what part of the body / when might this occur?
Why does not toxicity require bacteria in the blood?
Staphylococcus aureus
Vagina in menstruation
Toxin is produced and reaches blood (the toxin is what causes the effects)
454
What are memory T cells?
Antigen-specific T cells that have gone through a first primary immune response to antigen
(numerous subsets, live for years)
455
What occurs when memory T cells have a subsequent recognition of antigen?
* Activation with a lower level of co-stimulation
* Rapid and more robust production of cytokines
456
What is the function of IL-2?
Promotes T cell growth and activation, can act in an autocrine fashion
457
What are the functions of IL-4?
* Promotes B cell growth
* Promotes class switching to IgE and IgG
* Promotes differentiation of TH2 CD4+ T cells
* Inhibits differentiation of TH1 CD4+ T cells
458
What are the functions of IL-5?
* Differentiation/activation of eosinophils
* Class switching to IgA
459
What is the function of IL-10?
Turns off immune response (anti-inflammatory)
460
What is the function of IL-12?
* T cell growth factor
* Stimulates TH1 subset of CD4+ T cells
461
What is the function of IL-13?
Activates eosinophils
462
What is the function of IL-17?
Promotes neutrophilic inflammation
463
What are the functions of INF-gamma?
* Stimulates phagocytosis by macrophages
* Increases expression of MHC class I and II
* Promotes TH1 T cell response
* Inhibits TH2 CD4+ T cell response
464
In most cases of hypersensitivity, what is true?
Immune system has seen the antigen (or closely related antigen) before
465
How does sensitization to an antigen occur?
Primary antigen exposure gives rise to immune response with production of antibodies and/or memory T cells
Hypersensitivity response typically occurs on a subsequent exposure
466
AJ goes on a camping trip and develops a rash one day after she returns. You diagnose poison ivy reaction, a form of contact hypersensitivity to organic chemicals called urushiols produced by the poison ivy plants. What is true about the cause of her rash?
Her rash is caused by activation of memory CD4+ and CD8+ T cells specific for peptides of urushiol-modified self proteins
467
Which type(s) of hypersensitivity is/are antibody mediated?
Types I, II, and III
468
Which type(s) of hypersensitivity is/are T cell mediated?
Type IV
469
What is Type I hypersensitivity also known as?
Immediate/anaphylactic
470
What is the timescale of Type I hypersensitivity?
Very fast, develops in minutes
471
What cells and antibodies are involved in Type I hypersensitivity?
* Mast cells and basophils
* Preformed IgE (prior B cell response driven by TH2 helper T cells)
472
What is the mechanism of Type I hypersensitivity?
* First exposure sensitization to form IgE antibodies
* Subsequent exposure: IgE binds antigen and crosslinks mast cell Fc receptors
* Mast cells release preformed mediators and produce additional mediators
473
In Type I hypersensitivity, what does IgE do upon subsequent exposure?
IgE binds antigen and crosslinks mast cell Fc receptor
474
In Type I hypersensitivity, what do mast cells release?
Preformed mediators
475
What are examples of Type I hypersensitivity?
* Anaphylaxis
* Allergic rhinitis
* Asthma
* Hives
476
What do mast cells promote in Type I hypersensitivty?
Vasodilation and edema
477
What is Type II hypersensitivity also known as?
Cytotoxic/antibody-mediated
478
What is the timescale of Type II hypersensitivity?
Minutes to hours
479
What cells and antibodies are involved in Type II hypersensitivity?
* CD8+ cytotoxic T cells
* NK cells
* Neutrophils
* Preformed IgG/IgM (produced by B cells, driven by TH2 CD4+ helper T cells or naturally occurring)
480
What is the mechanism of Type II hypersensitivity?
* Preformed IgG or IgM antibody binds to fixed cell surface or extracellular matrix antigens
* Binding leads to complement activation and opsonization/phagocytosis and/or antibody-dependent cell-mediated cytotoxicity (ADCC) by NK or CD8+ cytotoxic T cells
481
Where do preformed IgG or IgM antibodies bind in Type II hypersensitivity?
Fixed cell surface or extracellular matrix antigens
482
What does binding of preformed IgG or IgM antibody to a fixed cell surface or extracelluilar matrix antigens lead to in Type II hypersensitivity?
* Complement activation and opsonization/phagocytosis
* Antibody-dependent cell-mediated cytotoxicity (ADCC) by NK or CD8+ cytotoxic T cells
483
What is the complement activation mechanism in Type II hypersensitivity?
1. Complement activated
2. Complement byproducts C5a and C3a act on neutrophils
3. Neutrophils release enzymes and reactive oxygen intermmediates
484
What is the antibody-dependent cell-mediated cytotoxicity mechanism in Type II hypersensitivity?
1. Antigen specific IgG antibody interacts with target antigen
2. Release of cytotoxic molecules
485
What are examples of type II hypersensitivity?
* Some drug allergies
* Incompatible blood transfusions
* Rh hemolytic disease of newborn
* Rheumatic fever
* Goodpasture's syndrome (antibody against basement membrane)
486
What is Type III hypersensitivity also known as?
Immune complex-mediated
487
What is the timescale of Type III hypersensitivity?
Hours to days
488
What cells and antibodies are involved in Type III hypersensitivity?
* Antigen and antibody complex (typically IgG)
* Neutrophils
489
What is the mechanism of Type III hypersensitivity?
* When antigen is abundant, soluble immune complexes (antigen bound to antibody) form and deposit in tissues (particularly in vessels)
* Immune complex deposition can activate complement and lead to inflammation (chemotaxis of neutrophils, vessel leakage, and vessel damage)
490
In Type III hypersensitivity, what forms and deposits in tissues?
Soluble immune complex (antigen bound to antibody)
491
In Type III hypersensitivity, what does immune complex deposition lead to?
Complement activation
492
Which types of hypersensitivities involve the activation of complement?
Type II and Type III
493
What are examples of Type III hypersensitivity?
* Serum sickness (e.g. drugs)
* Systemic lupus erythematosus
* Arthus reaction: local injection of antigen that reacts with preformed IgG
494
What is the Arthus reaction?
Local injection of antigen that reacts with preformed IgG
495
Which type of hypersensitivity is the Arthus reaction?
Type III hypersensitivity
496
What can be used to visualize immune complex deposition from a Type III hypersensitivitt?
Anti-IgG immunofluorescence
497
What is Type IV hypersensitivity also known as?
Delayed-type hypersensitivity
498
What is the timescale of Type IV hypersensitivity?
Days to weeks to months
499
What cells are involved in Type IV hypersensitivity?
* Antigen-presenting cells
* TH1 CD4+ helper T cells
* Sometimes CD8+ cytotoxic T cells
(no antibodies involved)
500
What is the mechanism of Type IV hypersensitivity?
* Antigen-presenting cells prime T cells to response to antigen and drive a TH1 CD4+ helper T cell response
* On subsequent response to the antigen, previously primed T cells (memory cells) proliferate rapidly and activate a macrophage response and cytokine release
501
In Type IV hypersensitivity, what sort of response do antigen-presenting cells drive?
TH1 CD4+ helper T cell response
502
In Type IV hypersensitivity, what do memory T cells activate upon subsequent response to the antigen?
Macrophage response and cytokine release
503
Which type hypersensitivity is involved in granuloma formation?
Type IV hypersensitivity
504
What are examples of Type IV hypersensitivity?
* Mycobacterium tuberculosis and PPD
* Graft vs. host disease
* Contact dermatitis
505
What type of hypersensitivity are M. tuberculosis and PPD?
In M. tuberculosis and PPD, what do the T cells recognize?
Type IV hypersensitivity
T cells recognize microbial peptides
506
What type of hypersensitivity is contact dermatitis?
In contact dermatitis, what do the T cells recognize?
Type IV hypersensitivity
T cells recognize chemically modified self proteins
507
What is the PPD assay used for?
Evaluate for a cell-mediated immune response to M. tuberculosis suggestive of infection or prior vaccination
(type IV hypersensitivity)
508
What occurs in the PPD test?
* Protein derivatives from M. tuberculosis are injected intradermally
* TH1 CD4+ T helper cells specific to M. tuberculosis antigens produce cytokines
* Leads to an increase in the permeability of local blood vessels, recruitment of T cells and macrophages, and local tissue destruction
* Produces swelling/induration of the skin ~48 hours after injection
509
What does a positive PPD test indicate?
TB infection or prior BCG vaccine
510
What cells does M. tuberculosis / PPD involve?
CD4+ T helper cells and macrophages
511
What type of hypersensitivity is this?
How do you know?
Type IV hypersensitivity
This is predominantly a lymphocyte response (type IV hypersensitivity is cell-mediated)
512
List the stages of B-cell development
1. Early hematopoietic stem cell
2. Lymphocyte progenitor
3. Pro B-Cell
4. Pre B-Cell
5. Immature B-Cell
6. Naïve B-Cell
513
Which protein stimulates the formation of T-cell and B-cell precursors from lymphoid progenitor cells?
IL-7
514
Which protein stimulates the formation of lymphoid progenitor cells from early hematopoietic stem cells?
IL-7
515
How would decreased IL-7 expression affect white blood cell development?
Decreased IL-7 might cause...
* Decreased lympoid progenitor cell formation (from early hematopoietic stem cells)
* Decreased B-cell and T-cell formation from lymphoid progenitor cels
* May eventually lead to impaired adaptive immune response
516
What components are expressed by a Pro B-cell?
None
Pro B-cells do not express heavy chains, light chains, or surface antibodies
517
What components are expressed by a Pre B-Cell?
* Mu heavy chain in **cytoplasm** (not as a surface receptor)
* No rearranged light chain
518
What components are expressed by an immature B-cell?
* Mu heavy chain and light chain = a fully formed IgM BCR
519
What components are expressed by a Naïve B-cell?
IgM and IgD
(Both sets of antibodies on an individual B-cell have the same antigen binding specificity)
520
What must happen in the transition from pro B-cell to pre B-cell?
Successful rearrangement of the Ig Mu heavy chain
521
What must happen in the transition from pre B-Cell to immature B-cell?
Successful rearrangement of the light-chain (kappa or lambda)
Together, the light chain and heavy chain combine to express IgM in the BCR
522
What must happen in the transition from immature B-cell to Naïve B-cell?
Clonal deletion
* Immature B-cells with IgM that **does not bind** to self-antigen begin expressing IgD with the same light chain specificity as IgM, and they are released from the bone marrow
* Immature B-cells with IgM that **does bind** to self-antigen have two fates...
* 1) undergo apoptosis
* 2) undergo receptor editing; VDJ recombinase is re-expressed via activation of Rag1/Rag2. VJ recombination is repeated to express a second type of **light chain,** which combines with the original heavy chain. If this second type of receptor **does not bind to self** it begins expressing IgD and is released from the bone marrow
523
What is clonal deletion?
The process by which immature B-cells become naive B-cells
B-cells that bind self-antigen must be eliminated or edited so that they do not mount an autoimmune response
* Immature B-cells with IgM that **does not bind to self-antigen** begin expressing IgD with the same light chain specificity as IgM, and they are released from the bone marrow
* Immature B-cells with IgM that **does bind to self-antigen** have two fates...
* 1) undergo apoptosis
* 2) undergo receptor editing; VDJ recombinase is re-expressed via activation of Rag1/Rag2. VJ recombination is repeated to express a second type of light chain, which combines with the original heavy chain.
* If this second type of receptor **does not** bind to self it begins expressing IgD and is released from the bone marrow
* If this second type of receptor **does** bind to self, the B-cell undergoes apoptosis
524
What is receptor editing?
When does it occur?
Receptor editing occurs in the bone marrow during clonal deltion. When a B-cell expresses IgM that binds to self-antigen, it must be altered to prevent that cell from being released and initiating an autoimmune response
**Receptor editing:** VDJ recombinase is re-expressed via activation of Rag1/Rag2. VJ recombination is repeated to express a **second type of light chain**, which combines with the original heavy chain. If this second type of receptor **does not bind to self** it begins expressing IgD and is released from the bone marrow
If the second type of of receptor **continues to bind to self**, the B-cell undergoes apoptosis
525
Which part of IgM is altered in receptor editing?
The light chain variable region
526
Why is B cell clonal deletion and receptor editing important?
* Clonal deletion is necessary to promote the apoptosis of immature B-cells with IgM that binds to self-antigen
* This is important in preventing B-cells from initiating an autoimmune response
* Receptor editing rearranges the light chain of a self-reactive IgM to basically give it a "second chance" to not bind to self-antigen
* If successful, the immature B-cell will begin expressing IgD and continue maturation
527
What is the major cytokine produced by APCs that drives a TH1 CD4+ T cell response?
IL-12
528
What would be a major risk if a patient with DiGeorge's syndrome received a thymus transplant from an adult?
Mature T cells present in an adult thymus may recognize the recipient's tissues as foreign and cause damage to many different organs in the recipient (graft vs host)
529
Production of which interleukins promote class switching of IgE and leads to an increased risk for allergy and anaphylaxis?
IL-4 is the predominant interleukin that drives class switching to IgE
IL-4 is produced by TH2 CD4+ T cells
530
What is MHC restriction?
TCR and co-receptor can only recognize peptides in the context of self-MHC molecule
531
What are the three subsets of T cells?
* CD4+ helper T cells
* CD8+ cytotoxic T cells
* Regulatory T cells
532
Which MHC class do CD4+ helper T cells express?
MHC class II
533
What is the function of CD4+ helper T cells?
Secrete cytokines to support other cells
534
What are the three types of CD4+ helper T cells?
* TH1
* TH2
* TH17
535
Which MHC class do CD8+ cytotoxic T cells express?
MHC class I
536
What are the functions of CD8+ cytotoxic T cells?
* Directly kill infected target cells
* Participate in macrophage activation
* Releases perforin and granzymes
537
What do TH1 CD4+ T helper cells produce?
IFN-gamma
538
What are the functions of TH1 CD4+ T helper cells?
* Promote cellular activity
* Participate in macrophage activation
539
What do TH2 CD4+ T helper cells produce?
IL-4, IL-5, and IL-13
540
What are the functions of TH2 CD4+ T helper cells?
* Promote humoral immunity
* Promotes antihelminth responses
541
What do TH17 CD4+ T helper cells produce?
IL-17
542
What are the functions of TH17 CD4+ T helper cells?
* Host defense
* Pathogenesis of autoimmune disease
543
Which two T cell subsets are involved in cell-mediated immunity?
CD8+ cytotoxic T cells and TH1 CD4+ T helper cells
544
How do CD8+ cytotoxic T cells mediate direct cellular killing?
* Perforins and granzymes are present in granules and released
* Activate caspases
* FasL is expressed on cytotoxic T cells that bind to Fas
545
What is the function of perforins released by CD8+ cytotoxic T cells?
Insert into the cell membrane and form a channel
546
What is the function of granzymes released by CD8+ cytotoxic T cells?
Granzymes are proteases that degrade proteins in the cell membrane
547
What does the activation of caspases by CD8+ cytotoxic T cells lead to?
Apoptosis
548
What does the expression of FasL on CD8+ cytotoxic T cells lead to?
Apoptosis after binding Fas on the target cell
549
Where do mycobacteria survive inside cells?
How?
Mycobacteria survive within a phagosome by preventing fusion with the lysosome and acidification
(infection is controlled by a cell-mediated immune response but not always eradicated)
550
What are the functions of mycolic acids and lipids for mycobacteria?
* Essential for survival in host
* May alter host immune response
551
What occurs when intracellular pathogens persist?
Pathologic immune response
552
What is the classic example of cell-mediated immunity that leads to persistent inflammation?
Granulomatous response to M. tuberculosis
553
Describe the steps involved in granuloma formation due to Mycobacterium tuberculosis infection
1. Chronic antigen stimulation of the organism drives CD4+ TH1 T cell responses (production of IL-2 and IFN-gamma)
2. IFN-gamma drives macrophages to secrete IL-12 and the cycle of activation continues
3. Macrophages secrete hydrolytic enzymes and form granulomas which often have central necrosis
4. These pathways lead to tissue damage but can keep the organism dormant
554
What does the chronic antigen stimulation of Mycobacterium tuberculosis drive?
CD4+ TH1 T cell responses (production of IL-2 and IFN-gamma)
555
What does IFN-gamma produced by CD4+ TH1 T cell responses lead?
Macrophage secretion of IL-12
556
What does macrophage secretion of IL-12 in the granulomatous response to Mycobacterium tuberculosis lead to?
Macrophage secretion of hydrolytic enzymes
(leads to formation of granulomas which often have central necrosis)
557
What does granuloma formation do to Mycobacterium tuberculosis?
Keeps Mycobacterium tuberculosis dormant
558
Which viruses can suppress cell-mediated immunity?
Measles and CMV
559
What can suppression of cell-mediated immunity by measles and CMV lead to?
Reactivation of M. tuberculosis infection
560
Infection with which bacterium clearly demonstrates the TH1 versus TH2 response?
Mycobacterium leprae (cause of leprosy)
561
Describe the T cell response in tuberculoid leprosy
* TH1 driven
* Intense cell-mediated response
* Few bacteria
* Non-caseating granulomas
562
Which type of CD4+ T helper cell drives tuberculoid leprosy?
TH1
563
Describe the T cell response in lepromatous leprosy
* TH2 driven response
* No cellular immune response
* Many bacteria
564
In which form of leprosy is there an intense cell-mediated response?
Tuberculoid leprosy
565
In which form of leprosy are there few bacteria?
Tuberculoid leprosy
566
In which form of leprosy do non-caseating granulomas form?
Tuberculoid leprosy
567
Which type of CD4+ T helper cell drives lepromatous leprosy?
TH2
568
In which form of leprosy is there no cellular immune response?
Lepromatous leprosy
569
In which form of leprosy are there many bacteria?
Lepromatous leprosy
570
What response to mycobacteria would you expect in a patient with IFN-gamma receptor deficiency?
Disseminated mycobacterial infection
(need IFN-gamma for granuloma formation)
(latent mycobacterial infection requires intact cell-mediated immunity)
571
What occurs in IL-12 receptor deficiency?
* Decreased TH1 response
* Disseminated mycobacterial infections
* Decreased IFN-gamma
572
How can cross-presentaiton by APCs impact the response to immunization?
Cross-presentation is when APCs, particularly dendritic cells, can present extracellular antigens on the MHC class I molecules to initiate a CD8+ T cell response
Cross-presentation involves a transfer of extracellular antigens from the endosomes into the cytosol of the APC
This can impact immunization design because an antigen that is extracellular (i.e. cannot infect the cell) can still elicit a CD8+ T cell memory response through cross-presentation after uptake by APCs
573
In HIV/AIDS, the CD4+ T cells are decreased. What types of pathogens would patients with HIV/AIDS be particularly susceptible to?
Wide array of all types of infections (bacterial, fungal, viral)
Particularly susceptible to opportunistic infections (infections by organisms that typically do not cause disease)
574
What is an antigen?
Anything that can bind to an anitobdy
We can form antibodies to almost anything
575
What is an immunogen?
An antigen that induces and immune response
Can be a
* Protein
* Large multivalent non-protein
* Immunogenicity depends on size, repetition
576
What is a hapten?
An antigen that does **not** induce an immune response on its own
Ex: A small chemical
577
How can a hapten induce an immune reasponse?
Describe teh process
If multiple haptens are bound to a carrier protein, the hapten/protein complex can elicit a T-cell response
* B-cell binds to haptens attached to carrier proteins
* BCR endocytosis; the receptor bound to the haptens + protein is internalized
* The protein is degraded to peptides
* The B-cell presents the peptides on MHC Class II to CD4+ helper T-cells
* The T-cell is activated and makes antibodies
578
What is the likely outcome of impaired activation-induced citidine deaminase (AID)?
* Imparied isotype switching
* Imparied somatic hypermutaiton
This can result in increased risk of infection, decrease antigen binding specificity
579
What processes are mediated by activation-indiced citidine deaminase?
Somatic hypermutation
Isotype/class switching
580
What are the functions of IgM?
* Fix complement
* Important in primary response
* 1st antibody produced upon exosure
* Main antibody in a T-cell independent response
581
Which antibody can cross the placenta?
Why is this important?
IgG
This is important in the maternal immune response to fetal red blood cells
582
What are the functions of IgD?
Expresses only on naive B-cells
Not secreted
Honestly, not much is known about their function
583
Which antibodies can fix complement?
Which pathway do they use?
IgM and IgG fix complement via the classic pathway
584
Which antibodies most effectivly opsonizes bacteria?
IgG
585
What are the functions of IgG?
* Fixes complement; activates the classic pathway
* Opsonizes bacteria
* The most effective opsonizer!
* Neutralizes bacterial toxins and viruses
* Most abundant antibody in the secondary immune response
* Can cross the placenta
* Most abundant circulating antibody
* Most effective antibody in many infections
586
Which antibody is most abundant in a primary immune response?
IgM
587
Which antibody is most abundant in a secondary immune response?
IgG
588
Which antibody is most important in fighting parasites?
IgE
589
What are the functions of IgE?
* Mediates antibody-dependent cellular cytotoxicity (ADCC) against parasites
* Binds to extracellular parasites, recruits other cells to kill them
* Mediates the killing of parasites by eosinophils
* Mediates allergies, anaphylaxis
590
Describe the process of ADCC against parasites
ADCC = antibody-dependent cellular cytotoxicity
* IgE binds to the helminth
* An eosinophil recognizes the Fc region of IgE
* The Fc(e)RI receptor on the eosinophil binds the Fc region of IgE
* Pretend (e) is the little epsilon symbol
* The eosinophil releases mediators to destroy the helminth
* This is enhanced by IL-5 released by Th2 CD4+ helper T-cells
591
What are some of the functions of IL-5?
Which cells secrete IL-5?
IL-5 is secreted by Th2 CD4+ Helper T-cells
* Enhance eosinophil release of mediators to destroy helminths
* Promote class switching to IgA
592
How does IgE mediate allergic and anaphylactic shock?
* Allergens cause crosslinking of IgE Fc receptors on mast cells
* This promotes histamine release
* Mediates allergies and anaphylaxis
593
What are the functions of IgA?
* Mucosal immunity
* Prevetns the attachment of bacteria and viruses to mucosal membranes
* This prevents bacteria from entering the mucosa
* Passively transferred in breast milk
594
Which antibodies protect neonates?
What kind of immunity is this?
Passive immunity
* **IgG** crosses the placenta to confer passive immunity
* Neonates are protected for about the first 6 months of life
* **IgA** is passed from mom to infant in breast milk; also passive immunity
* Breastfeeding infants are protected
595
Some studies have shown that infants who are fed breast milk develop fewer infections in their infancy.
Why?
IgA is passed from mom to baby in breast milk
IgA confers mucosal immunity, preventing attachment and invasion by bacteria and viruses through mucosal membranes
This can help prevent infection in infants
596
In a T-cell dependent B-cell response, will all B-cells undergo somatic hypermutation and class switching?
What determines this?
No; not all B-cells will undergo somatic hypermutation and class switching
* If the B-cell is in the germinal center...
* It will undergo class switching, somatic hypermutation, and proliferation
* The result is plasma cells and memory B-cells that make antibodies with increased affinity for the antigen
* If the B-cell is **not** in the germinal center
* It will **not** undergo class switching or somatic hypermutation
* It will become a short lived plasma cell
* It will make antibodies that have the same specificity/affinity as the original B-cell
* No increased affinity
597
A patient has high baseline levels of IgM and low levels of all other antibodies. Their medical history includes recurrent, severe, pyogenic infections
What is this condition called?
What causes it?
Hyper IgM syndrome
Caused by loss of CD40L on CD4+ helper T-cells
* The B-cells cannot class switch because a germinal center can't form
* The result is high IgM, but low levels of all other Igs
598
What is hyper IgM syndrome?
What do patients with hyper IgM syndrome suffer from?
Hyper IgM syndrome is a condition characterized by **high levels of IgM and low levels of all other Igs**
This is caused by loss of CD40L -\> Can't forma a germinal center -\> Can't class switch
Patients typically suffer from **recurrent, severe, pyogenic infections**
599
How do IgM and IgG enhance opsonization?
* IgM
* Complement deposition only
(classic pathway = formation of C3b)
* IgG
* Complement deposition
(classic pathway = formation of C3b)
* Phagocytes have IgG Fc receptors that bind to the Fc region of IgG, when it is attached to the pathogen
600
What are natural antibodies?
* Antibodies that are present in the body prior to exposure to an antigen
* Typically IgM
* Arise from B1 B-cells in a T-cell independent B-cell response
601
What are the most clinically significant natural antibodies?
Antibodies against ABO glycoproteins in people with red blood cells lacking A or B antigen
* Type O: Has natural antibodies to A and B antigens
* Type A: Has natural antibodies to B antigen
* Type B: Has natural antibodies to A antigen
602
What are the 4 major effector mechanisms of antibodies?
1. Neutralize toxins
2. Opsonization
* Via complement deposition (classic) by **IgM, IgG**
* Via exposure of **IgG** Fc (Binds Fc receptors on phagocytes)
3. Antibody-dependent cellular cytotoxicity (ADCC), **IgE**
4. Activates complement cascade; **IgG and IgM**
603
Describe the primary antibody response to a pathogen
* Takes 5-10 days
* IgM is the first secreted antibody
* B-cells specific for this antigen proliferate and differentiate
* Class switching, sompatic hypermutation occurs in the germinal center
* IgG is the second secreted antibody
* May have higher affinity for antigen than previously secreted antibodies
604
Describe the secondary antibody response to a pathogen
* Takes 1-3 days
* Driven by memory B-cells and memory T-cells
* Memory B-cells recognize the antigen
* Interact with antigen-specific T-cells in the germinal center
* Possible class switching and somatic hypermutation occurs with each subsequent exposure
* More robust response of class-switched IgG
* Produced in larger amounts, secreted more quickly
605
Why are booster immunizations recommended for some pathogens?
Booster immunizations initiatie a secondary antibody response
IgG specific for the antigen is produced; levels stay high, allowing the host to be fully prepared for exposure
606
Which antibodies would be elevated upon first exposure to a new virus?
IgM specific for that virus
607
Suppose a patient has high levels of IgG specific for herpes zoster virus.
What can you deduce about when the patient became infected?
The patient has been exposed to the virus at some point in their lives
It is not likely that the first exposure was recent; IgG specific for a virus takes time to generate. The patient has likely been exposed multipel times
608
Suppose a patient has low levels of IgA
What infections are they most susceptible to?
Patients with IgA deficiency are at an increased risk for mucosal infections, especially viral
609
Defects which interleukin might lead to IgA deficiency?
IL-5
IL-5 secreted by Th2 CD4+ helper T-cells promotes class switching to IgA
610
A patient in your ECMH has had several recurrent viral mucosal infections.
What kind of immunodeficiency should be on your differential?
IgA deficiency
611
You're shadowing in the ER and a patient comes in with severe trauma requiring a blood transfusion.
You look in the patient's chart, and see that they have had an abnormally high number of viral mucosal infections.
Why might this significant to the patient's ER care?
High numbers of viral mucosal infections might indicate **IgA deficiencey**
It is possible that patients with IgA deficiency have antibodies against IgA, which would put them at a **high risk of blood transfusion reaction**
If unsure about the possility of a reaction, it is recommended that this patient recieves blood from another person wtih IgA deficiency
612
When in life does SCID present?
How can it be treated?
SCID = severe combined immunodeficiency
Presents very early in life: the patient has very low levels of all immunoglobulins, putting them at extremely high risk of life-threatening infection
Permanent treatment = bone marrow transplant
Temporary treatment = give immunoglobulins intravenously
613
When in life does CVID present?
What are the symmptoms?
CVID = Common variable immunodeficiency
Patients typically present with present but low levels of Igs, especially IgA and IgG
Symtoms include recurrent bacterial, enteroviral, and giardia infections in later childhood/adolescence
614
What is CVID?
How does it affect patients?
CVID = common variable immunodeficiency
* Caused by multiple etiologies; a variety of different genes may cause an **underlying defect in B cells or helper T-cells**.
* Low immunoglobulins (IgG and IgA, maybe IgM)
* Decreased numbers of memory B-cells
* Impaired humoral immunity
* Increased risk of bacterial, enteroviral, giardial infections
* Presents in late childhood/adolescence
* Increased risk of autoimmune disease an lymphoma
615
A 15 year-old patient comes to urgent care complaining of diarrhea and upset stomach a few days after a hiking trip that included swimming in a mountain lake
Upon chart review, you notice that this patient has had multiple "stomach bugs" in the last year
Which immune disorder is on you differential?
Common Variable immunodeficiency (CVID)
Caused by a defect in B-cells or helper T-cells that results in decreased numbers of memory B-cells and impaired humoral immunity
616
What kinds of pathogens does the humoral immune response typically respond to?
Extracellular pathogens
617
If the humoral immune system typically responds to extracellular pathogens, how can it be involved in fighting viruses (which are typically intracellular?)
* Viral peptides can still be presented on MHC class II to CD4+ helper T-cells
* Can be captured by B-cells before the virus has been internalized
* Can be presented by dendritic cells infected with the virus
(Viral peptides can also be presented on MHC class I to CD8+ cytotoxic T-cells, but this is not humoral immunity)
618
What does elevated IgM indicate?
How is this indication different for elevated IgG?
Elevated immunoglobulins indicate exposure to an immunogen
* Elevated IgM = recent exposure to a new virus
* IgM is produced in the early primary response
* Elevated IgG = past exposure
* The individual has immunity to this immunogen
* Produced in later primary response or secondary response
619
How are B-cells co-stimulated?
What happens if there is no co-stimulation?
B-cell co-stimulation
* Cd3 on antigen binds CR2 (aka CD21) on B-cell
* -\> Enhancement of B-cell activation
* PAMP on antigen binds TLR on B-cell
* -\> Enhancement of activaton
If there is no co-stimulation...
* It is likely that the BCR has bound a self-antigen
* Self molecules don't have complement depositions or PAMPs
* To prevent an autoimmune response, the B-cell becomes anergic
620
Which proteins are expressed by all T-cells?
CD3
621
Which proteins are expressed by Helper T-cells?
CD3, CD4
622
Which proteins are expressed by cytotoxic T-cells?
CD3, CD8
623
Describe the basic structure of the T-cell receptor
* Alpha-beta heterodimer (except a small subset of gamma-delta)
* Alpha-chain undergoes VJ gene recombination during maturation
* Beta-chain undergoes VDG gene recombination during maturation
* No class-switching
* Antigen recognition region is variable between T-cells
* But remains the same for the life of the T-cell
* ITAMs mediate signaling from TCR to rest of cell
* Expresses CD3
625
What is an ITAM?
What processes is it involed in?
ITAM = Immunoreceptor Tyrosine-based Activating Motif
Transmits signal from TCR to the rest of the cell
* When the TCR recognizes antigen in the context of MHC, ITAMS are phosphorylated
* Recrutment and activation of ZAP70 tyrosine kinase
* Signaling cascade
* Increased expression of cytokines, cytokine receptors, cell proliferation genes
* T-cell immune response activation
* **Note: costimulatory signal is required for T-cell activaiton**
626
How are gamma-delta T-cell receptors different from alpha-beta T-cell receptors?
Gamma-delta T-cell receptors are a small subset of all T-cell receptors in our bodies
* Participate in innate immune response instead of adaptive
* Less variability in their antigen receptors
627
How to T-cell receptors acquire their antigen specificity?
T-cells acquire their antigen specificity as they mature in the thymus
* The alpha chain undergoes VJ recombination
* The beta chain undergoes VDJ recombination
After the T-cell leaves the thymus, its antigen specificity and that of its progeny **will not change;** The T-cell will not become more specific with repeated exposure
628
Which lymphocytes become more specific with repeat exposure to the same antigen?
B-cells
Only B-cells undergo somatic hypermutation to increase their antigen specificity
NK cells do not have antigen specificity, and T-cells do not alter their specificity after leaving the thymus
629
What kinds of thymocytes would you find in the cortex of the thymus?
How would you identify their stage of development?
* Double negative thymocyte
* Just arrived from bone marrow
* CD3-, CD4-, CD8-
* Double positive thymocyte
* CD3+, CD4+, CD8+
* Single-positive thymocytes
* CD3+, CD4+ **OR** CD3+, CD8+
* These are bout to migrate to the medulla to undergo negative selection
630
What is peripheral tolerance?
Why is it important?
Peripheral tolerance = the "check" to prevent B-cells and T-cells from reacting to self-antigen after they have completed maturation
* If a BCR or TCR binds to self-antigen, there will be no co-stimulatory signal (at least there shouldn't be)
* B-cell: TLR will not be activated, nor will Cd3 bind to CR2
* T-cell: B7 will not bind to CD28 on the T-Cell, nor will appropiate cytokines activate receptors on the T-Cell
* BCR or TCR binding without a co-stimulatory signal will make the lympcyte **anergic (nonresponsive to that antigen)**
* T-cells
* Anergy is antigen-specific, but **clonal deletion** will occur if a T-cell repeatedly encounters and reacts to self-antigen
631
What is the function of IFN-gamma?
Which cells secrete it?
* Drives AND is secreted by Th1 CD4+ helper T-cells
* Positive feedback loop
* Promotes and activates macrophages
* Stimulates IgG production
* Leads to more effective killing of **intracellular** pathogens
632
What are the major functions of Th1 CD4+ Helper T-cells?
Th1 CD4+ helper T-cells fight **intracellular pathogens**
* Promotes CD8+ cytotoxic T-cells to kill pathogens
* Secretes IFN-gamma and IL-2
633
How might a Th1 CD4+ helper T-cell response be pathogenic?
Th1 CD4+ helper T-cells may be involved in...
* Autoimmune disorders
* Chronic inflammaton
* Examples:
* IBD
* Psoriasis
* Granulomatous inflammation
634
What cytokines do Th1 CD4+ helper T-cells secrete?
* IFN-gamma
* Promotes and activates macrophages
* Stimulates IgG production
* Leads to more effective killing of intracellular pathogens
* Continues to drive the Th1 response
* IL-2
* Promotes T-cell growth and differentiation
* Can act in an autocrine fashion
635
What are the major functions of Th2 CD4+ helper T-cells?
* Fight **extracellular** pathogens
* Support humoral immunity
* Secrete cytokines in the context of CD40:CD40L that promote the formation of a germinal center
* Class switching and affinity maturation of B-cells
636
How might a Th2 CD4+ helper T-cell response be pathogenic?
Th2 CD4+ helper T-cells may be involved in...
* Chronic allergic rhinitis
* Asthma
637
Which cytokines drive the Th2 CD4+ helper T-cell response?
IL-2
IL-4
638
What proteins to regulatory T-cells (TRegs) express?
Surface
* CD4+, CD25+
Inside of cell
* FoxP: Regulates gene transcription
* CTLA-4: Binds B7 on APCs
* This prevents B7:CD28 costimulatory interaction needed to activate T-cell
639
What are the major functions of regulatory T-cells?
Modulate the immune reponse
* Inhibit effector function of CD4+ helper T-cells and CD8+ cytotoxic T-cells
* Loss of regulatory T-cell function -\> autoimmune problems
640
Which cells are CD3+, CD4+, CD25+?
Regulatory T-cells
641
Which cytokines are secreted by TRegs?
IL-10
TGF-beta
642
Which cytokines are secreted by Th2 CD4+ helper T-cells?
* IL-4
* Class switch to IgG and IgE
* IL-5
* Class switch to IgA
* IL-13
* Activation of eosinophils
* IL-10
* Anti-inflammatory (turns off immune system)
643
What are the major functions of Th17 CD4+ helper T-cells?
Th17 CD4+ helper T-cells enhance mucosal immunity
* Promote neutrophilic inflammation
* Via seretion of IL-17
* Recrute neutrophils and monocytes to the site of infection
644
How might the action of Th17 CD4+ helper T-cells be pathogenic?
* Chronic inflammatory and autoimmune diseases
* IBD
* Psoriasis
* MS
645
What is the possible consequence of loss of TReg function?
Autoimmune disease
646
What are the major functions of CD8+ cytotoxic T-cells?
Mediate direct cellular killing
647
What proteins do CD8+ cytotoxic T-cells express to aid their function?
* Perforins
* Form channels in the target cell membrane
* Granzymes
* Proteases that lead to apoptosis
* Degrade proteins in the target cell membrane
* Activate caspases
* FasL
* Binds to Fas proteins on the target cell
* Fas:FasL binding -\> apoptosis
648
Which subset of T-cells support class swithcing of B-cell immunoglobulins?
Th2 CD4+ helper T-cells
649
Which cytokine is critical for a secondary antibody response composed of IgG?
Il-4
650
Some patients with DiGeorge syndrome have decreased serum antibodies and recurrent pyogenic infections.
Why might this occur if B-cells develop normally?
Without a functional thymus, T-cells cannot develop
* There will be a lack of CD4+ Th2 helper T-cells, resulting in lack of support for B-cell differentiation
* No class switching, no affinity maturation
* B-cells do not become more specific, cannot generate memory
* Recurrent infections
651
What is hypersensitivity?
An exaggerated or inappropriate immune response to an external or self antigen
Can cause harm to the host
652
What mechanisms can cause a hypersensitivity reaction against self-antigen?
1. A foreign molecule cross-links or modifies a host cell
* The host cell recognizes these "new" epitopes as foreign and mounts an immune response
2. Molecular mimicry
* An antibody specific for a foreign antigen binds to similar-lookig self-antigens inside fo the host
653
What is the role of mast cells in hypersensitivity reactions?
Immediate hypersensitivity reaction (Seconds)
* Mast cells have effectors that are pre-formed in granules
* Histamine
* Kinins and Kininogenase
* Serotonin
* TNF
* Proteases
Slower hypersensitivity reactions (minutes)
* Mast cells synthesize effectors
* Arachidonic acid metabolites
* Leukotrienes and prostaglandins
* Cytokines and chemokines
654
How are mast cells able to respond so quickly in Type I hypersensitivity reaction?
* They constituitively express receptors for the Fc portion of IgE; they can bind immediately upon IgE binding antigen
* They have pre-formed effector molecules that are stored in granules and released immediately upon binding
* Histamine
* Kinins/kininogenase
* Serotonin
* TNF
* Proteases
655
Which types of hypersensitivity involve mast cells?
Predominantly Type I immediate/anaphylactic hypersensitivity reactions
656
What are the similarities and differences between a mast cell and a basophil?
Similarities
* Both are involved in inflammation
* Both express...
* Surface Fc receptors for IgE
* TLRs
* Both release...
* Histamines and cytokines
Differences
* Basophils exist in peripheral blood
* Mast cells exist in tissues
657
Which effector released by mast cells is most active in bronchoconstriction?
Is this an immediate or delayed effect?
Leukotrienes mediate bronchoconstriction
This happens after minutes (not seconds) because the mast cells must synthesize leukotriens from pre-cursors before release
658
Which type of hypersensitivity is described below?
## Footnote
**A hypersensitivity reaction involving mast cells, basophils, and pre-formed IgE**
Type I: Immediate/anaphylactic
659
Which type of hypersensitivity is described below?
## Footnote
**Complement is activated in response to IgG or IgM binding to fixed cell-surface or ECM antigens. Mediated by CD8+ cytotoxic T-cells, NK cells, and neutrophils**
Type II: Cytotoxic/antibody mediaed
660
Which type of hypersensitivity is described below?
## Footnote
**Antigen and antibody complexes mediate complement deposition and neutrophil recruitment**
Type III: Immune complex
661
Which type of hypersensitivity is described below?
**Macrophages and Th1 CD4+ helper T-cells mediate the formation of graulomas**
Type IV: Delayed type/cell mediated
662
What might cause a falsely negative *Mycobacterium tuberculosis* PPD skin test?
Why?
Immunosuppression
T-cells are impaired and cannot respond to the PPD antigens; no induration is formed, leading to a false-negative test result
663
Which types of hypersensitivity reactions involve complement activation?
Type II
Type III
664
Suppose you have a patient with anaphylactic allergies to peanuts and bees.
Which antibodies would you expect to find in excess in their blood, even when they are not having an allergic reaction?
IgE
665
What type of hypersensitivity reaction causes systemic anaphylaxis?
Type I (immediate/anaphylactic)
666
What mechanisms can cause a hypersensitivity reaction against self-antigen?
1. A foreign molecule cross-links or modifies a host cell
* The host cell recognizes these "new" epitopes as foreign and mounts an immune response
2. Molecular mimicry
* An antibody specific for a foreign antigen binds to similar-lookig self-antigens inside fo the host
667
Cell-mediated immunity protects us from which kinds of pathogens?
* Intracellular bacteria
* Viruses
* Fungi
* Parasites
* Tumors
668
Cell-mediated immunity protects us from which kinds of bacteria?
Be specific
Intracellular bacteria; they infect phagocytic cells and prevent phagolysosome formation
Obligate
* Mycobacterium spp
* M. tuberculosis
* M. leprae
* Legionella pneumophila
* Coxiella Burnetti
Facultative
* Francisella tularensis
* Brucella spp
* Listeria monocytogenes
* Salmonella spp
* S. enteriditis
* S. typhi
669
What are the major cellular components of cell-mediated immunity?
* Antigen presenting cells
* Macrophages
* Dendritic cells
* Sometimes B-cells
* Th1 CD4+ helper T-cells
* CD8+ cytotoxic T-cells
* NK cells
670
Describe the role of NK cells in viral immunity
NK cells = innate immunity
* Not specific
* Involved in the early antiviral immune response
* NK cells recognize virus infected cells due to both...
* The absence of an inhibitory ligand (MHC I)
* The presense of an activating ligand (ADCC)
* NK cells have an IgG Fc receptor, which binds to the IgG laid down on a virus-infected cell during ADCC
671
What are the predicted effects of a deficiency in cell-mediated immunity?
* Susceptibility to infections
* Bacteria (especially intracellular)
* Viruses
* Fungi
* Opportunistic pathgens
* Increased risk of neoplasia
* Especially from virus-driven tumors (HPV)
* Reactivation of latent viral or bacterial infections
672
Predict the effect of IL-12 receptor deficiency
* Decreased Th1 CD4+ helper T-cell response
* Decreased IFN-gamma secretion
* Reduced activation of CD8+ cytotoxic T-cells
* Disseminated mycobacterial infection (cell-mediated immunity can't contain the infection via granulomatous response)
673
How would an extracellular pathogen trigger a CD8+ cytotoxic T-cell repsonse?
Typically, extracellular pathogens activate humoral immunity that involves support from Th2 CD4+ helper T-cells
However cross-presentation can cause extracellular pathogens to have a CD8+ cytotoxic T-cell response
* After engulfment by an APC, the extracellular pathogen peptides escape the endosome, end up in the cytosol, and are transported to the ER, where they bind MHC I
* The peptide/MHC I complex is transported to the surface of the antigen-presenting cell
* Binding of Th1 CD4+ helper T-cells to the peptide on MHC I will **initiate a CD8+ cytotoxic T-cell response**
674
What are 4 causes of deficiencies in cell-mediated immunity?
HIV/AIDS
Immunosuppression (ie: transplant, chemotherapy)
Inherited T-cell deficiencies (SCID, DiGeorge)
Viral infections (Measles, CMV)
675
How does an acive HIV infection affect cell-mediated immunity?
(mechanism)
Active HIV infection leads to decreased CD4+ T-cells
* CD4 = a coreceptor for HIV
* The virus specifically infects and kills CD4+ helper T-cells
* This results in **decreased cell-mediated immunity**
676
What components of innate immunity in the lung epithelium will protect us from infection by a new virus?
Epithelial cell junctions
Cilia movement
Mucous protection
677
Pattern recognition receptors (PRRs) recognizes viral nucleic acids and trigger the production of \_\_\_\_\_\_\_\_\_\_\_\_\_, part of the innate immune response
Interferons
Interferons are produced by the infected cell when intracellular PRRs bind viral nucleic acids
678
Which cells are responsible for releasing histamine to trigger inflammation?
Mast cells
679
**Which cells exhibit the following properties?**
Can migrate from the blood to respond to inflammatory signals
Can phagocytose a virus
Cannot present antigen on MHC II
Neutrophils
680
Many viruses down-regulate MHC class I on the cells they are infecting to evade the host immune system
Which cells of the host will be able to kill these virus-infected cells?
NK cells
NK cells recognize and kill cells with missing or downregulated MHC I
681
Which antibodies cross the respiratory epithlium to protect us from bacteria and viruses?
IgA
IgA antibodies are the only ones that can dimerize and cross the mucosal epithelium
They are important in mucosal immunity, which prevents pathogens from entering our cells
682
Where do memory cells exist?
Lymphoid tissues
683
Where do plasma cells exist?
Bone marrow and tissue
684
Describe the basic organization and function of the mucosal immune system
* Outer epithelial layer
* Interfaces with the outside world
* Part of the innate immune system
* **Goal = prevent infasion of pathogens**
* Underlying connective tissue
* Contains lymphcytes, denderitic cells, macrophages, mast cells
* Mediates innate immune response
* Contains effectors of adaptive immune response
* MALT
* Contains effetors of adaptive immune response
* Specialized for each particular mucosa
* Draining lymph nodes
* Adaptive immune responses may also be initiatied here
685
What is a regional immune system?
A collection of immune cells and molecules that work together to perform the specific immune functions at a particular anatomic location
The regional immune systems are **adapted** to the location that they serve
686
What are the three regional immune systems most relevant to FDN3?
GI Tract
Respiratory
Cutaneous
(Genitourinary was mentioned in the learning guide briefly)
687
What challenges does the GI tract immune system face?
* Tolerance of food antigens
* Tolerance of commensal microbiota
* \>500 types
* Outnumber human cells in the whole body
* Must repond to pathogens that are relatively rare
* Large surface area
688
What specialized cells play a role in the GI tract immune system?
What are their functions?
* M cells
* Luminal antigen sampling
* Secretory IgA, IgM
* Neutralized microbes in the lumen
* Dendritic cell subsets
* Luminal and lamina proria antigen sampling
* T-cell tolerance induction
* Effector T-cell activation
* Induction of B-cell IgA class switching
* Imprint gut-homing phenotypes of B cells and T cells
689
In the regional GI tract immune system, which cells participate in antigen sampling?
M cells
Dendritic cells
690
What is antigen sampling?
(With specific reference to regional immune systems)
* A specialized cell recognizes and binds an antigen
* Dendritic cells
* M cells in gut
* Langerhans cells in cutaneous
* The cell delivers the antigen to the MALT or draining lymph nodes associated with that immune system
* There will either be no response (tolerance) or a response if effectory lymphocytes are activated by the antigen
691
Describe the components and functionof the mucus layer of the GI tract immune system
Part of the **innate** immune response
* Mucus is produced by goblet cells
* It contains...
* Glycocalyx
* Mucins + glycolypids
* A dense layer that prevents pathogens from contacting the intestinal epithelium
* Defensins
* Defend against luminal bacteria
* Kills microbes by disrupting their glycolipid membrane
692
Describe the intestinal epithelium of the GI tract, as it relates to its regional immune system
Single layer on a basement membrane
* Dominanted by goblet cells, M cells, Paneth cells
* Innate
* Forms a barrier to pathogens
* TLRs and NLRs recognize PAMPS and initiatie an immune response
* Participates in tolerance of commensals
* Limit inflammatory response
* Antigen sampling happens here
* Adaptive
* Antigen-sampling cells may activate effector B and T cells
693
Why is it important to limit inflammatory responses, especially at epithelial barriers?
Inflammation causes loss of epithelial integrity
* Cells ceparate
* Tight junctions open up
694
Describe the innate components of the connective tissue layer of the GI tract, as it relates to the regional immune system
The **Lamina propria is** made up of dendritic cells and macrophages
* Dendritic cells and macrophages inhibit inflammation and maintain homeostasis
* Innate lymphoid cells (NK cells) secrete IL-17, IL-22
* Immune defense against some bacteria
* Promotes epithelial barrier function
* Innate lymphoid cells (NK cells) secrete TGF-beta, IL-10, IL-2
* Maintain immune homeostasis in baowel walls
* Anti-inflammatory and/or regulatory function
695
Describe the adaptive components of the connective tissue layer of the GI tract, as it relates to the regional immune system
* IgA secretion by plasma cells (humoral)
* Antibodies neutralize pathogens
* Dimierized IgA can cross the epithelium and be released into the lumen
* Th17 CD4+ helper T-cells
* Secrete IL-17, IL-22
* Enhance epithelial barrier function
* Th2 CD4+ helper T-cells
* Defend against parasites, extracellular pathogens
* Secrete IL-4, IL-13
* B cell differentiation
* Promote fluid and mucus secretion
* TRegs
* Suppress immune response to food antigens and commensals
* Prevent inflamatory reactions
696
Which cells secrete IL-17 and IL-22?
What is their function in the GI tract immune system?
TH17 CD4+ Helper T-cells and innate lymphoid cells
Enhance epithelial barrier function
697
Which cytokines are secreted by innate lymphoid cells in the GI tract immune system?
What are their functions?
* IL-17, IL-22
* Defense against some bacteria
* Enhance epithelial barrier function
* TGF-Beta, IL-10, IL-2
* Maintain immune homeostasis in the bowel
* Anti-inflammatory/regulatory function
698
Which cells in the GI tract immune system play a large role in defending against parasites and intracellular bacteria?
How?
Th2 CD4+ helper T-cells
Secrete IL-4, IL-13 -\> B-cell differentation, fluid and mucus secretion
699
How do Th2 CD4+ helper T-cells and TRegs function together in the regional immune systems?
The balance between Th2 cells and TRegs is important
* Need Th2 cells to defend against pathogens
* Need TRegs to limit inflammatory/immune responses to food antigens, commensals, non-pathogenic particles
700
What is the GALT?
What does it contain?
The Gut-Associated Lymphoid Tissue; part of the regional immune system in the GI tract
* Found in the lamina propria
* Contains
* **Tonsils**
* **Peyer's patches** in the ilium
* **M-cells** that transport antigen from the epithelial lining
* **Dendritic cells** with processes that extend into the lumen
* **Diffuse effector lymphocytes** that may exert effect in other places in the body, but home back to the GALT
701
What are some of the challenges of the respiratory regional immune system?
* Exposure to a mix of airborne pathogens adn innocuous microbes/particles
* Must differentiate and respond to pathogens while tolerating harmless particles
702
What are some of the specialized components of the respiratory immune system?
* Tonsils
* Adenoids
* Ciliated respiratory epithelial cells (respiratory elevator)
* Secretory IgA, IgM, IgG
703
Describe the respiratory epithelium as it relates to the respiratory regional immune system
**Innate**
* Physical barrier
* Pseudostratified, ciliated, columnar epithelium
* Chemical barrier
* Mucins, defensins, cathelicidins trap foreign substances
* Surfactant
* In alveoli
* Prevents spread of infection
* Suppresses inflammatory allergic response in the lungs
* MALT
* Alveolar macrophages
* Anti-inflammatory
* Inhibit T-cell response
**Adaptive**
* Mast cells, eosinophils, dendritic cells, CD4+ helper T-cells
* IgA - mosty in upper airway
* IgE - mediates allergic response, asthma when bound to mast cells
704
Describe the epithelial layer of the respiratory system, as it relates to its regional immune system,\
Humoral
* Mast cells, eosinophils, dendritic cells, CD4+ helper T-cells
* IgA
* IgE
Cell-Mediated
* Dendritic cells
* Sample airway antigen, migrate to lymph node, and present to naive T-cells
* T-cells are activated by dendritic cell sampling and presentation
* Occurs in peri-broncial and mediastinal lymph nodes
* Effect response, return to broncial mucosa
*
705
Describe the respiratory immune response that promotes allergic asthma
* Dendritic cells sample airway antigen
* Migrate to lymph nodes to present to naïve T-cells
* Promote differentiation to Th2 CD4+ helper T-cells
* Th2 cells effect response
* Th2 cells return to bronchial mucosa
* Here they can be re-activated by allergens presented by dendritic cells next time they appear
706
What are some of the challenges of the cutaneous regional immune system?
Large surface area
Exposure to many things
707
What are some of the specialized components of the cutaneous immune system?
Keratinocytes
Langerhans cells
Dendritic cells
708
Where in the body would you find M cells?
What do they do?
GI tract
M cells participate in the GI tract regional immune system; they sample antigen and present it to B and T cells
709
Where in the body would you find Langerhan's cells?
What do they do?
Epithelial lining of the genitourinary system
Dermis
* Langerhan's cells are a type of dendritic cell; they basically sample antigens in the cutaneous and genitourinary regional immune systems
* Contain TLRs that are activated by PAMPS. When activated, the cell will migrate to a lymph node to initate a T-cell response
710
Describe the epithelial layer of the skin, as it relates to the cutaneous regional immune system
Epidermis
* Multi-layered, keratinized squamous epithelium
* Keratinocytes
* Secrete defensis, cathelicidins, inflammatory cytokines in response to microbes
* Innate immune system
711
Describe the dermis, as it relates to the cutaneous regional immune system
Innate
* Mast cells, macrophages, dendritic cells
* Respond to microbes, injury
* Mediate inflammatory response (ex: sunburn)
* Dendritic cells
* Transport microbial and environmental agents to lymph nodes
* Initiate a T-cell response
* Langerhans cells (a type of dendritic cell)
* TLRs are activated by PAMPs
* The cell detatches from the epidermis and migrates to the lymph node (via expression of CCR7)
712
How do Langerhan's cells migrade from the dermis to the lymph node?
Langerhan's cells express CCR7, a chemokine receptor that targets them to where T-cells are (in the lymph node)
713
Describe the adaptive components of the cutaneous regional immune system
* Activated T-cells
* Express chemokine receptors and adhesion molecules
* Home to CLA (Cutaneous lymphocyte-associated antigen)
* CD4+ helper T-cells
* Th1: fight intracellular pathogens
* Th2: fight extracellular pathogens
* Secrete IL-4, IL-13
* B-cell differentation
* IL-13 inhibits production of defensins and cathelicidins by keratinocytes
* This causes infections in Th2-driven skin diseases
* Th17: Fight extracellular pathogens
* Secrete IL-17, IL-22
* Increase epithelial barrer function via production of defensins, cathelicidins, keratinocytes
* Induce epidermal cell proliferation
* CD8+ cytotoxic T-cells
714
Describe the roles of the subsets of CD4+ T-cells in the cutaneous regional immune system
CD4+ helper T-cells
* Th1: fight intracellular pathogens
* Th2: fight extracellular pathogens
* Secrete IL-4, IL-13
* B-cell differentation
* IL-13 inhibits production of defensins and cathelicidins by keratinocytes
* This causes infections in Th2-driven skin diseases
* Th17: fight extracellular pathogens
* Secrete IL-17, IL-22
* Increase epithelial barrer function via production of defensins, cathelicidins, keratinocytes
* Induce epidermal cell proliferation
715
What is the function of dermal gamma-delta T-cells?
Gamma-delta T-cells function in the cutanous regional immune system
* Secrete IL-17 in chronic inflammatory skin diseases
716
Which cytokines increase epithelial barrier function?
Which cells secrete these cytokines?
IL-17, IL-22
Secreted by Th17 CD4+ helper T-cells in cutaneous and GI-tract immune systems
717
A patient presents with chronic, episoidic symptoms of rash, myalgias, diarrhea and bloating following eating, and fatigue
They report that this has been happening for years, but the episodes aren't worsening over time.
**What condition do you think this patient has?**
**What findings would support your diagnosis?**
Celiac disease
Confirm with colonoscopy of small bowel mucosa
* Look for atrophy (blunting) of intestinal villi following an episode
718
What is the mechanism underlying Celiac disease?
* CD4+ helper T-cells respond to gliadin (a component of gluten
* The body forms IgA, IgG, specific for gluten and transglutaminase 2A
* This leads to chronic inflammation
* Atrophy of the intestinal villi
* Malabsorption
* Nutritional deficiency
* Extra-intestinal manifestation
* Rash
* Myalgia
* Diarrhea/bloating
* Fatigue
719
What are the symptoms of Celiac disease?
* Chronic inflammation fo the small bowel muosa
* Atrophy of the intestinal villi
* Malabsorption
* Nutritional deficiency
* Extra-intestinal manifestation
* Rash (dermatitis herpetiformis)
* Myalgia
* Diarrhea/bloating
* Fatigue
720
What is the mechanism underlying food allergy?
Failure of the adaptive immune system to tolerate food antigen
* Too many Th2 CD4+ helper T-cells, not enough TRegs
* Overactive Th2-dependent IgE resposne to antigen
* Mast cells are activated
* Potent mediators/cytokines are released
* Acute inflammatory reactions (including systemic anaphylaxis)
721
What is the mechanism underyling MALT lymphoma?
* H. pylori infection leads to an inflammaory reaction
* Malignant transformation of B-cells in the lymphoid follicles in the gastric lamina propria
* Gets progressively worse over time (without treatment)
722
What are the symptoms of MALT lymphoma?
* Gets progressively worse over time
* Constant (not episodic)
* Treatment of H. pylori can cause regression
* Most common in patienst \>30 years old
723
A 27 yo male comes to urgent care complaining of 3 days of diarrhea. It started out watery, now has some streaks of blood. He's also had moderate abdominal pain with urgency, worse after eating. On exam he is quite thin, and says he has been eating less during these diarrhea episodes which occur every 2-3 months for the last year
## Footnote
**What is your diagnosis?**
IBD (Chron's disease)
No rash = unlikely to be Celiac
Long lasting = probably not allergies
Episodic = not MALT lymphoma
724
What is the mechanism underlying IBD?
* Polymorphisms of genes associated with bacterial processing, sensing, and autophagy
* Defective TReg function
725
What are the symptoms of IBD?
* Chronic inflammation
* Episodic
* Vomiting/diarrhea
* Urgency to defecate
* Weight loss
726
What is the difference between Crohn's disease and ulcerative colitis?
Location (both are forms of IBD)
* Crohns: any part of GI tract, usually terminal ilium
* Ulcerative colitis: Colonic mucosa
727
A 42 yo M comes to urgent care c/o diarrhea x4 days. He has also had intermittent lower abdominal pain and a low grade temp (100.1). Stool is mostly watery, but a couple episodes were had a bit of mucus and possibly a streak of blood this morning. With further history, he notes he just finished a 14 day course of antibiotics (Clindamycin) 3 days ago for a difficult to treat sinus infection.
## Footnote
**What is your diagnosis?**
Clostridium difficile (C. diff) colitis
Acute = not IBD or celiac
Fever = infection
Also supported by associated antibiotic use
728
What causes C. diff colitis?
Antibiotic treatment or ingestion of C. diff spores
This alters the quantity and/or diversity of normal flora, reducing the ability of the GI tract regional immune system to prevent harmful/inflammatory responses
729
What are the symptoms of C. diff colitis?
* Acute presentation
* Abdominal pain
* Diarrhea
* May have a low grade fever
* Associated with antibiotic use or spore ingestion
730
What is the mechanism underlying chronic rhinosinusitis?
* **Innate defects** in the epithelial barrier, mucociliary elevator, or production of anti-microbial peptides
* **Abnormal activation** of eosinophils, mast cells, innate lymphoid cells
* **Th2-skewed pathway**
* Direct activation of T and B cells promotes IgE and eosinophil activation
731
Describe the symptoms of chronic rhinosinusitis
* Chronic inflammatory response
* Nasal obstruction
* Smell loss
* Drainage
* Facial pain/pressure
* May or pay not have polyp overgrowth
* (No fever)
732
How would you differentate chronic rhinosinusitis from a sinus infection?
Chronic rhinosinusitis = no fever
Sinus infections may have fever
733
A 32 yo F comes to clinic for f/u. She reports about 3 weeks of increasing difficulty breathing through her nose. She also c/o b/l sinus pressure and a worsening sense of smell. She denies any fever, last used antibiotics for a sinus infection 4 months ago. She reports having surgery in her sinuses about 5 years ago when things used to be this bad, but did not bring records.
## Footnote
**What is your diagnosis?**
Chronic rhinosinusitis
No fever = not a sinus infection
Presentation in the nasal/respiratory airway and mucosa
734
A 26 yo M comes to clinic for f/u. Over the last year he's gained about 25 lbs due to exercising less and a stressful job. He's also noticed enlarging rash on his elbows and knees. It's only mildly itchy. It's starting to bother him because the skin "looks like a reptile that keeps shedding its scales."
## Footnote
**What is your diagnosis?**
Psoriasis
Red scaly plaques, itchy, on elbos and knees
Not itchy enough to be eczema
735
What is the underlying mechanism of psoriasis?
Dyseregulated innate and T-cell mediated immune responses
* Overactive plasmacytoid dendritic cells
* Respond to environmental stimuli
* Produce IFN-alpha
* T-cells circulate to the dermis
* Overactive Th1, Th17 cells
* Secrete too much IL-17
* Persistent keratinocyte proliferation
736
What are the symptoms of psoriasis?
* Chronic
* Red, scaly plaques
* Only mildly itchy
* Usually at elbows and knees
737
A 2 yo M comes to clinic for f/u. His mother notes he has trouble sleeping at night because he is "always scratching." His exam shows globally dry skin, with patches of redness and hyperpigmentation in his antecubital fossa and popliteal fossa
## Footnote
**What is your diagnosis?**
Eczema
Very itchy, dry skin, patches of redness and hyperpigmentation
738
What causes Eczema?
Innate barrier defects
* Filaggrin = a protien important in the keratinocyte structural barrier is compromised
* Abnormal environmental or food antigen response
* Increased antigen exposure
739
What is the mechanism underlying eczema?
Overactive Th2 response in genetically susceptible individuals
* Susceptible due to innate barrier defect, increased antigen exposure
* Leads to...
* B-cell production of IgE
* Mast cell activation
* Acute inflammatory response due to release of cytokines/mediators
740
What are the symptoms of eczema?
Dry skin
Patches of redness and hyperpigmentation
Very itchy
741
List the immune privileged tissues in the body
Brain
Eye
Testes
742
What is an immune privileged tissue?
Why is immune privilege important?
An immune privileged tissue is one that is protected from/not affected by systemic immune responses
This is important in order to prevent damage to these tissues
* Eye, brain, testes
* Damage would compromise the ability of the organism to survive and reproduce
743
What clinical findings and consequences would you expect in a patient with a B cell deficiency?
Histology
* Absent or reduced follicles and germinal centers in lymphoid organs
Disease
* Pyogenic bacterial infections
* Enteric bacterial infections
* Viral infections
744
What clinical findings and consequences would you expect in a patient with a T-cell deficiency?
Histology
* Reduced T-cell zones in lymphoid organs
* Reduced delayed hypersensitivity reactions to common antigens
* Defective T-cell proliferative responses to mitogens (in vitro)
Disease
* Infections due to **intracellular** microbes
* Viruses
* Intracellular bacteria
* Pneumocystis jiroveci (and other fungi\_
* Non-tuberculosis mycobacteria
* EBV-associated lymphomas
745
What clinical findings and consequences would you expect in a patient with an innate immune deficiency?
Variable; depends on the component that is defective
* May see a mix of pyogenic bacterial and viral infections
746
A 2-year old patient with a history of recurrent viral and pneumocystis jiroveci fungal infections (6 total in the last 6 months) presents with Q-fever.
Do you suspect an immune deficiency? Why?
If so, which cells are deficient?
**Yes, you should suspect an immune disorder**
* *P**neumocystis jiroveci* is not usually seen in patients with super healthy immune systems
* It is an opportunistic fungus
* Also commonly seen in HIV patients
Infection with viruses, fungi, and coxiella brunetti (cause of Q fever, obligate intracellular) point to a **T-cell deficiency**
* SCID
* DiGeorge syndrome
747
List the X-linked primary immune deficiencies that are relevant to FDN 3
* X-linked SCID
* X-linked Hyper IgM
* X-linked Agammaglobulinemia
* Wiskott-Aldrich Syndrome
All except Wiskott-Aldrich Syndrome can also be caused by autosomal defects
748
What are the clinical manifestations of chronic granulomatous disease (CGD)?
**Individuals with CGD don't have enough NADPH to kill via respiratory burst**
* They cannot create O2-, which is needed to make H2O2, and subsequently the hypochlorite ion
* They must kill organisms using the oxygen-independent pathway
**You would expect a patient to experience...**
* Recurrent infections from catalase positive organisms
* Catalase interferes with the oxygen-independent pathway of killing
* Granuloma formation (lungs, liver, brain)
* Severe infections of skin and bone
* Recurrent oral stomatitis
* Infections of respiratory tract and skin
* Abscess formation
749
Which immune deficiency is characterized by recurrent infections from catalase-positive organisms, granuloma formation, and abscess foramtion?
Chronic granulomatous disease (CGD)
750
What is the defect that causes Leukocyte Adhesion Deficiency (LAD)?
Explain
LAD is caused by a defect in the **CD18 subunit of integrin**
* Integrin is required for neutrophil adhesion to the endothelium; a key step in migration to the target tissue
* Without integrin, neutrophils cannot reach their destination and aid in the immune response
* The result is **recurrent bacterial infections without appropriate pus formation**
751
Which primary immune deficieincy is characterized by recurrent bacterial infections without appropriate pus formation?
Leukocyte adhesion deficiency (LAD)
Neutrophils cannot reach their destinations at the site of infection
752
Which cells are deficient in Chediak-Higashi syndrome?
What are the clinical manifestations?
Phagolysosomes do not form; there is a defect in phagosome-lysosome fusion
NK cells are also abnormal
**Clinical manifestation**
* Impaired killing of intracellular pathogens = recurrent **pyogenic infections**
* Bacterial and viral
* Other abnormalities
* Partial albinism
* Abnormal platelet function
* Defective NK cells
753
A patient with recurrent, pyogenic bacterial and viral infections suspects a primary immune deficiency.
Flow cytometry reveals abnormalities in NK cells, and physical exam is significant for partial albinism.
**Which PID do you suspect?**
Chediak-Higashi syndrome
754
List the PIDs that affect innate immunity
* Chronic granulomatous disease
* Leukocyte adhesion deficiency
* Complement defects
* Defects in TLRs
755
Describe the clinical manifestations a complement defect
Defects in C2 and C4
* Autoimmune disease
* Ex: Systemic lupus erythematosus
Defects in C2 and C3
* Infections by encapsulated bacteria
Defects in any of C5-C9
* Recurrent, invasive nesseria infections
756
Which PID is associated with recurrent, invasive infections by *Nesseria* spp?
Complement defect in any of C5-C9
Deficiencies in these proteins will result in failure to form the Membrane Attack Complex (MAC) that is very important in killing *Nesseria* spp.
Other gram-negative bacteria may also be a problem for these individuals
757
List the 4 major genetic defects that can lead to SCID
Describe each one briefly
SCID = severe combined immunodeficiency
* Mutation in the x-linked gene encoding the **common gamma chain**, an important component of many IL receptors
* Lack of IL-7, IL-15 signaling = defective T and NK cells
* A mutation in **RAG1/RAG2 that prevents VDJ recombination**
* No B or T cells
* **Loss of MHC II** due to loss of transcription factors required for expression leads to **bare lymphocyte syndrome**
* No T cell positive selection = **no T-cells**
* Impaired CD4+ T cell activation
* Defective cell-mediated immunity
* Defective T-cell dependent humoral immunity
* **Defective T cell signaling** due to defective TCR/CD3 complex component or T cell activation signal transduction cascade
* Decreased T cells
* Abnormal CD4+ : CD8+ ratio
* Defective cell-mediated immunity
758
In the most general sense, which arm of the immune system is most greatly affected by SCID?
Cell mediated arm of adaptive immunity
T-cells are defective or absent; this may or may not affect B-cell maturation, depending on the defect that is causing SCID
759
Which PID is caused by a mutation in the x-linked gene thae encodes the common gamma chain?
Which cells are defective?
SCID (The x-linked version)
T cell and NK cells are defective (B-cells are normal)
760
Which PID is caused by a mutation in RAG1/RAG2?
SCID; RAG1/RAG2 mutation prevents VDJ recombination during lymphocyte maturation
T cells and B cells are absent (NK cells are normal)
761
Which PID is caused by a loss of MHC II expression?
SCID; Bare Lymphocyte Syndrome
* CD4+ T-cell activation is impaired
* No MHC II for it to recognize
* Cell-mediated immunity is defective
* T-cell dependent humoral immunity is impaired
* No Th2 CD4+ T-cells
* No germinal center formation
* No class switching or somatic hypermutation
| (T-cell positive selection does not occur)
762
Which PID is caused by defective TCR/CD3 complex component or a defective T cell activation signal transduction cascade?
SCID
Decreased T-cells
Abnormal CD4+ CD8+ ratio
Defective cell-mediated immunity
763
What is the clincal presentation of an infant with SCID?
* Bacterial, viral or fungal pathogen infections
* Diarrhea/IBD-like symptoms
* Failure to thrive
* *Pneumocystis jiroveci* pneumonia
* Adenovirus
* RSV
* CMV
* Parainfluenza virus
* Rash
(Basically, lots of viruses
764
Delayed umbillical cord separation is associated with...
Primary immunodeficiecy Disease
Specfiically, a problem with neutrophil function
Most often **leukocyte adhesion defect (LAD)**
765
What are the clinical manifestations of an inherited defect in TLRs?
* Production of pro-inflammatory cytokines
* IL-1, IL-6, TNF-alpha, IL-12
* Increased risk of severe **pyogenic bacterial or viral infections**
* Usually accompanied by significant inflammatory response
766
Which PIDs are associated with **pyogenic** infections?
Which are associated with **failure to form pus**?
**Pyogenic (pus-forming) infections**
* B-cell abnormalities
* Chediak-Higashi syndrome (innate)
* Defect in TLRs (innate)
**Failure to form pus**
* Leukocyte adhesion defect (LAD)
767
Which cells are defective in DiGeorge syndrome?
Why?
**T cells are deficient**
DiGeorge is caused by a **22q11 deletion** that causes **developmental defects** (partial or complete) in the **thymus**
There is a **spectrum** of deficiency, depending on the fraction of the thymus that is nonfunctional
Note: patients with partial DiGeorge syndrome improve with age as their cell-mediated immunity catches up
768
What are the clinical presentations and consequences of antibody deficiency syndrome?
Histology
* Very small number of B cells in peripheral blood
Disease
* Infections by encapsulated bacteria
* Otitis media
* Sinusitis
* Pneumonia
* Enteroviral infections
* Meningoencephalitis
* Vaccine-associated poliomyelitis
* Mycoplasma (can lead to arthritis)
769
What causes antibody deficiency syndrome?
A defect in the pre B cell receptor or associated proteins causes an arrest of B-cell development (from pro to pre B-cells)
* Defect in bruton tyrosine kinase (BTK)
* Causes X-linked agammaglobulinemia (XLA)
* Defect in B cell linker protein (BLNK)
770
What causes X-linked agammaglobulinemia (XLA)?
What is the presentation?
A defect in **Bruton Tyrosine Kinase**
* Prevents maturation of B-cells (arrested as pro B cells, cannot become pre B cells)
* Presentation is the same as Antibody Deficiency Syndrome
* Infections by encapsulated bacteria
* Otitis media
* Sinusitis
* Pneumonia
* Enteroviral infections
* Meningoencephalitis
* Vaccine-associated poliomyelitis
* Infection by mycoplasma (may caus arthritis)
771
Which PID is caused by a defect in bruton tyrosine kinase?
X-linked agammaglobulinemia (XLA)
(the most common early-onset agammaglobulinemia)
772
What are the clinical presentations and consequences of Wiskott-Aldrich syndrome?
Histology
* Abnormal platelets and leukocytes
* Small
* Do not migrate normally
Disease
* Eczema
* Thrombocytopenia
773
Which PID is caused by an X-linked mutation in the gene that encodes WASP, a protein that binds to adaptor molecules and cytoskeletal components in hematopoietic cells?
Wiskott-Aldrich Syndrome
Results in abnormally small platelets and leukocytes that do not migrate properly
774
What causes Wiskott-Aldrich Syndrome?
An X-linked mutation in the gene that encodes WASP, a protein that binds to adaptor molecules and cytoskeletal components in hematopoietic cells
775
Which patients are most likely to present with Wiskott-Aldrich syndrome?
Boys
Inheritance is X-linked
776
What causes Hyper IgE syndrome?
A mutation in STAT3 that results in abnormal Th17 CD4+ helper T cell development
777
What are the clincal presentations and consequences of Hyper IgE syndrome?
Histology
* Few or defective Th17 CD 4+ helper T-cells
Disease
* Recurrent neonatal eczematous rash
* Retention of primary teeth
* High IgE
778
Which PID is characterized by recurrent neonatal eczematous rash and retention of primary teeth?
Hyper IgE syndrome
Also look for a mutation in STAT3, defective/absent Th17 Cd4+ helper T-cells, and high IgE
779
Which PID is chacterized by eczema and reduced size and number of blood platelets (thrombocytopenia)?
Wiskott-Aldrich Syndrome
780
Which PIDs are characterized by infections by encapsulated bacteria that cause otitis media, sinusitis, and pneumonia?
* Antibody deficiency syndrome
* Also look for
* Enteroviral infections
* Common Variable immune deficiency
* Also look for
* Lymphoid hyperplasia
* Granulomatous lesions
* Lymphoma and autoimmune manifestations
* Cytopenias
* IBD
781
Which PIDs can be treated with enzyme replacement therapy?
* Deficiencies in complement inhibitors
* SCID caused by ADA (adenosine deaminase) or PNP (Purine nucleoside phosphorylase) deficiency
782
Which PIDs can be treated with passive immunization?
Defects of antibody-mediated immunity
* Antibody deficiency syndrome
* Including X-linked agammaglobulinemia
* CVID
783
Which PIDs must be treated bone marrow transplant?
**SCID and LAD**
Bone marrow transplant is starting to be used as treatmetn for Wiskott-Aldrich syndrome **(WAS)** and **Hyper-IgM**
784
When can gene therapy be used as treatment for PID?
When the defective gene is known (this method is in development)
* X-linked SCID
* Adenosine deaminase deficient SCID
785
How is X-linked agammaglobulinemia treated?
Passive immunization - give pooled gamma globulin from healthy individuals intravenously (IVIG) or subcutaneously (SCIG)
786
What is the recommended treatment for SCID?
Bone marrow transplant
Gene therapy (in development)
787
How are newborns screened for SCID?
Use PCR to amplify T-cell recelptr excision circles (TRECs)
* TRECs are formed when the T-cell rearranges the variable region of its receptor
* TRECs serve as a surrogate for newly-synthesized naive T-cells
* There should be many in newborns!
* **Too few = SCID**
788
What is a TREC?
Why is it important?
A T cell receptor excision circle
* Forms when a T-cell rearranges the variable region of its receptor
* Too few TRECs in newborns = worry for SCID
789
Gene therapy:
Which kinds of diesease require lifelong expression of the corrective gene?
Genetic diseaes such as Cystic Fibrosis and Duchenne Muscular Dystrophy
790
Gene therapy:
Which kinds of disease may only require transient expression of the defective gene?
Acquired disesases
Cancer, HIV
791
What is *In vivo* gene therapy?
Genes are introduced directly into living tissues
792
What is *ex vivo* gene therapy?
Cells are removed from patients
Genes are introduced into these cells while they are replicating *in vitro*
The cells that successfully integrated the new gene are selected and then re-introduced to the patient
**Note: only works in cells that divide**
793
What are the advantages of *i**n vivo* gene therapy over *ex vivo* gene therapy?
* In vivo* therapy can be delivered into differentiated **dividing and _non-dividing_ cells**
* Ex vivo* therapy can only be delivered to dividing cells
794
What are the advantages of *ex vivo* gene therapy over *in vivo* gene therapy?
In *ex vivo* therapy, the new gene integrates into the host genome, making it **more stable**
Also, the gene will **persist for life**
(*in vivo* = unsatable because the DNA is episomal (not integrated), treatment is temporary and may need to be repeated)
795
What is cell tropism?
Why is it an important consideration when using viral vectors in gene therapy?
Cell tropism = specific viruses preferentially target specific species and/or cell types within those species
This is important because it **defines the ability of a viral vector to transduce (enter into) a particular cell type**
796
What is pseudotyping, as it relates to gene therapy?
Altering the cell tropism of a virus/viral vector to target a specific cell type
The result: you can choose which cells the viral vector will target
797
What are the two integrating vectors that can be used in gene therapy?
How are they similar?
How are they different?
Retrovirus and Lentivirus
* Both
* Long-term, stable integration
* Retrovirus
* Can only be integrated into **dividing cells**
* Lentivirus
* Can be integrated into **dividing and nondividing cells**
798
What are the 3 major non-integrating vectors used in gene therapy?
Describe the basic features of each one
All are episomal; not integrated into host genome
* Herpes virus
* Long-term
* Adenovirus
* Temporary
* Adeno-associated virus
* Stable
* Long term
Also: DNA, but not widely used because it's temporary and inefficient
799
What are the advantages of using a retrovirus in gene therapy?
What are the disadvantages?
Advantages
* Large cloning capacity
* Integrates into the genome of the target cell
* Does not transfer virus protein coding sequences
Disadvantages
* Only integrates into actively dividing cells
* Integration could lead to **gene inactivation** of tumor suppressor genes
* Depending on the site of integration
* Low titer
800
What is the difference between a retrovirus and a lentivirus?
Lentiviruses are basically retrovirus vectors that can be integrated into both **dividing and non-dividing cells** by making use of the _control elements_ of HIV
801
What are the advantages of using an adenovirus vector in gene therapy?
What are the disadvantages?
Advantages
* E1 is deleted (the gene required for viral replication)
* High transduction efficiency = can get DNA into many cells
* **Dividing and non-dividing cells**
* Wide cell tropism (many cell and tissue types)
* Large cloning capacity
* Can be grown to high titer
Disadvantages
* Immunogenic
* Transient transgene expresion (not long lasting)
802
What are the major differences between adenovirus vectors and adeno-associated viral vectors?
Adenovirus vectors have a **can contain larger genes**
Adeno-associated viral vectors **are less immunogenic**
Both have wide cell tropism
803
Give an example of a disease that is a target for *ex vivo* gene therapy
SCID
804
Give some examples of diseases that are targeted for *in vivo* gene therapy
Cystic fibrosis (inherited)
ALS aka Lou Gehrig's Disease (acquired)
Parkinson's disease (acquired)
805
What is the bystander effect in gene therapy?
Why is it imporant?
Bystander effect = only a few cells need to have induced gene expression to eradicate the whole tumor
Due to transfer of effector enzyme to adjacent cells through GAP junctions
Example: Induced expression of Type I Thymidine kinase (TK) that render cells sensitive to non-toxic prodrugs. Phosphorylated GCV, made from the prodrug, is transferred to adjacent cells, integrates into DNA, causes apoptosis
806
Why are somatic cells targeted for gene therapy when targeting germ cells would seemingly have a more efficient, long-term effect?
Ethical and safety problems altering germline cells
* Changes are heritable
* Unknown long-term effects
807
What are the two major determinants of success of gene therapy?
1. Ability to get the transgene into the appropriate cell
2. Abiltiy to express the transgene in that cell
808
What are the three requirements for feasibility of a gene therapy protocol?
1. Need to know the gene responsible for disease
2. Need a wild type allele of the gene to express
3. Need a convenient mentod to target the functional WT gene to appropriate sites
809
What is a syngenic transplant?
A transplant between genetically identical individuals
(Between identical twins)
810
Do you express MHC proteins from your mother or your father?
Both
Expression of MHC proteins is **codominant**
811
Which genes encode the MHC I proteins?
Which genes encode the MHC II proteins?
MHC I: Encoded by HLA-A, HLA-B, HLA-C
MHC II: Encoded by HLA-D (DR, DP, DQ)
812
Why is it important to match HLA proteins in transplants?
Close matching minimizes the immune response of the host to the graft
HLA proteins that are closely matched can be recognized as "self" by T cells, even if they come from another individual
813
A 10/10 HLA match is considered a perfect match.
Why are immunosuppressants still given to donors recieving a 10/10 HLA-matched organ?
A 10/10 HLA match means that all of the major HLA antigens are matched
There are still many minor antigens that could still trigger an immune response from the host
Pharmacologic immunosuppression is still necessary for a transplant between any individuals that are not genetically identical
814
What is the difference between organ rejection and graft vs. host disease?
Organ rejection = the **host attacks the graft**
Graft vs. host diseae = the **graft attacks the host**
(GVHD is most commonly seen when large numbers of lymphocytes are transplanted into a new host, i.e. hematopoietic stem cell or liver)
815
Describe chronic organ rejection
Time scale:
Mediated by:
Symptoms:
* Time scale: Months to years
* Mediated by: **CD4+ T cell response, macrophages**
* APCs present donor peptides to CD4+ T cells
* T cells secrete cytokines and activate **macrophages**
* ****This is a **Type IV hypersensitivity reaction**
* Donor specific antibodies can deveop, can contribute to chronic rejection in a **Type II hypersensitivity reaction**
* Symptoms:
* Vascular injury to donor graft
* Thickening/hardening of vessels
* FIbrosis
* Due to **chronic immune response, cytokines**
816
Describe acute organ rejection
Time scale:
Mediated by:
Symptoms:
* Time scale: Weeks (7-10 days after transplant)
* Mediated by: **CD8+ Cytotoxic T cells**
* The donor MHC is recognized as "non-self"
* Cytokine production by CD4+ helper T cells enhances killing of graft cells
* This is a **Type IV hypersensitivity reaction**
* Symptoms:
* Killing of graft cells results in decreased perfusion
* Necrosis of graft?
817
Describe hyperacute organ rejection
Time scale:
Mediated by:
Symptoms:
* Time scale: minutes
* Mediated by: Pre-formed antibodies
* Ex: anti-ABO antibodies
* Symptoms:
* Activation of complement damages endothelium and vessels: a **Type II hypersensitivity reaction**
* "White graft"
818
What is the difference between direct and indirect non-self MHC recognition?
Direct
* The **MHC I or MHC II from the donor** is recognized by the **recipient TCR**
* ****This does not fit with our paradigm of MHC restriction, because the donor's MHC I and MHC II **are not presented on self-MHC**
Indirect
* Phagocytosis of donor cells by host APCs
* Presentation of **donor MHC** peptides on **self-MHC I and self-MHC II**
* Fits better with MHC restriction paradigm
819
What test is used to determine whether a donor and a recipient are a good match?
Describe the test
Mixed lymphocyte reaction
* Donor lymphocytes are treated so they cannot divide
* Treated donor lymphocytes are mixed with recipient lymphocytes
* Recipient lymphocytes that recognize T cells as foreign will proliferate
* **More proliferation = more reactive to donor = less likely to have a successful transplant**
820
In which scenarios would the graft vs. host response be beneficial?
Killing leukemia or lymphoma in bone marrow transplants
The recipeints cells **need** to be killed; this is accomplished through the action of donor lymphocytes
821
Describe graft vs. host disease (GVHD)
Mediated by:
Mechanism:
Symptoms:
* Mediated by: **Immunocompetent donor T cells**
* Mechanism:
* Donor T cells expand in the immunosuppressed recipient
* Recognize recipient cells as "non-self" and destory them
* Usually recognize MHC antigens
* **Type IV hypersensitivity reaction**
822
Which transplants are most likely to cause graft vs. host disease?
Why?
Hematopoietic stem cell (bone marrow)
Liver
High number of donor lymphocytes are transplanted; likely to recognize new host as foreign
823
Why are corticosteroids a common choice for immunosuppression in transplant recipients?
Corticosteroids suppress the response of the **innate and adaptive immune systems**
* Increase transcription of IL-10
* General suppression of inflammation
* Can induce apoptosis of immune cells
824
Is immunosuppression required in transplants between identical twins?
Why or why not?
Low-level immunosuppression is recommended initially, but can most likely be safely stopped after a little while
Genetically identical individuals may have some differences in antigen presentation due to small differences in the development of their immune systems
825
A patient complains of rash, diarrhea, and jaundice a few weeks after recieving a transplant
What is the most likely cause?
Graft vs. Host Disese
826
Which two processes are involved in developing T cell central tolerance?
Which cells mediate each process?
**Positive selection:** Thymic cortical epithelial cells express MHC without any costimulatory activity
- Thymocytes must recognize self MHC to continue
**Negative selction:** Bone-marrow derived APCs in the thymic medulla present self antigen (generated by AIRE expression) on MHC
- Tight binding -\> apoptosis or TReg
- Weak binding -\> T cell maturation
827
Where does B cell positive selection occur?
Nowhere
(B cells do not undergo positive selection)
828
Which lymphocytes undergo somatic gene recombination during maturation?
Which genes mediate this process?
Both B cells and T cells
Rag1/Rag2
829
Which cells undergo receptor editing during maturation?
B cells only
830
How does a T cell become anergized to an antigen?
Is anergy permanent?
Anergy is induced when a T cell sencounters an antien on self-MHC **without costimulatory molecules.** The T cell **will not produce IL-2 in response to this antigen**
Anergy can be overcome **if the T cell is exposed to high levels of IL-2** (ex: during a robust inflammatory response). This can cause autoimmunity
831
What are the three major mechanisms of peripheral tolerance?
What is the major mediator of each process?
1. **Clonal anergy:** Lack of costimulatory molecule on APC
2. **Clonal deletion:** FasL-mediated Activation-Induced Cell Death (AICD)
3. **Regulation/suppression:** TRegs secrete IL-10, TGF-beta
832
Describe the process of clonal deletion
* T cell repeatedly encounters high levels of self-antigen in the periphery
* Repeated TCR activation -\> T cell expresses FasL
* FasL binds the Fas receptor expressed on B cells and T cells
* FasL:Fas induces caspase cascade
* Apoptosis
833
Which autoimmune disease occurs when the Fas-FasL response is deficient?
Autoimmune lymphoproliferative syndrome (ALPS)
Symptoms are similar to systemic lupus
T cells that react to self-antigen are not deleted
834
Describe the role of TRegs in peripheral tolerance
TRegs (especially CD4+CD25+Foxp3+) are important
Direct cell-cell contact, as well as expression of IL-10, TGF-beta
835
How can Th1 cells inhibit allergic reactions?
Th1 CD4+ helper T cells secrete IFN-gamma, which inhibits the Th2 response
Inhibition of Th2 response = inhibition of allergic response
836
How can Th2 cells inhibit excessive Th1 inflammatory effects?
Th2 cells secrete IL-4, which inihibts Th1 effector functions
Inhibition of Th1 = inhibition of excessive inflammation
837
How is a normal immune response turned off?
* Eliminate the antigen
* Programmed cell death or apoptosis of responding lymphocytes
* CTLA-4 and PD-1 expression
* 48-96 hours after initial T cell activation
* Inhibit co-stiumlation by preventing CD28 from binding to B7 (CD80/86)
* Inhibit TCR signal transduction
* **Note: small subset of T cells remain; they become memory T cells**
838
What is the unifying feature of all autoimmune diseases?
All autoimmune diseases reslt from a breakdown of tolerance
839
What are the 4 main pathways by which autoimmune diseases develop?
1. Inappropriate expression of costimulatory molecules
2. Infection
3. Molecular mimicry
4. Mutation or defective function of regulatory molecules
840
How can tissue injury or damage cause an autoimmune response?
Damage to tissues can release self-antigen that was sequestered away (hidden from immune system)
These antigens activate local APCs to phagocytose them
This upregulates the expression of co-stimulatory molecules
**The antigens are presented to T-cells in the presence of costimulation -\> Autoimmune disease**
Note: These T-cells that react to the self antigen slipped through central tolerance mechanisms
841
What is epitope spreading?
How can it lead to autoimmune disease?
Epitope spreading: When an immune response against a microbe leads to an immune response against an unrelated self-antigen
Often occurs when infection -\> tissue destruction -\> exposes a typically-sequestered self-antigen to the immune system
Phagocytosis and presentation by APC -\> immune response to self-antigen
842
How can infection lead to autoimmune disease?
* Tissue injury or damage due to inflammatory response -\> epitope spreading
* Induction of APC maturation
* Increased expression of costimulatory molecules
* Infections can alter self antigen to a **neoantigen**
Note: Many of these responses occure when self-reactive T-cells have slipped through central tolerance. This typically isn't a problem when antiens are sequestered away or co-stimulation is low
843
Give an example of molecular mimicry
Rheumatic fever
M protein of strep. pyogenes resemles cardiac myocytes -\> immune response to M protein destroys cardiac myocytes
844
Which hereditary mutaitons can predispose an individual to autoimmune disease?
Mutations in...
* Fas/FasL
* Downstream caspase machinery that induces apoptosis
* AIRE
* Problems creating central tolerance
845
What is the gold standard of treatment for autoimmune diseases?
Specifically target only the autoreactive T cells or B cells:
## Footnote
**Induced antigen-specific tolerance**
846
What is the predicted effect of a mutation that results in loss of expression of CTLA-4 or PD-1?
Autoimmune disease
Increased co-simulation = reaction to self tissues
(Normally CTLA-4 and PD-1 inhibit co-stimulation)
Note: Loss of CTLA-4 means that TRegs are not working
(TRegs express CTLA-4, but all cells may express PD-1?)
847
Which cells are most important in recognizing tumor cells as "non-self?"
* CD8+ cytoxoic T cells
* Recognize foreign antigen on tumor cell's MHC I
* NK Cells
* If tumor cell downregulates MHC I to avoid the T cell, the NK cell **recognizes the lack of MHC I**
848
Which two methods do NK cells use to kill tumor cells?
1. Direct killing of cells that lack MHC I
2. Binding to Fc portion of antibodies on the tumor cell -\> **Antibody-Dependent Cellular Cytotoxicity (ADCC)**
849
What 4 methods do tumor cells use to evade the immunes system?
1. Downregulate expression of tumor antigen
2. Decrease expression of MHC molecules to present antigen *(but NK cells may swoop in)*
3. Suppress T cell response through **production of anti-inflammatory cytokines**
4. Suppress T cell response through **expression of cell surface molecules that interact with inhibitory proteins on T cells**
* Example: Increase PDL1 expression on tumor cells -\> interact with PD on T cells -\> dampen response
850
From the tumor cell's perspective, why would it be beneficial to increase expression of PDL1?
If PDL1 on the tumor cell binds to PD1 on T-cells, it **dampens the immune response of the T cell**
851
Immune therapy can be used to treat cancer.
Which cells would be most affected by antibodies against PD1 or PDL1?
Antibodies against PD1 or PDL1 would **prevent the PD1:PDL1 interaction** (PD1 on tumor cell, PDL1 on T cell), thus **preventing the down-regulation of T cell activation**
**The result: Increased T cell activation -\> increased killing of cancer cells**
(Normally, the PD1:PDL1 downregulates T cell activity)
852
How are monoclonal antibodies used in the treatment of cancer?
Monoclonal antibodies can be targeted against tumor antigens
The antibodies bind to the tumor antigens and lead to killing of tumor cells
853
What si the most successful and widely used monoclonal antibody against tumor cells?
anti-CD20 (rituximab)
Binds CD20 on B cells (normal and malignant), leading to the killing of these cells
Used to treat B cell cancers (ex: non-Hodgkin lymphoma)
854
Describe the following IgE-mediated immune response:
**Systemic allergen**
Location:
Reaction:
IgE-mediated = mast cell activation
Location: All blood vessels
Reaction: Systemic anaphylaxis (ex: bee sting)
855
Describe the following IgE-mediated immune response:
**Ingestion**
Location:
Reaction:
IgE-mediated = mast cell activation
Location: Mast cell activation in **GI tract**
Reaction: Smooth muscle contraction -\> Vomiting, diarrhea
Location: Mast cell activation in **skin**
Reaction: Disseminated swelling under the skin
856
Describe the following IgE-mediated immune response:
**Inhalation**
Location:
Reaction:
Location: Mast cell activation **beneath the nasal mucous membrane**
Reaction: Sneezing, runny nose (allergic rhinitis, hay fever)
Loaction: Mast cell activation **in lower airway**
Reaction: Bronchial constriction (allergic asthma)
857
Describe the following IgE-mediated immune response:
**Skin administration of an allergen (ex: insect bite)**
Location:
Reaction:
IgE-mediated = mast cell activation
Location: **Local**
Reaction: **Wheal and flare (hives)**
(Wheal = swelling, flare = redness)
858
What treatment strategies are used to treat Type I allergic reaction?
Asthma
* Epinephrine
* Sodium cromolyn
Allergies
* Corticosteroids
* Anti-histamine
* Leukotriene receptor antagonist
Anaphylaxis
* Epinephrine
859
What is the goal of allergy shots?
Decrease levels of IgE specific for a given antigen (IgG often rises as a result)
(Suppress Th2 resposne, promote Th1, TReg)
860
Why would anti-IL-4 or anti-IL-13 antibodies treat allergies?
IL-4 and IL-13 promote class switching to IgE
Antibodies against these ILs decreases IgE response
861
Which antibodies mediate Type II allergies?
List 6 examples
Type **II** hypersensitivity = **2** words for _Ig**G** and Ig**M**_ against cell surface or ECM antigens
**GArG-MAtH**
* **G**oodpasture's syndrome
* Antibodies specific to Type IV collagen attack basement membrane of kidney glomeruli
* **A**cute **r**heumatic fever
* Antibody against M protein of strep pyogenes attacs cardiac myocytes
* **G**raves disease
* Thyroid disease: autoantibodies bind to the TSH receptor, mimicking natural ligand -\> excess thyroid hormone production
* **M**yasthenia gravis
* Autoantibodies destory ACh receptors
* **A**utoimmune **t**hrombocytopenic purpura
* Antibodies against platelet surface antigens
* **H**emolytic disease of the fetus
* Maternal IgG specific for fetal blood group antigens cross placenta and destory fetal RBC
* Treat wtih Rhogam during delivery
862
Which antibodies mediate Type III hypersensitivity reaction?
Give 4 examples
**Soluble IgG/IgM** immune complexes
**PSAS**
* **P**ost-streptococcal glomerulonephritis
* Only kidney =\> antigen binds here, then antibody follows
* **S**erum sickness
* **A**rthus reaction
* **S**ystemic lupus erythematosus (SLE)
863
Which cells mediate Type IV hypersensitivity reactions?
Give 3 examples
**T cells**
**Th1 CD4+ helper T cells** -\> Delyaed type hypersensitivity
**CD8+ cytotoxic T cells** -\> Classic cytotoxic reaction against cells expressing self or foreign antigen
**Examples = CTC**
* Contact dermatitis
* Poison ivy product modifies host self-antigen
* New epitope is not recognized, presented to CD8+ cytotoxic T cells
* Tuberculin test
* Th1 CD4+ T cells are activated, produce cytokines, chemokines, cytotoxins
* Celiac disease
* Th1 CD4+ T cells respond to peptides from gluten, presented on MHC II
864
What are the likely target organs for type III hypersensitivity reactions?
Whye?
Type III = soluble immune complexes
Attack kindey, glomerulus, synovium of joints, blood vessels
**Why?** Immune complexes float around in the blood and are trapped or formed in the above tissues
865
Why are Type II hypersensitivity reactions (diseases) organ specific?
Type II reactions are mediated by IgG and IgG that are membrane bound (in cells or basement membrane), resulting in a localized response
866
What factors might predispose an individual to type I hypersensitivity
Atopic (hyperallergic) individuals may have genetic changes in IL-4 and/or MHC II genes
They may also have had different exposures early in life, or have an altered gut microbiome
867
Is serum sickness acute or chronic?
Why?
Acute
Antigen/antibody complexes are produced as a result of IV bolus of a soluble antigen
Resolves after complexes are cleared
