EXAM 2: Master Deck Flashcards
1
Q
A child with reoccurring pyogenic infections such as those caused by Staphylococcus aureus suggests a defect in what parts of the immune system?
Group of answer choices
T-cell development
Antibody, complement, or phagocyte function
Eosinophil function
T-cell responses
A
Antibody, complement, or phagocyte function
2
Q
A boy with a mutated IL2RG gene will most likely present with
Group of answer choices
High antibody levels
Low T cell count
Low B cell count
No symptoms
A
Low T cell count and NK
3
Q
The following flowing flow cytometry plot comes from a boy with reoccurring pyogenic infections. Based on plot, what disease does this child most likely have?
Hint CD3 is a marker for T cells and CD19 is a marker for B cells
Group of answer choices
XLA
Perforin deficiency
Elastase deficiency
SCID due to gamma chain deficiency
A
XLA
4
Q
True or False
The immune system cannot control nor eliminate an HIV infection
Group of answer choices
True
False
A
False
5
Q
Which of the following is true regarding immune amnesia after a measles infection?
Group of answer choices
Memory cell diversity is unchanged but antibody levels are low against other antigens
None of the answers provided are true
Memory cells against measles antigens are high but low for other antigens
Memory cells against measles antigens and other antigens are low
A
Memory cells against measles antigens are high but low for other antigens
6
Q
The site where immune cells are activated is called the ________ site
A
Inductive
7
Q
The following intestinal epithelial cells fall under the secretory subset except
Goblet Cell
Paneth cell
Tuft cell
Microfold Cell
A
Microfold cells
8
Q
What is the function of an intraepithelial lymphocyte?
None of the answers provided
Travel to the lymph nodes to activate B cells
Activate the innate immune response
Eliminate IEC that are infected, damaged or stressed
A
Eliminate IEC that are infected, damaged or stressed
9
Q
True or False
Treg cells are the primary T cell response in mucosal tolerance
True
False
A
True
10
Q
All of the following are true regarding the microbiota except
All of the answers provided are functions of the microbiota
Plays a role in the development of the mucosal immunity
Prevents the colonization and/or overgrowth of pathogenic microbes
Provides factors to maintain mucosal tolerance
A
All of the answers provided are functions of the microbiota
11
Q
Which hypersensitivity reaction is mediated by immune complexes?
Type III
Type I
Type II
Type IV
A
Type III
12
Q
What is common among all IgE mediated hypersensitivity reactions?
Degranulation of mast cells
Tissue damage by immune complexes
Tissue damage by cytokines production by T cells
Degranulation of neutrophils
A
Degranulation of mast cells
13
Q
True or False
Allergic reactions caused by urushiol in poison ivy require the binding of a host protein in order to illicit and immune response
True
False
A
True
14
Q
Bronchial constriction, increased mucus production, airway inflammation, and bronchial hyperactivity are all responses to what reaction or disease?
Select all that apply
Asthma
Urticaria
Systemic anaphylaxis
Food allergy
A
Asthma, Rest are vasodilation not constriction
15
Q
True or False
According to the hygiene hypothesis, a child raised in a developed urban environment will less likely develop allergies and autoimmune diseases compared to a child raised in a developing rural environment
True
False
A
False
16
Q
True or False
In multiple sclerosis, antibodies are mainly responsible for activating the immune system against the myelin sheath
True
False
A
False
17
Q
In the following image, what will be the response to the graft that is transplanted into the host mouse (recipient)?
The graft will not be rejected
The grafted will be rejected
A
The graft will be rejected
18
Q
________ is when the immune system targets transplanted tissue
A
Alloimmunity
19
Q
Cross-reactive antibodies that cause damage to the heart valve tissue occurs in which disease or condition
Select all that apply
Rheumatic fever
Grave’s disease
Multiple sclerosis
hemolytic anemia
A
Rheumatic fever
20
Q
True or False
Damage to an immunologically privileged site can induce an autoimmune response
True
False
A
True
21
Q
Which of the following APC mainly presents antigens to activate naive T cells?
Plasmacytoid dendritic cell
Conventional dendritic cell
B cell
Macrophage
A
Conventional dendritic cell
22
Q
True or False
Monocyte-derived dendritic cells directly present the antigen to naive T cells
True
False
A
False
23
Q
Match the following signals with their purpose in the T cell:
TCR/co-receptor and MHC:peptide complex, Co-stimulatory signals, Cytokines
Bank:
Survival and proliferation, Activation of the T cell, direct differentiation
A
TCR/co-receptor and MHC:peptide complex
Activation of T cell
Co-stimulatory signals
Survival and proliferation
Cytokines
Directs differentiation
24
Q
Based on the diagram below, the CD4 T cell will develop into which subset?
Th1
Th2
Th17
Tfh
Treg
A
Th1
25
What is the function of serglycin in a cytotoxic T cell?
Facilitates the release of cytochrome C
Forms pores on the target cell
Serves as a scaffold to form complexes with perforin and granzymes
Activates the apoptosis pathway in the target cell
Serves as a scaffold to form complexes with perforin and granzymes
26
Which if NFkB pathway is illustrated below?
Canonical
Noncanonical
Canonical
27
______ zone is the site where centroblast proliferate
Dark
28
Which of the following antigens can result in polyclonal B cell activation?
TI-2
TD
TI-1
TI-1
29
True or False
IgG can directly cross the placenta without a carrier
True
False
False
30
Double strand breaks is required for which of the following
Somatic Hypermutation
Antibody class switching
Dendritic cell maturation
CD4 T cell differentiation
Antibody class switching
31
Which of the following T helper cell subset is illustrated below
Th1
None of the answers provided
Th17
Th2
Th2
32
What is a complement fixation test?
- Used to detect presence of antibody or antigen in sera
33
What is ELISA?
- Enzyme-linked immunosorbent assay
- Plate based assay to detect and qualify solubles (peptides, proteins, antibodies, hormones
- Uses antibody conjugated to enzyme
- Horseradish Peroxidase (substrate TMB)
34
How is an ELISA carried out?
35
What is IGRA?
- Interferon gamma release assay
- Whole blood tests that can aid in diagnosis of tuberculosis
- Incubate blood with TB antigens, if person has TB they will have TB specific T cells
36
What is flow cytometry?
- Provides rapid multiparameter analysis of single cells in solution (NIH)
- Provides size, shape, complexity, fluorescence
- Uses forward scatter and side scatter fluorescence
- Enumberates and sorts cells
- 3 major components - fluidics, optics, electronics
37
What type of particles can be analyzed?
- Viruses, exosomes, bacteria, rbc, animal cells, plant cells, oocytes
- 100 um to 100 nm
38
What type of data can be gathered from flow cytometry?
- Histogram, Dot plot, Pseudocolor, Contour
39
What is forward scatter? What is side scatter?
FSC
- Indicates cell size
- Proportional to cell size
- Higher FCS is larger cell
SSC
- Indicates cells internal complexity/granularity
- More granules and organelles a cell has the higher the SSC
40
How are FSC and SSC plotted on a graph?
41
What is fluorescence?
- Tag cells using fluorescent antibodies to measure cell concentrations
- Measures single or multiple targets
42
What is Gating?
- Selecting of data points for analysis using graphical or numerical boundaries
43
How can cells be sorted in flow cytometry?
- Fluorescence activated cell sorting
44
What do secondary lymphoid structures do?
- Facilitate interaction of circulating T and B lymphocytes with antigen
- Makes surveilling entire body possible because antigen must be transported to secondary lymphoid to encounter naïve lymphocyte
(3)
45
What does the spleen do? Where do circulating pathogens delivered? What are periarteriolar lymphoid sheath (PALS) or follicles?
- Specialized to capture antigens that enter bloodstream
- Circulating antigens, B and T cells are delivered to **marginal sinus**
- Rich in dendritic cells, macrophages and marginal
zone B cells
- T and B cells leave marginal sinus and travel to PALS or follicle
- Reticular fibroblast makes chemokines (CCL 19TH,21) to attract T cell (CCR7) from the sinus
- Follicular dendritic cells make chemokines CCL 13TH to attract B cell (CXCR5) from sinus
46
How do antigens enter the lymph node? How do B and T cells enter?
- Antigens enter via **afferent lymph vessels** in subcapsular sinus
- Lined by phagocytes that trap free antigen/pathogens
- T and B cell enter via small blood vessel **High endothelial venules** (HEVs)
47
How are antigens transported to peyer's patch? Where do B and T cells enter? What do dendritic cells in peyer's patch do?
- Antigens transported from lumen via microfold cells (M cells)
- T and B cells enter via HEVs
- Antigen-loaded dendritic cells are surveyed by T cells in T cell zone, If antigen is unrecognized it will be transported to mesenteric lymph node for further surveying
48
Describe the recirculation of T cells through lymph vessels.
- A T cell starts at lymphatic capillaries and makes its way through afferent LVs. Afferent lymph vessels to lymph nodes where it can encounter an antigen presenting cell. T cell will travel through efferent lymph vessels through a series of lymph nodes until it reaches the Thoracic duct. After the Thoracic duct T cells will enter circulation to reach tissue and continue to cycle through. (7)
49
How is the development of secondary lymphoid tissue initiated?
- Initiation by lymphoid tissue inducer cells and cytokines of the tumor necrosis factor family
50
How does T cell entry to lymphoid tissue occur? What is it similar to?
- Entry is mediated by the sequential actions of adhesion molecules and chemokine receptors
- Similar to recruitment of leukocyte to inflamed tissue (9)
51
Do all tissue use the same adhesion molecules?
- No, different tissues use different adhesion molecules
- CCL19, CCL21, CCR7, L-selectin, Integrins
52
Describe the motility of T cells. What is in the surfaces of sinusoid-like spaces? How are follicular dendritic cells networks similar?
- Highly motile within T-cell zone to survey dendritic cells for cognate antigens
- Surface of sinusoid-like spaced decorated with CCL19 and CCL21
- Chemokines used to help transport T cells and attract dendritic cells
- Similar network formed by FDCs in B cell follicles and is decorated with B cell chemoattractant CXCL13
53
What do FRCs do?
- Produce extracellular matrix that forms a meshwork(conduit) in T cell zone
54
What happens if a naive T cell recognizes a specific antigen on the surface of an activated dendritic cell?
- Its locomotion is arrested and it is retained in the T cell zone
- Proliferation for several days = effector T cells and memory cells
- Most effector T cells exit the lymphoid organ and reenter the bloodstream to site of infection
- Others migrate to B cell zone where they participate in germinal center response to help make antibodies
55
Explain how T cell screening is very efficient. Outline the motility, density, surface area, TCR, and circulation rate is related.
- Each T cell has a high probability of encountering antigen anywhere in the body
- High motility of T cells, 2 cell diameters per minute
- High density of T cells and recruitment of dendritic cells in T cell zone
- Large SA of dendritic for MHC complexes and contact
- TCR is very sensitive to antigen, one peptide can be enough to activate MHC and some T cells
- High rates of circulation if T cell does not encounter its antigen
56
How many dendritic cells does a T cell encounter in an hour?
- 100 per hour
- Local inflammation stimulates marked increase in influx and decrease efflux of lymphocytes into and out of lymph node contributing to node swelling
57
How is the exit of T cells from the T cell zone controlled? What role do S1P and S1P lyase play in this?
- Exit is controlled by chemotactic lipid (sphingosine-1-phosphate) S1P
- There is a gradient bt T cell zone and lymph. S1P made by epithelial cells lining lymph vessels, lyase made by lymphatic tissue
- S1PR1 (receptor)
- Low levels on surface of naive T cells that recently entered T cell zone
- If S1PR1 does not recognize antigen, upregulated = directs cell into cortical sinus = into efferent lymphatic vessel
- Activated T cell upregulated CD69 = S1PR1 internalized. Eventually CD69 will fade and S1PR1 will reexpress
58
What MHC molecules is antigen presenting? What are the three major APCs?
- MHC II
- Dendritic cells, macrophages, B cells
59
What are the two major classes of dendritic cells?
- Plasmacytoid dendritic cells
- Sentinels for viral infections, produced by T1 interferons
- Conventional dendritic cells
- Present antigen to T cell, found in nonlymphoidal tissue particularly at barrier tissue sites (NLT)
- Lymphoid tissue found in T cell zone of secondary lymphoid tissue (LT)
60
What happens when a conventional dendritic cell activates?
- The maturation is stimulated and migration to T cell zone to induce naive T cell activation
Immature cDC
- Low expression of co-stimulatory molecules and cannot activate naive T cell
- Actively phagocytic
Mature cDC
- High expression of co-stimulatory and MHC molecules can activate t cells
- Non-phagocytic
61
What routes of antigen processing and presentation are possible by dendritic cells?
- Receptor mediated phagocytosis, Macropinocytosis, viral infections, cross presentation after phagocytic or macropinocytic uptake, transfer from incoming dendritic a cell to resident Dendritic cell
- Different responses vary on viruses, bacteria, or fungi
62
What is the purpose of having subsets of conventional dendritic cells?
- Some are specialized for different modes of antigen presentation
- cDC1- T1 conventional dendritic cell
- Specialized for activating/priming naive CD8 T cells
- cDC2 - T2 conventional dendritic cells
- Specialized for activating/priming CD4 T cells
63
What are Monocyte-derived DCs? What are Langerhans cell?
- MoDCs take up antigen and deliver it to T cell zones
- Transfer antigen to LT-resident cDCs
- Specialized macrophages that reside in epidermis
- no cDCs in skin
- Take up antigen and transfer it to LT resident cDCs
64
How can MHC molecules and TCRs interact?
- Transient binding of T cells to dendritic cells
- Transient adhesion interactions are stabilized by specific antigen recognition
65
What type of signals can be delivered from cDCs to activate naive T cells?
- Interactions bt TCR/coreceptor and MHC:peptide complex, essential for activation
- Co-stimulatory signals, essential for Proliferation and survival
- Cytokines, essential for directing differentiation
66
What preparations occur when a T cell is activated?
- Induces metabolism to prep for rapid clonal expansion and differentiation
- Naive T cells have condensed chromatin arrested in G0
- Within hours of activation, the cell will undergo metabolic shift and change in morphology to prep for cell division
67
What is occurring in this image?
- Naive T cells is being activated by TCR and CD-28 mediated signaling leading to waves of signaling proteins leading to gene expression and cell cycle progression and clonal expansion
68
What happens to T cells after antigens are cleared?
- Most will be cleared via apoptosis (clonal contraction)
- 5-10% remain as memory T cells
69
What does the rapid expression of IL-2 result in? What Cytokines respond?
- Allow for the activation of T cells to respond to cytokines
- IL-2R
- IL-2RB/CD122, IL-2R lambdaC/CD132, IL-2Ra/CD25
70
What does IL-2 promote? What do Treg cells do?
- Promotes proliferation and differentiation However it more importantly generates and maintains Treg cells
- Mice without IL-2 have uncontrolled T cell proliferation and autoimmunity
- Treg cells cannot produce IL-2 and produce IL-2Ra
- take up most IL-2 until activated T cells express IL-2Ra
71
How are IL-2 and IL-2Ra induced in activated T cells?
- Secretion and expression are deferentially induced
- Based on TCR signal strength
- IL-2 Produced by one cell binds to high affinity IL-2 receptor of different T cells (paracrine)
72
What happens with receptors when T cell activation occurs? Why does this occur
- Inhibitory and co-stimulatory receptors are engaged to control clonal expansion and contraction
- CD80 and CD86 are important costimulatory molecules on APCs that bind to CD28 on T cells
73
What does CTLA-4 do? What can activate NFkB pathway?
- Inhibitory receptor for B7 molecule
- Multiple members of the TNF-TNFR superfamily can activate the pathway to sustain T-cell response
74
What happens to proliferating T cells?
- Differentiate into effector T cells programmed for altered tissue homing and loss of requirement for costimulation to act
- Cells presenting antigen on MHC may not express costimulatory molecule
75
What type of cell surface molecules are found on naive vs effector cells?
- TCR, L-selectin, CCR7, LFA-1, CD45RO
76
How can CD8 T cell be activated?
- Will become cytotoxic effector cell
- Can take up cDC1
- APC stimulation to induce expression of CD40L and IL-2 which cascade leading to production of IL-12
77
WHat subsets do CD4 T cells differentiate into? What are the two pathways of Treg development?
- TH1, TH2, TH17 are called non-TFH cells
- Positive selection in thymus
- Naive CD4 T cells develop into Treg in peripheral lymphoid organs (pTreg)
78
What role do cytokinesplay in the differentiation of CD4 T cells?
- Antigen presenting cells (mainly dedritic) and other innate immune cell can provide cytokines to induce naive CD4 development
79
What are TFH cells and how do they develop with respect to CD4 T-cells?
- Effector CD4 T cell subsets develop in concert
- TFH cells can produce Cytokines that influence isotype class-switching
- Primarily produce IL-21 which is important for optimal production of high-affinity, class-switched antibodies
- Helps antigen activated B cells develop into effector cells of different isotypes
80
What transcription factor is important for TFH development? What happens to naive T cells that produce IL-2?
- BCL-6 is important for TFH development. Expresses chemokines receptor CXCR5 which is essential for TFH localization in follicles
- Naive T cells that produce IL-2 become TFH cells while those that do not become non-TFH cells
- IL-2 Induces expression of tf BLIMP-1 which represses BCL-6
81
When do peripheral Treg cells develop? How do mucosal surfaces maintain tolerance for microbiota? What happens to a naive T cell in the presence of IL-6?
- Naive t cells are activated in the presence of TGF-beta and IL-2 (produced by dendritic cells)
- All-trans-retinoic acid (at-RA) binds to RA receptor (RAR) on T cell
- IL-6 and proinflammatory Cytokines are absent
- Development of pTreg maintains tolerance of microbiota
- In presence of IL-6 naive T cell will develop into Th17 cell
- Occurs when dendritic cell senses the antigen through TLR
- microbiota or pathogen penetrate epithelial barrier
82
How can CD4 T cell subsets be regulated?
- Subsets cross regulate each other's differentiation through Cytokines production
- For immune response to be controlled efficiently, coordinated effector response must be orchestrated by one dominant subset
83
How can a T cell ensure it releases its effector molecules correctly?
- A synapse can form between the T cell and target to direct the release of the effector molecules
84
How are the effector functions of T cells determined?
- Determined by the array of effector molecules they produce, which can act locally or at a distance
85
How can cytotoxic T cells induce target cells to undergo programmed cell death?
Extrinsic (death receptor)
- Activated by FAS ligand (FasL)
- Formation of the death-inducing signaling complex(DISC)
Intrinsic
- Activated by the cytotoxic granules
- Formation of the apoptosome
86
What are the three major proteins in the granules of CD8 T cells? Why is apoptosis the preferential method of killing infected cells?
- Perforin - helps deliver contents of granule into cytoplasm of target cell
- Granzymes - serine proteases activate apoptosis when inside cytoplasm of target cell
- Granulysin - has antimicrobial action to induce apoptosis
87
How do T cells recognize their target and not harm other cells?
- Effector molecules are released from cytotoxic granules of a cytotoxic T lymphocyte in a highly polar way to prevent spillover to nearby cells
88
What else can cytotoxic T cells release?
- Cytokines IFN-gamma, TNF-a, LT-a all contribute to host defense
89
What does the NFkB family consist of? Do the Del homology domain have transcriptional activation domains?
- 5 transcription factors P50, p52, RelA(p65), c-Rel, RelB
- Form dimers through RHD
- RelA/p50, c-Rel/p50, RelB/p52
- RelA, c-Rel, RelB contain transcriptional activation domains (TADs)
- p50 and p52 do not have TAD and need to be bound to TAD-containing protein
- They're all derived from p105 and p100 precursor
- Contain ankyrin repeats (ANK)
- Inhibited by IkB proteins in cytoplasm
90
What is the canonical/classical pathway? What is the noncanonical pathway?
Canonical
- IKK complex is activated by transforming growth factor-beta-activated kinase 1 (TAK1)
- Activated IKK phosphorylates IkBalpha
- Degraded by proteosome
- Predominant dimer is RelA/p50
Noncanonical
- IKKalpha is activated by NFkB-inducing kinase (NIK)
- Phosphorylates p100
- Undergo processing to p52
- Predominant dimer is RelB/p52
91
What is humoral immunity? How do antibodies protect (3)?
- Immunity due to proteins in the blood
- Complement and antibodies
- Protects extracellular spaces
- Neutralization
- Opsinization
- Complement activation
92
How are B cells activated? What are three signals like T cell activation?
- Activation by antigen involves signals from BCR and either helper T cells or microbial antigens
- BCR
- Costimulatory with TCR or microbial antigens
- Cytokines
93
How does B cell activation by antigen and helper T cells occur?
- Thymus dependent antigen
- Requires T cell help to produce antibodies
- Signaling by BCR is enhanced by co-receptors CD21, CD19 which interact with C3b on opsinized microbial surfaces
- TCR and co-stimulation provides second signal
94
What causes the transcription factor STAT3 to become activated? What happens?
- IL-21 actives the tf which enhances B cell proliferation and survival
95
How does a thymus independent antigen activate a B cell?
- Do not require T cells to produce antibodies
- TLR may provide second signal
- Less affinity and less functionally versatile
- Mostly IgM antibodies
- Two types of antigens
96
What does linked recognition of antigens result in?
- Linked recognition of antigen by T or B cells promotes robust antibody response
- Epitopes recognized by both B and T cells must be physically linked
97
What happens when a B cell encounter its antigen?
- B Cells that encounter their antigens migrate toward the boundaries between B and T cell areas in secondary lymphoid tissue
98
How do opsinized antigens entering the lymph nodes reach a Follicular dendritic cell and why do they go there?
- Opsinized antigens enter lymph node form afferent lymphatic vessel and bind are bound by receptors on macrophages. Antigens are then transported to Follicular dendritic cells which allow for the activation of memory and effector B cells
99
What do BAFF and APRIL do?
Promote B cell survival and differentiation
100
How is TFH cell development promoted?
- T cells express surface molecules and Cytokines that activate B cell to promote TFH cell development
- Activated B cells express ICOSL which is ligand for ICOS on T cell
- Signaling through ICOS completes TFH differentiation as it Induces Bcl-6
- Induction of SAP in TFH cells allow SLAM family receptors to mediate sustained contact with B cells
101
What are plasmablasts and plasma cells?
- Activated B cells that differentiated
- Plasmablasts are immature plasma cells that have the characteristics of activated B cells
- Proliferate, secrete antibodies, interact with T cells. Eventually die or mature into plasma cells and move into bone marrow
- Plasma cells are terminally differentiated effector B cells that secrete the most antibodies
102
What happens in the second phase of a primary B-cell immune response?
- Occurs when activated B cells migrate into follicles from the primary focus and Proliferate to form germinal centers
103
What is the mantle zone? What is the dark zone? What is the light zone?
- When germinal centers B cells displace the resting B cells towards the periphery of the follicle forming a mantle zone
- Site of proliferation of centroblasts. Express chemokine receptors CXCR5 and CXCR4
- Site of positive selection of centrocytes after somatic hyper mutation. Express CXCR5 but not CXCR4. Increased expression of BCR. Abundant FDCs for positive selection
104
What is the cyclic reentry of cells into the dark zone dependent on?
- Reexpression of CXCR4 on centrocytes
105
What happens to germinal centers B cells in the V region? How are mutations initiated?
- Undergo V region somatic hyper mutation and cells with mutations that improve antigen affinity are selected
- Intiated by the enzyme activation-induced cytidine daminase (AID)
- Expressed in extrafollicular and germinal centers B cells
- Mutation rate in V region is 10^3 vs 10^10 in other DNA regions
- Most mutations are detrimental which leads to apoptosis
- Involves class switching
106
What does positive selection of germinal centers B cells involve? Where do B cells move after hypermutation? What happens if a receptor has strong affinity? What if it has weak affinity?
- Involves contact with TFH cells and CD40 signaling
- After hyper mutation B cells move to the light zone
- If receptor has strong affinity on FDCs then B cell will internalize antigen and present it on MHC II molecule. TFH will recognize MHC II and will promote the B cells survival
- If receptor has weak affinity, Antigens on FDC cannot outcompete B cells with higher affinity and will die to apoptosis
107
What happens when when activation induced cytidine deaminase introduces mutations into genes transcribed in B cells?
- Deamination of cytidine results in uridine. Occurs in ssDNA during transcription
- When AID deaminates cytidine residues in the immunoglobulin V region, somatic hyper mutation is initiated
- When cytidine residues in switch regions are deaminated, class switch recombination is initiated
108
What pathways contribute to somatic hyper mutation after initiation by AID?
- Mismatch and base excision repair pathways
- Triggered by the presence of Uridine in DNA
- In Mismatch repair, DNA synthesis is error prone due to error prone polymerase (Pol n and Pol 0)
109
What does AID initiating class switching allow for?
Allows the same assembled VH exon to be associated with different Ch genes in the course of an immune response
110
What must occur in the switch regions?
- Transcription
- Switch region of isotype is determined by specific transcription factors activated by specific chemokines
- Transcription produced is sterile
111
What do Cytokines made by TH cells direct?
- Direct the choice of isotype for class switching in T dependent antibody response
ex. IL-4 will lead to IgG1 or IgE
112
What are Tl-1 antigens?
- Antigens that do not require T cell help to induce antibody response
- Helps in early stages of infection
Ex. B cell mitogens, LPS. Activates immature and mature B cells. Do not lead to affinity maturation nor memory B cells
113
What are TI-2 antigens?
- Highly repetitive structures such as bacterial capsule
- Can only activate mature B cells. Marginal B cells. Infants lack marginal B cells
114
What are some qualities of TD antigens, Tl-1 antigens, and Tl-2 antigens?
115
Where do antibodies of different classes operate(distribution) and what are their effector functions (IgM, IgD, IgG1, IgG2, IgG3, IgG4, IgA, IgE)
116
How are immunoglobulin classes distributed in a pregnant woman?
- IgG and IgM are primarily in blood and both activate compliment
- IgG and monomeric IgA are the major antibodies in extracellular fluid within the body. IgA mainly responsible for neutralization
- Dimeric IgA predominates in secretions across epithelia (breast milk)
- IgE mainly associated with mast cells just beneath epithelial surfaces (resp, gastro, skin)
- Fetus recieves IgG from mother by transplacental transplant
117
How are IgA and IgM transported across the epithelial layer?
- Polymeric immunoglobulin receptor binds to the Fc region and transports them
118
What does neonatal Fc receptor do?
- FcRn carries IgG across the placenta and prevents IgG excretion from the body
- Baby can get IgA via breast milk to protect the baby's gut
119
What do high affinity IgG and IgA do?
- Neutralize toxins and block infectivity of viruses and bacteria
120
Outline the steps involved in antibodies blocking adhesins from being uptaken.
- Bacteria binds to surface via adhesins and some is internalized via vesicle and may propagate
- Antibodies are able to block colonization and uptake
121
What happens when an antigen:antibody complex binds to C1q?
- Activation of the complement pathway
122
What do complement receptors and Fc receptors contribute to?
- The removal of immune complexes from circulation
123
What is the purpose of the Fc receptors of accessory cells?
- Signaling receptors for immunoglobulins of different classes
- A variety of Fc receptors can be found on macrophages, neutrophils, eosinophils, platelets, Langerhan cells, mast cells, basophils, and B cells with a variety of effects
124
How are Fc receptors on macrophages activated and what happens?
- Activated when antibodies bound to surface of pathogens and enable phagocytes to ingest and destroy pathogens
- Can involve C3b and CR1
125
How do Fc receptors activate NK cells?
- Antibodies bind to antigen surface, Fc receptors on NK cells recognize antibodies and cross linking signal results in target cell dying to apoptosis
126
Why are mas cells relevant to Fce receptors?
- Mast cells and basophils bind IgE antibody via high affinity Fce receptor
- Antibody is bound to receptor
- Initiate the immune response at epithelial surfaces
- Recruit and promote inflammation
- Play major role in allergies
- Allergens bind to antibodies
- Trigger muscle contraction to help expel parasite
127
What is histamine?
- Hormone/neural transmitter
- Different receptors found in different cells
- Mechanism of action is dependent on receptor and cell type
128
What is IgE mediated activation of accessory cells?
- Plays an important role in resistance to parasite infection
Steps:
1. Activated CD4+ results in IgE production
2. Mast cells is activated by toxic proteins
3. Eosinophils are activated resulting in deganulation
4. S IgA produced to kill infection
129
What are the stages of immune response?
Primary
- Adaptive immune response that follows first exposure of a particular antigen
Secondary
- The immune response that follows second exposure to a particular antigen
130
What happens when someone experiences severe COVID-19?
- Their viral load continues to rise as does the innate immunity to try to compensate, T cell levels will remain low
- For asymptomatic, the innate immunity rises and falls quickly as does the viral load
131
Outline the steps involved in a infection penetrating epithelium resulting in the activation of the adaptive immune system.
1. Pathogens will enter the epithelium which Induces antimicrobial peptides, phagocytes, and complement to destroy invaders
2. COmplement activation occurs. Dendritic cell will capture antigens and travel to lymph node. NK cells are activated. Phagocytic action occurs, and Cytokines and chemokines are produced.
3. Once antigen is trapped in lymphoid tissue, adaptive immunity is initiated by dendritic cells
4. Infection will be cleared by specific antibody, T cell dependent macrophage activation and/or CD8 cytotoxic cells
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How do ILCs and T cells differentiate? What are the cytokines and their isotypes?
Effector Modules, NK cells, naive CD8
133
What are the main antibody isotypes found on innate effector cells?
- IgG1, IgG3, IgA, IgE
134
What are MAMPs?
- Microbial-associated molecular patterns are expressed by different types of pathogens which stimulated distinct Cytokine responses from innate sensor cells
- Dendritic cells, macrophages, epithelial cells, specialized tuft cells
- Subset of ILCs are early responders of immune response
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What are cytotoxic ILCs? Group 1? Group 2? Group 3?
- IL-12,15
- IL-12,18
- TSLP, IL-25,33
- IL-23,1beta
136
What do CD4 T cells do to effector functions?
- Augment the effector functions of innate immune cells
137
What do TH1 cells do to host response? Why must TH1 activation of macrophages be regulated?
- TH1 cells coordinate and amplify host response to intracellular pathogens through classical activation
- Intracellular bact that cannot be killed by macrophages. Various mechanisms such as inhibiting fusion of phagosome with lysosome. Activation will enhance intracellular killing. Induction of key lysosomal enzymes will occur
- Activation of macrophages by TH1 cells must be regulated to avoid tissue damage
- Through orientation and secretory machinery towards macrophage
- Targeting only cells with antigen presentation on MHC II
138
What are the ways in which TH1 effector cells can function against infections by intracellular bacteria?
139
How is tuberculosis dealt with by T cell immunity?
- Tb taken up by macrophage is dealt with by TNF, IL-1, Vita D or C and if this fails CD8 T cell kills phagocyte and a no uninfected macrophage tires again
140
What happens if there is chronic activation of macrophages due to intracellular pathogens not being cleared?
- Ganulomas form
- Core includes multinucleated giant cells which are fused macrophages
- Surrounded by large macrophages often called epithelioid cells
- In granulomas caused by mycobacteria the core usually becomes necrotic (caseous necrosis) because of a cheese like consistency of material that accumulates in the necrotic centers
141
What do TH2 cells do?
- Coordinate type 2 responses to expel intestinal helminths and repair tissue injury
142
What do TH17 cells do?
- Coordinate type 3 responses to enhance the clearance of extracellular bacteria and fungi
143
How can effector T cells be activated ?
- Effector T cells can be activated to release Cytokines independently of antigen recognition
- T cells can be activated by pairs of Cytokines, independently of antigen recognition by T cell receptor
- Same pair of Cytokines that activate the ILC of the same subset
- Acquire innate-like functional properties that allow T cells to amplify different types of immune responses without the requirement for antigen recognition
144
How are CD4 T cells able to adapt during antipathogenic responses?
- Effector CD4 T cells demonstrate plasticity and cooperatively
- T cells can transition into different Cytokines producing cells based on local inflammatory environments or as a result of cooperatively bt different T cell subsets
145
What happens when your body encounters salmonella?
- As Salmonella enters, Macrophages capture them and mucus layer thickens and more antimicrobial peptides are produced. Neutrophils are recruited and the bacteria is cleared as the mucus is expelled from the body resulting in diarrhea
146
How long does immunity last after infection or vaccination?
- Long lasting
- Memory is sustained by long-lived, antigen specific lymphocytes that were induced by original exposure and persists until second encounter
147
Compare naive T cells to memory T cells. How does secondary immune response work?
- Persist at numbers 10-100 times greater than memory T cells
- More sensitive to antigens
- Faster proliferation, and more robust response when same dose of antigen
- More rapidly displayed heightened effector response
- Have a greater range of surveillance capabilities
- When second exposure, APCs activate memory T cells and memory helper T cells and memory B cells resulting in a faster response
148
How is the development of memory T cells related to the development of effector T cells?
- They're parallel
- Linear model of memory cell development
- Memory T cells arise from effector T cells
- Branching (or asymmetrical division) model of memory cell development
- An antigen activated naive T cell gives rise to daughter cells that preferentially commit to either the effector or memory path
149
What are the three classes of memory T cells?
- Memory T cells are heterogeneous
Central memory T cells: TCM
- Recirculate between blood, T cell zone of secondary lymphoid tissue, and lymph
Effector memory T cells: TEF
- Recirculate bt nonlymphoidal tissue, lymph, lymph nodes, and blood
- May not enter T cell zone in lymph node
Tissue resident memory T cells: TRM
- Confined to a single tissue
150
What proteins can be found in TCM, TEM, and TRM?
151
What signaling is involved in recruiting CD4 TRM into the epidermis?
- Activated CD4 and CD8 T cells enter dermis and other peripheral tissue
- CD69 induction reduces S1PR1 expression and retains TRM in dermis
- Alpha e Beta 7 is induced on TRM cells by TGF-beta for retention in epidermis
152
What trait is aquired for a T cell to undergo metabolic reprogramming to survive for longer?
- Heightened sensitivity to IL-7 and/or IL-15 allows for metabolic reprogramming = longer life
- Memory T cells require IL-7 and a subset of CD8 T cells also require IL-15
153
What metabolic pathways are involved in Naive T cells activation, Effector T cell activation, and Memory T cell formation? How long do they take to respond and how long do they last?
154
How do memory B cells responses compare to the response by naive B cells?
- Memory B cells respond more rapidly and with higher affinity than naive B cells
- Memory B cells can reenter germinal centers and undergo additional somatic hyper mutation and affinity maturation during the secondary immune response
155
What does the immune response rely on for secondary and subsequent responses?
- Relies mainly on memory lymphocytes
- Naive cell responses are suppressed after primary response
156
How would someones immunity respond as time passes and the virus changes its Epitopes?
- Shortly after infection all Epitopes would be recognized
- After a longer time and exposure to a mutated virus, the previously recognized Epitopes can still be recognized
157
What was smallpox?
- Antigens disease that resulted in 3/10 people dying. eventually people developed vaccines
158
What is variolation/inoculation?
- The process of exposing an individual with small pox material
- Goal was to make a weaker version of the disease that people could survive and develop immunity
- 2-3% mortality rate
- Originated in Asia?
- Dry scabs under sun and inhale (China)
- lace the pustule and transfer it to arm of healthy individual
-1721 first documented inoculation in England
159
Edward Jenner
- First to inoculate with cowpox and led to a boy developing smallpox protection. this processed coined as vaccination (1796)
160
What is a vaccine?
- A biological product that can safely induce the immune response that confers protection against infections and/or disease on subsequent exposures
- Vaccine must contain antigens the immune system can recognize on a pathogen
161
What are six components of a vaccine?
- Active ingredient to activate immune system
- Adjuvants to boost immune response to vaccine
- Antibiotics prevent contamination by bacteria during vaccine manufacturing process
- Stabilizers for stable storage
- Preservatives to prevent bacterial and fungal growth
- Trace components are residual inactivating components
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What are the types of vaccines?
- Whole cell virus or component based
- Alive(attenuated) or not alive (inactivated)
163
What are live attenuated vaccines?
- Use pathogens that have reduced virulence and don't cause disease
- Attenuated is most common
- Grow poorly in human host but illicits full immune response
- Attenuation is achieved by serial passage of virus through non human cells
- Tissue culture, live animals, embryonic eggs
- The virus adapts to the non-human cells
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What are pros and cons of live attenuated vaccines?
- Ex. Measles, mumps, rubella, varicella, smallpox
Pros:
- More potent as they activate cell mediated immune response
- Long lasting and may even be life long
- Requires 1-2 immunizations for max immunity
Cons:
- A immunocompromised person may have sever disease or even death
- Cannot be given to pregnant women
- Attenuated virus can return to its pathogenic form (oral polio virus)
- Stability is very temperature sensitive
165
How is genetic engineered Attenuation different from liver stage development?
- Genetically attenuated parasite can provoke an immune response but infection does not progress further. Liver stage results in the death of the host
166
What are inactivated vaccines?
- Composed of a killed pathogen that cannot replicate and cause disease
- Inactivation can occur chemically or physically
- Chemical - formaldehyde is most common agent. Is not a high amount and does not cause a disturbance. biochemical modification may result in some epitope loss
- Physical - Heat, ultraviolet light, gamma radiation, pH. Influenza uses formaldehyde and UV
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What are pros and cons of inactivated vaccines?
- Ex. Polio, Influenza, Rabies
Pros:
- Generally safer for people especially with weak immune system
- Less adverse reaction
- Easier to transport
Cons:
- Do not activate cellular immune response
- Little to no cellular immunity, mostly antibody production
- Require three or more doses for max immunity
- Protection (antibody titers) fades over time
- Boosters needed
168
What is a subunit vaccine?
- Composed of specific antigens from the pathogen
- Recombinant protein/ peptide vaccine
- Various expression systems. Bacterial, yeast, insect cells
- Ex. Covid, acellular Pertussis
169
What are conjugated vaccines?
- Polysaccharides from bacterial capsules covalently attached to a protein antigen
- Polysaccharides alone cannot be processed and displayed on MHC unless attached to a protein
- Instead interact with a special set of B cells called marginal B cells
- Takes 1-2 years to develop therefore infants cannot mount immune response
- Ex. PCV, Haemophilus influenza
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What are toxoid vaccines?
- Chemically inactivated bacterial toxins
- Formaldehyde most common
- Specific aa are altered with slight conformational change
- Overall struct is maintained as well as immunogenicity
Ex. Diphtheria, tetanus, DTaP
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What are the pros and cons of subunit vaccines?
Pros:
- Less adverse reaction compared to inactive vaccines
- Target toxins and bacterial capsules
Cons:
- Do not activate the cellular immune response
- Little to no cellular immunity, mostly antibody production
- Protection (antibody titers) fades over time
- Need booster
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What is an mRNA vaccine?
- Synthetic mRNA in which ribosomes in the host recognize and translate the antigen (spike protein)
- mRNA is delivered in lipid nanoparticles (LNPs)
- Fuses with endosome to release mRNA into cytosol
- Consist of ionizable lipid, helper lipid, cholesterol, and PEGylated lipid
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What are the pros and cons of an mRNA vaccine?
Pros:
- Effective at inducing cell mediated response
- Safe
- Can be quickly modified
Cons:
- Stability, must be kept frozen
- New
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What are the other components of a vaccine?
ADJUVANTS: Enhance immunogenicity of vaccines
- Required in inactive vaccines, subunit, and other non living vaccines
- Triggered the innate receptors to stimulate an immune response
Antibiotics: Prevent contamination during manufacturing
- Antibiotics have rare change to cause allergic reaction
- Found in trace amounts
- Neomycin, Polymycin, streptomycin, gentamicin
Preservatives: Prevent microbial growth
- Used only in vials that contain multiple doses
- Thimerosal (only flu vaccine) no evidence of harm
Stabilizers: Protect active ingredient during manufacturing, storage, and transport
- Gelatin
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What does the mucosal immune system do?
- Protects internal surfaces of the body
- Comprises the internal body surfaces that are lined by mucus covered epithelium
- In gastro tract, upper and lower resp,urogenital, biliary,middle ear,exocrine eye glands, salavary gland, and lactating breast
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How do the thickness of tissue in the body vary?
Mucosae:
Pseudostratified ciliated - Line nasal cavity paranasal
Simple ciliated - Single cell thickness lines bronchi
Simple ciliated cuboidal - lines terminal and resp bronchioles
Simple squamous - forms alveolar ducs and alveoli
Stratified squamous is multilayered
Skin:
Keratinized stratified squamous epithelium
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What types of cells can be found in the different sections of the digestive tract? How much mucous is there in the different sections?
Corpus to pylorus has a single thick layer of mucous
Duodenum to ileum has single thin layer
Proximal to distal colon has two thick layers
178
What are the distinctive features of the mucosal immune system?
179
What happens if a mucosal surface is compromised?
- Antigens will attach to epithelium and cause invasion
-If the barrier is intact, binding is blocked and antigens can be trapped and cleared safely
180
Where are immune cells deployed?
Inductive site
- Where immune cells are activated
- Lymph nodes and the mucosa-associated lymphoid tissue (MALT)
Effector site
- Where immune cells act to protect the site
- (Intestinal) epithelium, lamina propria
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What is a peyer's patch? What is an isolated lymphoid follicle? Why does follicle associated epithelium lack a thick layer of mucus?
Peyer's patches
- Mainly found in distal ileum
- Large aggregates of lymphoid tissue
- Contain multiple germinal centers
Isolated lymphoid follicle (ILF)
- Found in small and large intestine
- Single aggregates of lymphoid tissue
- Mainly B cells
- Follicle associated epithelium lacks thick layer of mucus because it does not produce mucins
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How does ILFs develop? What are cryptopatches?
- ILFs develop from cryptopatches after birth in response to microbiota
- Composed of dendritic cells and lymphoid tissue inducer cells (LTi)
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What does intestinal epithelium contain? What does the lamina propria contain?
- Variety of conventional and unconventional T cells, intraepithelial lymphocytes (IELs)
- Populated by innate immune cells and effector T cells as well as antibody secreting cells (Plasma cells)
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How does the maturation of gut associated lymphoid tissue occur?
- Maturation of gut associated lymphoid tissue is driven by acquisition of the commensal microbiota
185
What happens when antibiotics kill the commensal bacteria?
- If microbiota is killed it opens a niche for bacteria such as clostridium to infect causing necrosis. This must be treated with a targeted antibiotic
186
What is the epithelial turn over rate like? What are intestinal stem cells?
- High turnover rate
- Days to a few weeks
- Intestinal epithelial cells (IECs shed about 3-5 days
- Intestinal stem cells give rise to transient amplifying (TA) cells which give rise to two groups of IECs
- Absorptive and secretory
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What are some features of microfold cells, goblet cells, paneth cells?
- Microfold cells are from absorptive IECs and are important for antigen uptake and bacterial translocation
- Goblet cells are from secretive IECs and are important for producing mucins and antigen uptake
- Paneth cells are from secretive IECs and are important for supporting intestinal stem cells and secretion of antimicrobial peptides
188
What is the cellular source for alpha defensins, beta defensins, calprotectin, C type lectins, lysozymes, and phospholipase A2?
189
How is a continuous intercellular barrier formed?
- Membrane adjacent epithelial cells are tethered together near their apical surface by tight junctions and adhesion complexes. Claudine and occluding are responsible for permeability of tight junctions
190
What is the major mucin in the intestine? What does glycosylation lead to?
- The major mucin in the intestines is MUC2 a gel forming mucin
- Glycosylation leads to a bottlebrush like structure that binds water and gives mucus its lubricating gel like properties
191
How is invasion of intestinal microbes prevented?
- Antimicrobial peptides and mucus function prevent invasion
- Small intestine: Antimicrobial peptides from paneth cells keep the microbes away from epithelium
- Large intestine: The inner layer of mucus cannot be penetrated by bacteria due to the extensive cross linking
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How is intestinal epithelium barrier maintained and defended?
- Conventional and unconventional T cells
- Intraepithelial lymphocytes
- Major function is to eliminate IEC that are infected, damaged, or stressed
- Release growth factor to promote epithelial proliferation and repair
193
How can intestinal cells uptake and deliver antigens to antigen presenting cells?
Intestinal cells can use secreted IgA, M cells, FcRn transport, Goblet cells, tight junctions, apoptosis dependent transfer, and trans epithelial dendritic cells
194
Outline important features of protective immunity and mucosal tolerance. Include antigen, primary Ig production, primary T cell response, and response to antigen reexposure.
195
How does adaptive immunity aid in the regulation of mucosal homeostasis?
- Intestinal dendritic cells favor the induction of antigen specific Treg cells that are critical for the maintenance of mucosal immune homeostasis
- Major factors that include protolerogenic DC functional stat include TGF-B, IL-10, retinoic acid, and thymic stromal lymphopoietin (TSLP)
- Products of bact, epithelial cells, stromal, neuronal, and dietary and microbial metabolites
196
What are the four stages of a bacteria penetrating the mucus layer and attaching to epithelium
- Colonization, innate response, adaptive response, clearance
197
What recognizes bacteria leading to the recruitment of neutrophils, macrophages, and dedritic cells?
- TLRs which start a cascade eventually recruiting leucocytes which are able to eventually manage the bacterial invasion
198
What cells are in the respiratory tract?
199
What happens when influenza attaches to the cells in the respiratory tract?
200
How does Immunodeficiency occur? What are the two types of immunodeficiencies?
- Occurs when one or more component of the immune system is impaired
Primary:
- Cause recurrent infections early in life
- 6 million people are affected world wide
Secondary (aquired):
- Result of disease, medical interventions(drugs), and nutritional deficiency
- Recurrent infections by pyogenic, or pus forming, bact suggests a defect in antibody, compliment, or phagocyte function
- Persistent fungal skin infection or recurrent viral infections suggest a defect in host defense mediated by specific functions of T lymphocytes
- Global T cell dysfunction impairs both B cell responses and aspect of innate immunity, giving rise to broad defects in host defense
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What is SCID? What are the signs and symptoms?
Severe combined immune deficiency
- Group of genetic disorders
- Cannot make T cell dependent antibody responses nor cells mediated immune response. This results in NO IMMUNOLOGICAL MEMORY
- Diagnosed in early childhood
Signs and symptoms
- Infections that do not resolve after 2 months of treatment
- infections that require intravenous antibiotic treatment
- Persistent ear infections
- Persistent thrush in mouth or throat
- Repeated cases of pneumonia or bronchitis
- Repeated bouts of diarrhea
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What is X-linked SCID and what are its features?
- Most common SCID
- Mutations in the gene IL2RG on the X chromosome
- Encodes IL2 receptor common gamma chain Yc
- Gamma chain is required for all IL2 Cytokine family receptors
- IL2, IL4, IL7, IL9, IL15, IL21
- T cells and NK cells fail to develop normally
- Low T cells and NK count
- B cells develop normally but without T cells they do not function normally
203
How common is X-linked SCID? What are the treatment options?
- 1/50-60K births
- Males overwhelmingly affected
- Without treatment, infant dies within 2 years
- Gene therapy and bone marrow transplant
204
What is XLA and what are possible treatments?
- X linked agammaglobulinemia
- 1/200K births
- Mutation of BTK on the X chromosome disturbs BCR signal transduction
- Fail to develop and mature B cells
- B cell development is halted with Pro B stage
- Very low levels of antibodies and low B cell count
- Treatment is weekly infusion of antibodies
205
What is Job syndrome?
- Hyper-IgE syndrome
- Mutation in STAT3
- STAT3 is involved in broad spectrum of adaptive and innate immune functions such as Th17 differentiation and epithelial regeneration
- Cold abscess abscess without heat, redness, fever, significant pain, or inflammation
(IMAGE 11)
206
What is GATA2 deficiency and what treatment is availible?
- Mutation of GATA2 gene
- GATA 2 transcription factor is important for hematopoiesis
- Affects varrious blood cells
- Mainly affected cells are monocytes and dendritic cells
- Most common initial symptom is infections with NTM and viral infections
Treatment: Bone marrow transplant
207
What type of offspring would result if an affected parent had children with a unaffected mother? What are some features of GATA2 deficiency?
208
What is HIV?
- Aquired autoimmune disease
- HIV is a retrovirus that establishes a chronic infection that slowly progresses to AIDS
- HIV infects and replicates within cells of immune system
- Requires CD4 receptor and a chemokine coreceptor
- Initial infection begins with R5 variants
- Use CCR5 coreceptor
- X4 variant emerges after initial infection
- Uses CXCR4 coreceptor
- Activated CD4 T cells are the major source of HIV replication
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How does HIV bypass the epithelium and replicates?
1. Enter via DC-SIGN binding on DC
2. HIV internalized into early endosomes
3. Transported to lymph nodes to transfer HIV to CD4 T cells
210
What is the immune response to HIV like?
211
What are the stages of HIV? What is the CD4 lymphocyte count for each stage?
Stage 1 - 500 or more leukocytes, 26% or more are CD4
Stage 2 - 400-299 leukocytes, 14-25% CD4 lymphocytes
Stage 3 - less than 200 leukocytes, CD4 is less than 14 percept categorized as AIDS
212
What is the graph that compares the time after onset of HIV infection and CD4 cell concentrations?
213
What is immune amnesia?
- Immune system loses its ability to fight infections that a patient was previously immune to
- Loss of memory lymphocytes
- Measles virus infects B and T cells
214
What is a hypersensitive reaction? What are the four types and their mediators?
- Inappropriate or exaggerated immune response towards an innocuous antigen/allergen
- Type I mediated by IgE, Type II mediated by IgG or IgM, Type III immune complex mediated, Type IV T cell mediated
215
What are type I allergic diseases?
- IgE mediated allergic reactions
- Usually occur due to a person becoming sensitive resulting in IgE production and production of memory B cells
- Atopy - Genetically based tendency to produce IgE mediated reactions
- All IgE mediated responses involve Mast-cell degranulated but symptoms vary based on route of entry
216
Outline the steps involved in an allergic reaction.
1. Allergen is encountered and presents it to TH2
2. B cell is activated by TH2
3. B cell proliferates and produces plasma cells to secrete IgE
4. IgE binds to mast cells
5. Subsequent exposure results in allergic symptoms
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What causes allergens?
- No physical, chemical, or functional feature has been found that is common to all allergens
- Many clinically significant Allergens are proteases
- One ubiquitous protease allergen is cysteine protease Der p 1. Causes allergy to dust mites and is present in 20% of americans
218
Outline the steps involved in Der p 1 eliciting an allergic reaction.
1. Der p 1 cleaves occludin in tight junctions and enter mucosa
2. Dendritic cell primes T cells in lymph node
3. IgE specific for Der p 1 travels to mucosa
4. Der p 1 specific IgE binds to mast cells triggering degranulation
219
Do genetic factors contribute to IgE mediated allergic diseases?
Yes, many genes have an important role in dealing with asthma, T cell differentiation, and other functions
220
What other factors contribute to IgE mediated allergic diseases?
Environment, children raised in rural settings are less likely to have allergic diseases than children raised in urban areas
221
What are the two possible results of being exposed to an allergen?
Immediate reaction
- Due IgE mediated mast cells activation and starts within seconds
- Activity of histamine, prostaglandins, and other mediators that cause a rapid increase in vascular permeability and contraction of smooth muscle
Late phase reaction
- Due to continuous release of inflammatory mediators by mast cells and recruit eosinophils, basophils, neutrophils, monocytes, and lymphocytes
- Mediators include leukotrienes, chemokines, and cytokines
- Resistant to anti-histamines
- Can lead to chronic inflammatory response
222
What is allergic rhinitis?
- IgE antibodies recruit signaling molecules which recruit inflammatory cells that secrete soluble mediators that can lead to sneezing congestion and more
223
Outline the steps involved in signal induction by FceRI
- Cross linking by receptor recruits and activates Syk tyrosine kinase
- Activation of PLC-y
- Generation of IP3 which releases calcium
- Cytosolic calcium Induces secretion of mast cell's granules
224
How does mast cells activation and granule release affect the gastrointestinal tract, Eyes, Nasal, and air passageway, and blood vessels?
225
What molecules are released by the activation of mast cells?
- Enzymes, toxic mediators, Cytokines, chemokines, and lipid mediators
226
What are the possible routes of entry for an allergen?
- Allergens can encounter connective tissue mast cells intravenously or subcutaneously
- Allergens can encounter mucosal mast cells via inhalation or ingestion
227
What molecules can be released by eosinophils and basophils? what do they cause in an allergic reaction?
- Release ezymes, toxic proteins, Cytokines, chemokines, and lipid mediators
- Cause inflammation and tissue damage in allergic reactions
228
Compare a normal airway and an asthmatic airway.
Normal:
- Thin layer of mucous and a low amount of mast cells and eosinophils under epithelial layer
- Good airflow with no blockage
Asthmatic:
- Mucous hypersecretion
- Eosinohil inflammation
- Restricted airway
229
What leads to the differences that can be observed in someone with mild asthma vs chronic asthma?
- Increased mucus
- Increased fibrosis
- Increased inflammatory cells (CD4 and eosinophils
- Increased muscle thickness
230
What happens when someone with hives encounters pollen or another allergen?
- Pollen enters the body and is taken up by mast cells resulting in the release of histamines which increases blood vessel impermeability resulting in redness and swelling
231
What happens as lesions progress in individuals with eczema?
- Healthy skin gets reduced barrier function as barrier integrity is disrupted which leads to ILCs releasing inflammatory molecules
232
How does an IgE mediated allergic reaction occur to food?
- Allergen is taken up by dendritic cell and eventually Mast cells will get IgE antibodies and it will cross link resulting in vasodilation
233
What is anaphylaxis?
- Systematic allergic reaction
- Occurs when Allergens enter the bloodstream directly or when the allergen is rapidly absorbed by the gut (bee sting or eating food)
- Mast cells associated with blood vessels throughout the body are activated
- Acute urticaria occurs when the allergen is delivered to the skin from the blood stream
- Anaphylactic shock occurs due to widespread increase in vascular permeability and smooth muscle contraction
- Drop in blood pressure
- Constriction of airways
234
What receptors does epinephrine target and what are the results?
235
What can be targeted by allergen immunotherapy to treat allergic diseases?
236
What is type II hypersensitivity?
- Mediated by IgG and IgM
- In susceptible individuals, binding of the drug to the surface of circulating red blood cells or platelets cause the destruction of the cells by antibody mediated mechanisms
237
What is type III hypersensitivity?
- Mediated by immune complexes or antibody: antigen aggregates
- Pathogenic potential is determined in part by their size and by the amount, and affinity, and isotypes of the responding antibody
- Immune complexes are deposited in tissue
Local
- Arthus reaction (Low dose)
- The immune complexes are formed only close to site of injection where they activate mast cells with Fcy receptors
Systematic
- Serum sickness
- Immune complexes from throughout the body
- Follows the admin of large quantities of poorly catabolized antigens
Pathogenic immune complexes from due to antigen persistence during infection
238
What is type IV sensitivity?
- Mediated by TH1 cells and cytotoxic CD8 T cells
- Delayed hypersensitivity
- Antigen is injected into the skin and reaction occurs hours to days later
- Specific T cells are rare and because there is little inflammation to attract cells into site, can take several hours for a T cell to correct specification
239
What are cellular hypersensitivity reactions mediated by?
- Antigen specific effector T cells
240
How is an antigen processed by tissue macrophages? And how does it stimulate TH1 cells?
241
What is contact hypersensitivity?
- Antigen absorbed into the skin
- Activation of CD4 or CD8 cells
- Depends on antigen processing pathway
- Poison ivy or poison oak
Hapten
- Small molecules that illicit an immune response only when attached to a carrier protein
242
What is autoimmunity? What is xenoimmunity and alloimmunity?
- Immune system targets self antigens
- Xenoimmunity: immune system targets microbiota
- Alloimmunity: immune system targets transplanted tissue
243
What are some examples of autoimmune diseases and what is their prevalence?
244
What are the layers of self-tolerance?
245
What is negative selection?
- Medullary epithelial cells express tissue specific proteins that are found outside the thymus to present to the T cells
- Controlled by the gene AIRE (autoimmune regulator)
246
What is immunological ignorance?
- Lymphocytes that bind self antigens with relatively low affinity usually ignore them
- But some circumstances become activated when the threshold for lymphocyte activation is sufficiently reduced
247
How is the costimulatory signal sent out using B cell receptors and DNA?
- B cells have low affinity for DNA can escape deletion in the bone marrow and persist in the periphery bit are not normally activated
- When extensive cell death occurs under conditions of inadequate clearance of apoptotic fragments, these B cells can bind and internalize the DNA
- TLR-9 recognizes unmethylated CpG sequences in DNA found in the mitochondria
- Provides the Costimulatory signal for B cell activation
248
How would the body respond to trauma to the eyes?
- Release of intraocular protein antigens carried to a lymph node and activates T cells. Effector T cells return via bloodstream and encounter antigen in both eyes
249
What are immunologically privileged sites?
- certain sites in the body that do not mount an immune response against tissue allografts
- Can be due to both physical barrier to cell and antigen migration and the presence of immunosuppressive cytokines
- Damage to an immunologically privileged site can induce an autoimmune response
250
What is molecular mimicry?
- Pathogens express antigens that are similar but not identical to host molecules which can result in antibodies that cross react with those host molecules
251
How can autoimmune reactions be regulated?
- Controlled by various stages by regulatory T cells
- Regulatory cells can suppress auto reactive lymphocytes that recognize a variety of different self antigens, as long as antigens are from the same tissue or are presented by the same APC
252
What are the two classifications of autoimmune diseases? What are some examples?
- Organ specific or systemic disease
253
How are some common autoimmune diseases classified by immunopathogenic mechanisms?
- Antibody against cell-surface or matrix antigens
- Immune complex diseases
- T cell mediated diseases
254
What are 4 autoimmune diseases involved in aspects of the immune response?
- Systemic lupus, T1 diabetes, Myasthenia, and multiple sclerosis
255
What is autoimmune hemolytic anemia?
- Antibodies target red blood cells
- Can occur at warm temperatures above the body's natural temperature or when exposed to cold temperatures
- Causes are not well understood, occurs after infections, cancers or along other autoimmune disorders
256
What is multiple sclerosis?
- Immune system destroys myelin sheaths structure
- TH1 and TH17 cells are primarily associated with pathogenesis
Symptoms:
- Blurred/ double vision
- Red green color distortion
- Pain and loss of vision due to swelling of optic nerve
- Trouble walking and difficulty with balance
- Numbness, prickling, or pins and needles
Causes:
- Unknown possible various factors contribute to development of MS
257
What are the survival rates for organ transplantations?
258
How does transplantation rejection occur?
- Mediated by T response to MHC molecules
- To increase success rate, MHC molecules must match between donor and recipient
- Very difficult to find a perfect MHC match, the greater the MHC match the less sever the reaction is
- Medication that induces immunosuppresive state helps
- Acute rejection - the rejection of tissue after 10-13 days cannot be prevented unless immunosuppressive treatment is done
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What results in identical MHC grafts being rejected?
- Peptides from other alloantigens bound to graft MHC molecules
- Self-proteins that are presented on MHC molecules are different between donor and recipient
- Minor histocompatability antigens
- Rejection is not as rapid but immunosuppressive drugs are still required to prevent organ damage
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What is direct allorecognition?
- Host T cell recognition of donor APCs directly without antigen processing
- Occurs in the graft itself or upon the migration of donor APCs from the graft regional lymph node
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What is indirect allorecognition?
- Recipient's APC process and present the alloantigens to T cells
- Antigens presented include peptides derived from the minor H antigens and from allogeneic HLA class I and class II allotypes
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What is hyperacute rejection?
- Preformed antibodies react with endothelium
- Immediate reaction
- Activates complement and blood clotting cascade leads to damage
- Preformed antibodies include those that target blood group antigens and polymorphic MHC molecules
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What is late failure of a transplanted organ?
- Caused by chronic injury to graft
- Chronic allograft vasculopathy
- Arteriosclerosis of graft blood vessels, which leads to hypoperfusion of the graft and its eventual fibrosis and atrophy
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What are the targets of immunosuppressive drugs that are used in organ transplantation?
