Immunology Flashcards
Intro, innate, B-cell differentiation, humoral
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
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
How might a Th2 CD4+ helper T-cell response be pathogenic?
Th2 CD4+ helper T-cells may be involved in…
- Chronic allergic rhinitis
- Asthma
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
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
What is your diagnosis?
IBD (Chron’s disease)
No rash = unlikely to be Celiac
Long lasting = probably not allergies
Episodic = not MALT lymphoma
Give 3 examples of a Type III hypersensitivity reaction
Serum sickness (reaction to drugs)
Systemic lupus erythematosus
Arthus reaction
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
Which complement protein is chemotactic to neutrophils?
What does this mean?
C5a
Chemotactic = ~attractive~
C5a recruits neutrophils
What is the function of C1 esterase inhibitor?
Inhibits the formation of C3
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
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
A patient in your ECMH has had several recurrent viral mucosal infections.
What kind of immunodeficiency should be on your differential?
IgA deficiency
What are the mediators of a Type I hypersensitivity reaction?
Mast cells, basophils, pre-formed IgE
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
What are the functions of C5a?
- Triggers mast cells to degranulate and release histamine (anaphylatoxins)
- Chemotactic for neutrophils
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
Which types of hypersensitivity are cell-mediated?
Type IV
What is deleted during B cell isotype switching?
Intervening heavy chain DNA
B cells cannot revert back to expressing IgM antibodies after isotype switching
On which cells is CD14 expressed?
What is the function of CD14?
Monocytes/macrophages
Co-receptor for TLR4 that recognizes LPS
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
Which antibodies can fix complement?
Which pathway do they use?
IgM and IgG fix complement via the classic pathway
Which interleukins lead to an increased risk for allergy and anaphylaxis?
IL-4
IL-4 promotes class switching to IgE
Increased IgE -> Activation of mast cells/basophils -> Anaphylactic reaction
Where is CD19 expressed?
Expressed on B cell surface
Component of BCR
On which cells is CD19 expressed?
All B cells
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)
Which cells are responsible for releasing histamine to trigger inflammation?
Mast cells
Which interleukins are pyrogenic?
Pyrogenic = causes fever
IL-1, IL-6
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)
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 in later childhood/adolescence (not seen in young children)
Symtoms include recurrent bacterial, enteroviral, and giardia infections in later childhood/adolescence
Which immunoglobulin do all very young infants (under 6 weeks) have?
Maternal IgG
(And Maternal IgA if they are nursing)
What are the possibilities for the constant region of a light chain?
- Kappa
- Lambda
Which cytokine drives B-cell differentiation?
IL-13
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
What is fibrosis?
Wound healing that occurs in parenchymal organs
- Excessive deposition of collagen and other extracellular matrix components in the tissue in response to injurious stimuli
In general, what is required for B-cell activation?
2 signals
- Antigen recognition by a surface antibody (B-cell receptor)
- From T cells through…
a) Costimulatory molecules in T-cell dependent immune response
b) complement in T-cell indepenent immune response
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
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
- -> Cannot make hypochlorite ion
- -> Failure to produce hydrogen peroxide
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
What mechanisms can cause a hypersensitivity reaction against self-antigen?
- A foreign molecule cross-links or modifies a host cell
- The host cell recognizes these “new” epitopes as foreign and mounts an immune response
- Molecular mimicry
- An antibody specific for a foreign antigen binds to similar-lookig self-antigens inside fo the host
What are the roles of T-cells and macrophages in adaptive immunity?
Mediate cell-mediated immunity
- Directly kill virus-infected cells
List the PIDs that affect innate immunity
- Chronic granulomatous disease
- Leukocyte adhesion deficiency
- Complement defects
- Defects in TLRs
What components of our immune system recognize extracellular pathogenic patterns?
Toll-Like Receptors (TLRs)
Mannose Receptors
Which complement proteins form the membrane attack complex?
C5a, C6, C7, C8, C9
-> Direct microbe killing
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
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
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
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
- Glycocalyx
A B-cell receptor is made up of which antibody isotype?
Surface IgM or IgD
What is acute inflammation?
What are the cells involved?
Acut inflammation is predominantly an innate immune response mediated by fluid in the tissues and neutrophil migration into tissues
Macrophages arrive after neutrophils and release further cytokines
Can resolve or progress to chronic inflammation
Mutations in RAG1 or RAG2 can cause which immune disorder?
A form of SCID - Severe Combined Immunodeficiency
No B-cells or T-cells; VDJ recombination cannot occur without RAG1/RAG2 gene expression
Normal NK cells
(Boy in a bubble)
What molecular compounds do neutrophils have that allow them to recognize opsonized bacteria?
Neutrophils have Fc receptors for the Fc region of IgG (constant region) and complement receptors for C3b
This allows them to recognize and attach to the bacteria to initiat phagocytosis
What are the basic steps in inflammation produced by the innate immune system?
- Cells of the innate immune system recognize pathogens through PAMPs
- These cells release pro-inflammatory cytokines
- Cytokines acute phase response and releazse of numerous mediators of inflammation
Which proteins are expressed by Helper T-cells?
CD3, CD4
What two chains are present in an antibody?
Heavy chain
Light chain
What are the cellular mediators of inflammation?
- Neutrophils and monocytes first
- Then monocytes, lymphocytes, and plasma cells
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
What kinds of pathogens are often associated with chronic inflammation?
Intracellular pathogens
Often triggers granulomatous response mediated by macrophages, CD4+ (helper) T cells
What proteins do plasma cells express?
CD38, CD138, and cytoplasmic immunoglobulins
What are the mediaors of a Type IV hypersensitivity reaction?
Antigen presenting cells (Usually macrophages)
Th1 CD4+ Helper T-cells
Sometimes CD8+ Cytotoxic T-cells
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 be 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
Is oxygen-dependent killing or oxygen-independent killing more effective?
Oxygen-dependent
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
- Increased expression of cytokines, cytokine receptors, cell proliferation genes
- Signaling cascade
- Recrutment and activation of ZAP70 tyrosine kinase
- Note: costimulatory signal is required for T-cell activaiton
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
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 :)
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
Which cytokine increases cyclooxygenase?
TNF-alpha
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
In a humoral immune response, why is prevention of immune-complex formation important?
How is this accomplished?
- Immune complexes (aka antibody-antigen complexes) have harmful effects on our bodies
- Continuous activation of complement via classical pathway
- Inflammation
- Immune complex formation is prevented by feedback inhibition
- Fc(g)RIIB receptors on the surface of B-cells binds the Fc portion of IgG
- Binding activates downstream signaling through ITIM
- This terminates the BCR response to the antigen
What is IL-1?
(Basically the same function as IL-6)
- Pro-inflammatory cytokine
- Endogenous pyrogen (Causes fever)
- Induces acute phase response
Defects which interleukin might lead to IgA deficiency?
IL-5
IL-5 secreted by Th2 CD4+ helper T-cells promotes class switching to IgA
What causes DiGeorge’s Syndrome?
Thymic aplasia due to a developmental defect in the 3rd and 4th pharyngeal pouches
- T-cells do not develop properly, leading to T-cell deficiency
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
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)
Describe the general process of T-cell activation
2 signals are required (this provides a “safety” against an immune response to self-antigen)
- Antigen recognition in the context of MHC
- ITAMS are phosphorylated
- Recognition of a costimulatory molecule
- CD28 recognizes B7 or
- Complement receptors recognize complement
What do antigen-activated B-cells undergo in the germinal centers of the lymphoid tissues?
- Rapidly divide
- Interaction with antigen-specific T cells, APCs, and follicular dendritic cells
- Undergo isotype switching, somatic hypermutation, and affinity maturation
What components are expressed by a Pre B-Cell?
- Mu heavy chain in cytoplasm (not as a surface receptor)
- No rearranged light chain
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)
- Cross-linking of IgE (which is bound by IgE Fc freceptor)
- Binding of their toll-like receptors to PAMPS on bacteria and viruses
- Release histamine and other mediators of inflammation
How would you differentate chronic rhinosinusitis from a sinus infection?
Chronic rhinosinusitis = no fever
Sinus infections may have fever
What would be the biggest concern preventing thymus transplants in patients with DiGeorge syndrome?
Graft vs. host disease
- The T-cells in the donor thymus are trained to not attack the self-antigen of the donor
- As a result, they may attack the cells of the new host
(Additionally, they may not recognize the MHC of their new host, resulting in decreased immunity; this danger is less immediate)
What are the clinical presentations and consequences of Wiskott-Aldrich syndrome?
Histology
- Abnormal platelets and leukocytes
- Small
- Do not migrate normally
Disease
- Eczema
- Thrombocytopenia
Give 4 examples of a type II hypersensitivity reaction
Drug allergies (some)
Blood transfusion response due to ABO mismatch
Rh hemolytic disease of newborn
Good pasture syndrome (body forms antibodies against basement membrane or Type IV collagen)
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
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
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
What are the characteristics of innate immunity?
- Present at birth
- Rapid
- Relies on pattern recognition
- Not specific
- No memory
- Primarily mediated by neutrophils
Which patients are most likely to present with Wiskott-Aldrich syndrome?
Boys
Inheritance is X-linked
List the stages of B-cell development
- Early hematopoietic stem cell
- Lymphocyte progenitor
- Pro B-Cell
- Pre B-Cell
- Immature B-Cell
- Naïve B-Cell
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
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)
What are the mediators of a Type III hypersensitivity reaction?
Antigen and antibody (typically IgG) complexes
Neutrophils
In general, what is required for CD4+ Helper T-cell activation?
2 signals
- TCR and co-receptor CD4 recognize and bind the peptide bound to MHC II on the APC
- The APC also expresses B7, a protein that binds to CD28 on the T-cell
Activation -> Cytokine production
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
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
Does a Type II hypersensitivity reaction require sensitization?
Why or why not?
Not always
Type 2 hypersensitivity reactions can be mediated by naturally occuring IgG or IgM that exists prior exposure
However, IgG and IgM can also increase due to prior sensitization
What is the B cell receptor (BCR)?
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
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
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
What are the symptoms of IBD?
- Chronic inflammation
- Episodic
- Vomiting/diarrhea
- Urgency to defecate
- Weight loss
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
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)
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
- Promotes B cell differentiation
- IL-10
- Anti-inflammatory (turns off immune system)
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 -> IgE)
- The result is different host response to antigen binding
- Antigen specificity (VJD) is not altered by isotype switching
What is ITIM?
Why is it important?
ITIM = immunomodulatory Tyrosine-based inhibition motif
- ITIM is important in feedback inhibition of the humoral immune response
- Activation: Fc(g)RIIB on surface of B-cells binds Fc portion of IgG
- Result: termination of the BCR response to the antigen
What are the causes of chronic inflammation?
- Persistent infection
- Prolonged exposure to a toxic agent
- Autoimmunity
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
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
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
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)
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
Describe the role of B-cells in viral immunity
Humoral response = antibodies
- Protection from infection; prevents virus particles from invading cells
- Antibodies can bind directly to the virus
- Prevents binding to cell surface receptors
- Opsonizes the virus
- Antibodies can bind directly to the virus
- Antibodies can bind to new antigens on the surface of infected cells
- Activate complement
- Promote killing of the virus-infected cell via MAC
- ADCC can kill virus-infected cells
- Targets infected cells for killing by macrophages, neutrophils, or NK cells
- Activate complement
But viruses can evade humoral immunity via antigen variability!
- This is why cell-mediated immunity is needed to kill infected cells
- What is RIG-1 helicaase
- Where is it found?
- What does it do?
- RIG-1 helicase is a pattern recognition protein that recognizes intracellular pathogens
- RIG-1 helicase is found in cytoplasm of immune-competent cells
- RIG-1 helicase recognizes nucleic acids of viruses
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
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)
Which cytokine drives T-cell differentiation?
IL-2
Which immunoglobulin do nursing infants have?
Maternal IgA, acquired through breast milk
Acquired via passive immunity
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)
What components are expressed by a Pro B-cell?
None
Pro B-cells do not express heavy chains, light chains, or surface antibodies
What is hypersensitivity?
An exaggerated or inappropriate immune response to an external or self antigen
Can cause harm to the host
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
What components are expressed by an immature B-cell?
- Mu heavy chain and light chain = a fully formed IgM BCR
Where does T-cell maturation occur?
The thymus
When a T-cell leaves the thymus, its antigen specificity does not change
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
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
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)
- Infections by encapsulated bacteria
Which white blood cells are involved in the innate immune response?
- Neutrophils
- Monocytes/macrophages
- Basophils
- Mast cells
- NK cells
Which cells releases IL-1, IL-6, and IL-8?
Macrophages
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
What are the major functions of CD8+ cytotoxic T-cells?
Mediate direct cellular killing in cell-mediated immunity
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
Which antibody can cross the placenta?
Why is this important?
IgG
This is important in the maternal immune response to fetal red blood cells
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.
What is your diagnosis?
Chronic rhinosinusitis
No fever = not a sinus infection
Presentation in the nasal/respiratory airway and mucosa
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
Which cytokine is critical for a secondary antibody response composed of IgG?
Il-4
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
T-cell cytokine production in the context of CD40:CD40L binding causes B-cells to undergo which process?
Describe the process
T-cell cytokine production in the context of CD40:CD40L induces the formation of a germinal center
Somatic hypermutation, isotype switching, and affinity maturation of B-cell antibodies occurs in the germinal center
- Isotype switching
- Modification of the heavy chain constant region leads to different Ig molecules, resulting in different protective responses
- Somatic hypermutation
- Antibody variable regions are subject to random point mutations (by 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
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
What do the three mechanisms of complement activation converge on?
C3 convertase
Which PID is chacterized by eczema and reduced size and number of blood platelets (thrombocytopenia)?
Wiskott-Aldrich Syndrome
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
- Secrete cytokines in the context of CD40:CD40L that promote the formation of a germinal center
Describe B-cell anergy
B-cell anergy = peripheral tolerance
Anergy occurs when a B-cell cirulating in the periphery becomes self-reactive
- Self-reactive B-cell encounters self antigen in the absence of co-stimulation
- The B-cell becomes anergic; it does not repsond to the antigen
This prevents autoimmune responses
Where are basophils present?
What are basophils activated by?
What do basophils release?
- Present throughout connective tissue
-
Activated by..
- Trauma
- Complement proteins (C3a and CD5a)
- Cross-linking of IgE (which is bound by IgE Fc freceptor)
- Binding of their toll-like receptors to PAMPS on bacteria and viruses
- Release histamine and other mediators of inflammation
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
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
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
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)
What are the basic stages of phagocytosis?
- Recognition and attachment
- Engulfment
- Destruction
- Resolution
What type of immune response does poison ivy trigger?
How does it trigger this response?
Type IV: delayed type hypersensitivy reaction
- Poison Ivy chemical modify self-antigen
- T-cells recognize chemically modified self-proteins as foreign and mount an immune response
- Cytokine release
- Macrophage activation
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
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
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
Which immune deficiency is characterized by recurrent infections from catalase-positive organisms, granuloma formation, and abscess foramtion?
Chronic granulomatous disease (CGD)
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)
What is the function of C3a?
Triggers mast cells to degranulate and release histamine (anaphylatoxins)
Describe the resolution phase of phagocytosis
Neutrophils undergo rapid apoptosis after the inflammatory stimulus is removed
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
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
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)
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
Which protein stimulates the formation of lymphoid progenitor cells from early hematopoietic stem cells?
IL-7
Which antibodies most effectivly opsonizes bacteria?
IgG
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
What do deficiencies in the membrane attack complex (C5b, C6, C7, C8, C9) lead to?
Predispose to infections with Neisseria
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
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
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
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
What might cause damage to the ciliary elevator?
Alcohol, cigarettes, viral infections
What type of response do intracellular pathogens tend to give rise to?
Which cells/substances are involved?
Granulomatous response
Macrophages, CD4+ T cells
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
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)
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)
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
What is the difference between a caseating and non-caseating granuloma?
A caseating granuloma has central necrosis (Ex: TB, fungal infection)
A non-caseating granuloma lacks central necrosis (Ex: foreign material reaction, sarcoidosis, cat scratch disease)
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
Describe CD4+ Helper T-cell activation
The APC ingests an extracellular pathogen, digests it, and presents it on MHC class II
- The TCR (CD3) and coreceptor CD4 bind the peptide that is on MHC II
- CD28 on the T-cell binds B7 on the APC and/or cytokine recepotors on the T-cell bind cytokines
If signal #2 is not present, the T-cell becomes anergic to this antigen
Which cells are active in immunity against viruses?
CD8+ Cytotoxic T-cells
NK cells
B-cells
What is an antigen?
Anything that can bind to an anitobdy
We can form antibodies to almost anything
What are the functions of IgD?
Expresses only on naive B-cells
Not secreted
Honestly, not much is known about their function
Why do complement proteins circulate as active precursors?
To prevent errant tissue damage and inflamation
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 creation of a germinal center
- Class switching, affinity maturation, somatic hypermutation occur here
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
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
Which cells express MHC class II?
Professional antigen-presenting cells have MHC class II. They present antigen to CD4+ Helper T-cells
What occurs in the “proliferation of epithelial cells” 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
Which PID is caused by a defect in bruton tyrosine kinase?
X-linked agammaglobulinemia (XLA)
(the most common early-onset agammaglobulinemia)
What components of our immune system recognize intracellular pathogens?
NOD receptors
RIG-1 helicase
What is the function of IL-2?
Promotes T cell growth and activation
What are some of the specialized components of the respiratory immune system?
- Tonsils
- Adenoids
- Ciliated respiratory epithelial cells (respiratory elevator)
- Secretory IgA, IgM, IgG
Which antibody is most abundant in a primary immune response?
IgM
What is AIRE?
Which immune process is it important in?
AIRE = Autoimmune regualtor
- A transcription factor expressed in T-cell maturation during positive selection
- Induces the synthesis of an array of self-peptides that are presented on MHC I and II by medullary thymic epithelial cells
- If a TCR binds too tightly, the thymocyte undergoes apoptosis or becomes a regulatory T-cells
What are the functions of follicular dendritic cells (FDCs) in the germinal center?
- 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
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
In the processing and presentation of intracellular antigens on MHC class I, where does the antigen bind to MHC class I?
The endoplasmic reticulum
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
Where is CD20 expressed?
B-cell surface
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
Which cells are CD3+, CD4+, CD25+?
Regulatory T-cells
What is a T-cell superantigen?
What does it do?
A superantigen is a protein that can directly bind to MHC class II and subsequently a TCR without internal processing by the APC.
- The superantigen can activate multiple T-cells at a time, regardless of TCR antigen specificity
- -> uncontrolled cytokine release by the T-cell and APC
- -> Increased IL-2, IL-1, TNF
- Can contribute to illness and death
(ex: toxic shock syndrome)
- Can contribute to illness and death
- -> Increased IL-2, IL-1, TNF
- -> uncontrolled cytokine release by the T-cell and APC
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
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
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
Which cells are defective in DiGeorge syndrome?
Why?
T cells are deficient
DiGeorge is caused by a 21q11 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
What are “clusters of differentiation”?
Nomenclature system for the proteins used to identify cells
Ex: B-cells are CD19+
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
Pneumococcal vaccines consisting of polysaccharide components must be conjugated with proteins in order for children under the age of 2 to be protected.
Why?
Conjugation with proteins allows T-cells to recognize the polysaccharide comonents and mount an immune response.
Children under the age of 2 have impaired T-cell independent B-cell immune responses; they are relying on a T-cell dependent response for protection, and protein conjugation is required for T-cells to recognize and respond
Describe oxygen-dependent killing by neutrophils
- In the respiratory burst, NADPH oxidase forms the superoxide radical
- Superoxide dismutase turns the superoxide radical into hydrogen peroxide
- Myeloperoxidase turns hydrogen peroxide into a hypochlorite ion
- The hypochlorite ion is the most effective killer of pathogens
Describe “organization of the wound” in 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
What is the general mechanism of sensitization to an antigen?
Sensitization occurs the first time the immune system sees the antigen (primary exposure)
- Antibodies form and/or memory T-cells form
- This primes the immune repsponse for a stronger reaction upon any subsequent exposure
Describe feedback inhibition of the humoral immune response
- IgG produced in an immune response provides negative feedback
- B-cells have receptor for Fc portion of IgG (Fc(g)RIIB)
- Binding activates signaling through immunomodulary Tyrosine-based inhibition motif (ITAMs)
- Terminates BCR response to the antigen
What is an immunogen?
An antigen that induces and immune response
Can be a
- Protein
- Large multivalent non-protein
- Immunogenicity depends on size, repetition
Why is it important to limit inflammatory responses, especially at epithelial barriers?
Inflammation causes loss of epithelial integrity
- Cells ceparate
- Tight junctions open up
Which two molecules are the most common costimulatory molecules in T-cell activation?
- B7 on the APC, which binds to CD28 on the T-cell
- Cytokines that bind to cytokine receptors on the T-cell
- Usually IL-2
What is the effect of affinity maturation?
Why is it important?
Affinity maturation increases a the specificity of antibodies produced by B-cells for a specific antigen
The more tightly antibodies can bind to an antigen, the stronger and more targeted the immune response is
What are the mediators of endothelial cell contraction?
(Endothelial cell contraction -> Increased vascular permeability)
- Prostaglandins
- Leukotrienes
- Bradykinins
- Histamines
- Others
Which mediators of inflammation increase vascular permeability?
Prostaglandins
Leukotreines
Bradykinins
Histamines
What compounds are key to immunity against encapsulated bacteria?
Antibodies and complement
They opsonize bacteria so that neutrophils and macrophages can recognize and phagocytose them
What are the 4 stages that T-cells go through in T-cell development?
What is expressed at each stage?
Where does each stage occur?
-
T-cell precursor develops in the bone marrow and migrates to the thymus
- CD3-, CD4-, CD8- (on surface)
- CD3 is expressed in the cytoplasm, not on the surface
- CD3-, CD4-, CD8- (on surface)
-
Double-negative stage occurs in the cortex of the thymus
- CD3-, CD4-, CD8-
-
Double-positive stage occurs in the cortex of the thymus
- CD3+, CD4+, CD8+
- Double-positive thymocytes undergo positive selection
-
Single-positive stage begins in the cortex and ends in the medulla of the thymus
- CD3+, CD4+ OR CD3+, CD8+
- Single-positive thymocytes undergo negative selection
What type of hypersensitivity reaction causes systemic anaphylaxis?
Type I (immediate/anaphylactic)
What are the soluble mediators of inflammation?
- Proinflammatory cytokines
- Arachidonic acid products
- Bradykinins
- Histamines
Where do memory cells exist?
Lymphoid tissues
What are the steps of antigen recognition and B cell activation?
- Antibody variable region of the IgM component of the BCR recognizes and binds a specific antigen
- Binding leads to receptor cross-linking in association with Ig-alpha/Ig-beta (CD79a/CD79b) and phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs)
- ITAM phosphorylation triggers downstream signaling pathways
In general, what is required for CD8+ cytotoxic T-cell activation?
2 signals
- TCR and coreceptor CD8 recognize and bind to the peptide bound to MHC I, presented by an APC
- Cytokines secreted from CD4+ cells
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
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
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
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
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)
Which complement proteins inhibit the formation of C3 convertase?
C1 esterase inhibitor
Decay accelarating factor (CD55)
Describe the specificity of a BCR on a B cell
Each B cell has a BCR specific for only one antigen
(Or very similar antigens)
How are complement proteins activated?
Activated in a cascade of cleavage reactions
This allows proteins and immune complexes to be destroyed or eliminated
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
What is CTLA-4?
Which cells express it?
A T-cell inhibitory molecule
- Secreted 48 to 96 after T-cell activation
- Expressed by TRegs
- Binds to B7 on APCs
- This prevents binding of B7 to CD28, a costimulatory signal in T-cell activation
- Inhibits Il-2 synthesis, leading to T-cell cycle arrest
- preventsT-cell growth and differentiation
- Inhibits Il-2 synthesis, leading to T-cell cycle arrest
- This prevents binding of B7 to CD28, a costimulatory signal in T-cell activation
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
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
Which mediators of inflammation mediate pain?
Prostaglandins
Bradykinin
What costimulatory signals are required for an effector T-cell to initiate an immune response?
None!
Effector T-cells initiate an immune response immediately after binding to antigen
What is the major cytokine involved in fibrosis?
TGF-beta
List the hypersensitivity reactions from fastest to slowest.
Give their time-frames
- Type I; seconds to minutes
- Type II; minutes to hours
- Type III; hours to days
- Type IV; days to weeks, even months
- Think latent TB infection
Which type of hypersensitivity is described below?
A hypersensitivity reaction involving mast cells, basophils, and pre-formed IgE
Type I: Immediate/anaphylactic
What are the possibilities for the constant region of a heavy chain?
- Mu (IgM)
- Delta (IgD)
- Gamma (IgG)
- Alpha (IgA)
- Epsilon (IgE)
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
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
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)
Describe the engulfment stage of phagocytosis
Neutrophils ingest bacteria by invagination of the cell membrane around the bacteria to form a vacuole (phagosome)
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
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
A defect in organelle trafficking that prevents the formation of phagolysosomes; this prevents the killing of pathogens, leading to recurrent infection
What are the stages of repair in healing by first intention?
- Hemorrhage and formation of a blood clot
- Acute inflammation
- Proliferation of the epithelial cells
- Organization of the wound
- A scar composed of connective tissue w/ scant inflammatory cells
What is affinity maturation?
- The process of selection for increased affinity/avidity in B cells in the germinal center
- The B-cells whose antibodies bind most tightly to the antigen presented by FDC are selected for
- They go on to become memory B-cells and plasma cells
- This occurs after B cells have undergone somatic hypermutation in the germinal center
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 (Encoded by RAG1/RAG2)
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
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
What is the pattern on pathogens that cells of our innate immune system recognize?
PAMPs (pathogen-associated molecular patterns)
What is an invariant chain? What does it do?
A protein sythesized in the ER
Binds to MHC II to prevent inappropriate binding to peptide fragments before MHC II reaches the specialized endosomal intracellular vesicle
How are monocytes/macrophages involved in inflammation?
- Monocytes and macrophages express pattern recognition proteins
- Recognize PAMPs (ex: CD14/TLR4 recognizes LPS)
- Release pro-inflammatory cytokines/mediators and stimulate acute phase reponse
Macrophages also release anti-inflammatory cytokines to control immune response
What determines specificity in innate immunity?
Proteins recognize common patterns of infectious organisms (PAMPS)
Not very specific
Which cells link innate and adaptive immunity?
Antigen presenting cells (APCs): Macrophages and dendritic cells
What are some of the specialized components of the cutaneous immune system?
Keratinocytes
Langerhans cells
Dendritic cells
Where is the complement binding region (IgM and IgG) of an antibody found?
Fc portion of the antiboty (part of the heavy chain contant region)
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
Which components of the BCR are expressed in each stage of B cell development?
- Pro-B cell has no heavy chains
- Pre-B cell has cytoplasmic mu heavy chains and is pre-BCR, successful gene rearrangement of mu heavy chain
- Immature B cell has IgM surface BCR, successful gene rearrangement of the light chain (kappa or lambda)
- Naive B cell has IgM, IgD surface BCR
What is the principal mechanism of repair in healing by first intention?
Epithelial regeneration
What is the role of neutrophils in acute inflammation?
- Drawn towards inflammatory mediators from macrophages and mast cells (Chemotaxis)
- Phagocytose and destroy organisms
- Release further cytokines to draw additional neutrophils
Note: Neutrophils have a hard time engulfing encapsulated bacteria
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
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
