Humoral Immunity Flashcards
What two properties of antibodies are determining factors for effector function?
Heavy chain isotope switching (C region) and affinity maturation to enhance function
What are the effector functions of IgG?
Neutralization of microbes and toxins, opsonization for phagocytosis, activation of classical complement pathway, ADCC, neonatal immunity, feedback inhibition of B cell activation (Fc receptor)
What is the effector function of IgM?
Classical complement pathway activation
What is the effector function of IgA?
Mucosal immunity
What are the effector functions of IgE?
Defense against helminths and mast cell degranulation
What receptor extends the half life of IgG?
Neonatal Fc Receptor
How does the neonatal Fc receptor extend the half-life of IgG?
- Soluble IgG is phagocytosed into the endosome.
- IgG binds the Fc receptor in the endosome and is sorted to the recycling endosome instead of being degraded.
- At the plasma membrane, FcRn lets go of IgG at physiologic pH
Where is the neonatal Fc receptor expressed?
Placenta (important for passive immunity), endothelium, and phagocytes
How does IgG neutralize toxins and microbes?
Binds microbes or toxins and keeps from binding receptors or crossing epithelium. Most effective vaccines work via this method (diphtheria toxin)
What type of microbes are killed by opsonization and phagocytosis by IgG?
Encapsulated bacteria
What are the steps to opsonization and phagocytosis?
- IgG coats microbe
- IgG with microbe (IgG1 or IgG3): IgG Fc region binds high-affinity Fc receptors (FCgammaR1) on phagocytes. (requires >1 Ab binding)
- Fc receptor signal activates phagocyte and microbe ingested.
What type of infections are patients who undergo splenectomy susceptible to?
Infections by encapsulated bacteria because spleen is a major site for opsonization
Describe the affinity for IgG, where it is found, and the function of the FCgammaR1 receptor
High affinity for IgG
Found on macrophages, neutrophils, and eosinophils.
Function= phagocytosis
Describe the affinity for IgG, where it is found, and the function of the FCgamma RIIA receptor
Low affinity for IgG
Found in macrophages, neutrophils, eosinophils, and platelets
Function= phagocytosis
Describe the affinity for IgG, where it is found, and the function of the FCgamma RIIB receptor
Low affinity for IgG
B lymphocytes, dendritic cells, and mast cells
Feedback inhibition****
Describe the affinity for IgG, where it is found, and the function of the FCgammaRIIIA (CD16) receptor
Low affinity for IgG
Natural killer cells**
Antibody-dependent cellular cytotoxicity**
Describe the affinity for IgG, where it is found, and the function of the FCEpsilon R1 receptor
High affinity for IgE**
Mast cells, basophils, eosinophils
Degranulation of mast cells and basophils
What is antibody dependent cellular cytotoxicity and what Fc receptor is used?
Natural killer cells express FC gamma RIIIA and bind IgG stuck to antigen coated cells. Can also be used for tumor cells
Describe mast-cell mediated reactions with IgE
- IgE binds helminth
- IgE binds to FCEpsilonR1 receptor on eosinophils and receives IL-5 from TH2 cells
- Both receptor binding and IL-5 cause activation of eosinophils, degranulation, and release of toxic mediators
How is the alternative complement pathway activated?
C3 spontaneously activates to C3b
**Does NOT require antibodies
What happens after C3b binds the microbe plasma membrane in the alternative complement system?
C3a is released and Bb binds to C3b to form C3 convertase
What is the function of C3 convertase?
Cleavage of C3 into C3b and C3a
How is the C5 convertase complex formed in the alternative pathway?
C3b binds the C3 convertase complex.
What is the function of C5 convertase?
Massive cleavage of C5 into C5b and C5a
How is the classical complement system initiated?
C1qr2s2 binds Fc on IgG on microbe PM
What happens after C1 binds the Fc receptor on IgG in the classical complement system?
C1 undergoes conformational change to activate the r&s serine proteases
What do the r&s serine proteases do in the classical complement pathway?
Cleave C4 and C2 into C4b and C2a
What molecules make up the C3 convertase in the classical complement pathway?
C4b and C2a
How is the lectin complement system pathway initiated?
Mannose binding lectin binds terminal mannose residues of microbial carbohydrates
What happens after MBL binds the microbe in the lectin complement system?
MBL associated protease cleaves C4 into C4b and C2 into C2a
What are the functions of C3 in the alternative pathway?
Opsonin and component of C3/C5 convertase. C3a stimulates inflammation
What is the function of factor B in the alternative complement pathway?
Serine protease that is the active component of C3/C5 convertase
What is the function of factor D in the alternative complement pathway?
Serine protease that cleaves factor B bound to C3b to activate it
What is the function of properdin in the alternative complement pathway?
Stabilizes C3 convertase
What is the function of C1 in the classical complement pathway?
binds Fc on Ab. R&S components cleave C4 and C2
What is the function of C4 in the classical and lectin complement pathways?
C4b binds microbe surface and binds C2 for its cleavage by C1 or MBL protease.
C4a stimulates inflammation
What is the function of C2 in the classical and lectin complement pathways?
Serine protease for active C3/C5 convertase
How is the membrane attack complex formed and what is its function?
C5b is bound by C6, C7, C8, and C9.
C9 polymerizes to form a pore so water and ions can enter to lyse the cell
What are the three functions of the complement system?
- opsonization and phagocytosis (via C3b binding microbe and being recognized by C3b receptor on phagocytes)
- complement-mediated cytolysis
- Stimulation of inflammatory reaction
What three complement proteins formed in the complement pathways stimulate inflammation?
C5a, C3a, C4a (in order of potency)
Recruit leukocytes
How do DAF and C1 inhibit the alternative and classical complement pathways?
Interfere with C3 convertase formation by either displacing Bb or C4b
What is the function of MCP?
Cofactor for factor 1 cleavage of C3b to inhibit it.
What is the role of C1-INH in the classical pathway?
C1 inhibitor that inhibits the C1 complex and can bind the MBL to inhibit the lectin pathway
What is the role of CD59 in the complement system?
blocks C9 binding and prevents MAC formation
What diseases are associated with deficiencies in C1, C2, C4?
Increased recurrence of infections and susceptibility to lupus
Are C3 deficiencies common clinically?
No, C3 deficiency is usually fatal
A deficiency in C9/ MAC formation is associated with what disease?
Nisseria infections
Describe the pathology of paroxysmal nocturnal hemoglobinuria
RBCs lack DAF/CD59 complement inhibitors. RBCs are susceptible to MAC attack and lysing.
What is one treatment for paroxysmal nocturnal hemoglobinuria?
Eculizumab anti-C5 antibody
A defect in what component of the complement system is associated with hereditary angioedema?
Lack of C1-inhibitor. C1-inhibitor also functions to inhibit the cleavage and activation of kallikrenin. Active kallikrenin= bradykinin release. NOT a complement-mediated disease
Heterozygous mutations in what genes are associated with atypical hemolytic uremic syndrome?
MCP (cofactor for C3b cleavage/ inactivation) Factor H (binds C3b to prevent Bb binding) Factor I (cleaves C3b and C4b to inactivate)
Describe the pathology and treatment for atypical hemolytic uremic syndrome
Small clots form in blood vessels (systemic thrombotic microaniopathy)
Treat with Eculizumab
What is the CH50 test?
Measurement of classical complement pathway efficiency by measuring amount of RBC lysis. Result= amount of serum for 50% RBC lysis
What are three ways pathogens have evolved to evade the humoral immune system?
- Antigenic variation (switch up Ags: HIV/ flu)
- Inhibition of complement activation
- Resistance to phagocytosis (pneumococcus)
