L19/20 - Effector Mechanisms in Humoral Immunity I Flashcards
What are the effector mechanisms of antibodies?
- Opsonization
- Neutralization
- Activation of Complement System
Where are complement components found and how are they activated?
Found as inactive plasma proteins widely distributed in tissues and body fluids and activated by proteolysis
What does complement do?
- Promote lysis of bacteria, infected cells, transplanted cells
- Promote opsonization
- Promote inflammation
How many / what produces complement proteins?
More than 30 proteins
- Produced by liver cells, monocytes and macrophages and some epithelial cells e.g. skin
Which fragment is the smaller fragment, ‘a’ or ‘b’?
a is the smaller fragment except for C3, C3b is the smaller fragment
What are the three pathways of complement activation?
- Classical
- Alternative
- Lectin
What is the C3 convertase for the classical pathway?
C4bC2a
What is the C3 convertase for the lectin pathway?
C4bC2a
What is the C3 convertase for the alternative pathway?
C3bBb
What is added to change a C3 convertase to a C5 convertase?
C3b. C4bC2aC3b and C3bBbC3b
Explain the steps of the alternative pathway
- Natural low level hydrolysis of C3 (tickover) leads to intermediates that cleave C3 to C3b and C3a
- C3b can bind to microbial surfaces and binds to B
- B is cleaved by Factor D to Bb (C3bBb convertase)
- Properdin binds and stabailizies the complex
What factor cleaves B?
Factor D
What stabilizies the C3 convertase on microbial surfaces?
Properdin
What degrades C3b in fluid phase?
Factor I and H
Can C3b bind to host cell surfaces?
Yes, but is rapidly inactivated by complement regulatory proteins
What makes up the C1 complex?
C1q, C1r and C1s
What activates C1q and what is the result?
IgM or IgG antibodies or C reative protein (CRP). Induces C1r to cleave C1s to create an active protease
Which IgGs are the best for complement activation?
IgG1 and IgG3
What are the conditions of C1q binding to IgM and IgG?
- IgM must be antigen bound (comformational change)
- Must be bound to 2 IgGs
Explain the steps of the classical pathway?
- C1q binds cell bound Ab and activates C1r2s2
- Activated C1s cleaves C4 (homologous to C3)
- C4b binds to the surface, binds C2 (cleaved by C1) and a C4bC2a convertase forms
Explains the steps of the lectin pathway
- Involves MBL (similar to C1q), binds to MASP (C1rC1s) producing C4a and C4b
- C4b binds to C2, which is cleaved by MASP-2
What is the result of C5 convertase?
Cleavage of C5 into C5a, C5b. Recruitment of C6, C7, C8 and C9 pore onto C5b forming MAC
What are three functions of the complement system?
- Opsonization and phagocytosis
- Stimulation of inflammatory reactions
- Complement mediated cytolysis
How can complement stimulate the inflammatory reaction?
Via C5a and C3a which are anaphylatoxin
What are the opsonins of the complement system
C3b and C4b
Which receptors have high affinity for C3b and what does this mean?
CR1 (CD35) and CR3, macrophages and neutrophils. High functions for phagocytosis
How does CR1-mediated phagocytosis work?
Enhanced by specific IgG also binding to microbe. C3b/CR1 binding and IgG/FcγR binding
How does CR1 help clear immune complexes with respect to erythrocytes?
Erythrocytes have CR1 complexes which bind C3b and antibody/C1q complexes which can be removed by the spleen and liver
What is CR2?
Complement receptor 2 (CD21). A co-receptor for B-cell activation and also a receptor for Epstein Barr virus
- BCR binding to microbial antigen and CR2 to bound C3d enhances BCR signal
How do anaphylatoxins cause inflammation?
Bind to C3a and C5a receptors found on mast cells, endothelial cells and phagocytes
- Induce TNFα release and histamine release by mast cells
What additional role does C5a have?
It is a chemoattractant acting on neutrophils and monocytes
What are some regulatory elements of the complement system?
- C1 inhibitory molecule C1 INH
- DAF, CR1 and MCP regulate C3 convertase production
- Factor I (and H) cleaving (inactivating C3b)
- CD59 (inhibits MAC formation)
How does C1 INH inhibit C1 complex?
Prevents C1r2s2 from becoming proteolytically active, also inactivates MASP2
How does inhibition of C3 convertase work?
DAF, MCP (in classical) and CR1 displace the 2 C3 convertase components. E.g. displacing C2b from C4b or Bb from C3b
How does Factor I mediated cleavage work?
MCP and CR1 act as cofactors for Factor I, mediating proteolytic cleavage of C3b producing iC3b
How does CD59 work?
Inhibits poly-C9 assembly
How do microbes evade complement?
- Recruitment of host complement regulatory proteins. E.g. sialic acid, synthesise proteins to recruit factor H, incorporation of host regulatory proteins. e.g. DAF and CD59
- Inhibition of complement mediated inflammation
What are some diseases of complement deficiency?
- Complement: deficiency in C1, C2 and C4 (systemic lupus erythematosus SLE)
- Alternative: B, D and properdin. Increased infection with Neisseria bacteria
- C3: Increased infection with Strep pneumoniae, Neisseria spp.
