Complement

Question 1

Complement system

Answer 1

~30 serum proteins/membrane components
Activated by classical, alternative, lectin pathways
Activation involves sequential proteolytic cleavage of substrates that results in cascade reaction
Function is to lyse cells, promote phagocytosis, induce inflammatory response, clear immune complexes

Question 2

Classical complement (A)

Answer 2

Activation requires 1 or more antibody-antigen complexes
C1qr2s2 binds antibody (IgM or 2 IgG)
Release of C1 inhibitor activates C1r, which cleaves and activates C1s
C1s cleaves C4 into C4a and C4b
C2 complexes with C4b and is cleaved by C1s to yield C4b2a (C3 convertase)

Question 3

C3 convertase (Classical B)

Answer 3

Splits C3 into C3a and C3b

C3b complexes with C4b2a to generate C5 convertase

Question 4

C5 convertase (Classical C)

Answer 4

Splits C5 into C5a and C5b
C5b complexes with C6, leading to recruitment of C7, C8, C9
C5b789 promotes C9 polymerization, forming cytolysis membrane attack complex which creates pores in target cell membrane, bacterial cell walls and viral envelops (perforin pore)

Question 5

Alternative Complement Pathway (A)

Answer 5

In absence of antibody
Initiated by spontaneous hydrolysis of C3 to C3a and C3b
C3b deposits on microbial surfaces and complexes with Factor B from serum
Factor D cleaves complexes Factor B to generate C3bBb (C3 convertase)

Question 6

C3 Convertase (Alternative B)

Answer 6

C3 convertase is stabilized by properdin
Generates additional C3b which combines withFactor B to produce more C3bBb (amplification)
C3b complexes with C3bBb to yield C3bBb3B (C5 convertase)
Now same as classical pathway

Question 7

Lectin Complement Pathway

Answer 7

Involved in innate immunity, no antibody
Activated by interaction of mannose-binding lectin with mannose residues on glycoproteins/carbohydrates expressed by certain microorganism
MASP1 and MASP2 bind MBL on microbe surface, forming complex (C1 like) that is able to cleave C4 and C2
Proceeds like classical pathway

Question 8

Biological functions of complement

Answer 8

Inflammation is stimulated by anaphylatoxins (C3a, C4a, C5a)
C3a and C5a are chemotactic for granulocytes and monocytes and cause platelet aggregation
Opsonization of microbes by C3b, C3bi, C4b promotes phagocytosis
C3b interacts with CR1 on erythrocytes to opsonize clearance