lecture 13 complement system

Question 1

What is the complement system needed for?

Answer 1

Lysis of targets
Opsonization of particular antigens
Activation of inflammatory responses
Clearance of immune complexes by phagocytic cells

Question 2

Describe the classical complement pathway

Answer 2

Requires antibodies to bind to multivalent antigen on the cell membrane and formation of the C1 complex

IgM molecules bind to antigens on bacterial surface, planar → staple form
C1q binds to one bound IgM molecule
Activation of C1r, which cleaves and activates the serine protease C1s
Cleavage of C4 → C4a/C4b
Cleavage of C2→ C2a/C2b
Combination of C4b and C2a → C3 convertase
Cleaves C3 → C3a and C3b
C4b2a3b → C5 convertase

IgG molecules bind to antigens on the bacterial surface
C1q binds to at least 2 IgG molecules
Activation of C1r, which cleaves and activates the serine protease C1s

Question 3

Describe the lectin complement pathway

Answer 3

Mannose binding lectin and ficolins recognize and bind carbohydrates on pathogen surface
Specific to bacteria and viruses since mammalian cells do not have mannose on cell surface
MBL, produced during inflammation, binds to mannan on glycoproteins on surface of microbes
MBL associated serine proteases (MASP) bind to MBL
Similar to C1r and C1s
Come together to form C1-like complex
Cleaves C4 and C2 to cleave into a and b
Produces C4bC2b aka C3 convertase
Cleaves C3 → a and b
C4b2a3b → c5 convertase

Question 4

Describe the alternative complement pathway

Answer 4

Initiated by the particles of microbial origin (G- bacteria, LPS, fungal cell walls etc)
Requires Factor B, Factor D and properdin protein
Complement proteins bind to cell surface
Plasma factor B via factor D → Bb and Ba
Bb binds with spontaneously cleaved C3H20 to make fluid [hase C3 convertase (C3h20Bb)
C3bBb → stable C3 convertase also made
Cleaves C3 → C3a/C3b
Forms C3bBb3b→ C5 convertase

Question 5

At what point do the complement pathways converge? What is the purpose?

Answer 5

At the formation of C5 convertase
Cleaves C5 inot C5a and C5b
C5 b binds w C6,7+8 to polymerize C9 and form a poly C9 complex (MAC)
membrane attack complex → disruption of osmotic integrity, resulting in cell lysis and death

Question 6

What is the role of C5a and C3a in inflammation?

Answer 6

C5a/C3a receptors on granulocytes and macrophages stimulate the release of proinflammatory cytokines from basophils, eosinophils, neutrophils and macrophages
act as chemotactic agents
The 2 are anaphylatoxins and cause the systemic activation mast cells (anaphylaxis)

Question 7

What is the outcome of complement deficiency?

Answer 7

Reduced inflammatory response and lysis of microbes

Reduced bacterial clearances with longer periods of infection

Question 8

Explain the regulation of C1r and Cs

Answer 8

C1q binds to Ag-Ab complexes, activating C1r2s2 (C1 complex)

Via acute phase plasma protein C1 inhibitor that prevents C1 complex from being proteolytically active

Question 9

What does a complement inhibitor deficiency cause?

Answer 9

Hereditary angioedema resulting in cutaneous angioedema and severe abdominal pain