L8 - Complement System

Question 1

classical pathway

Answer 1

IgM and/or IgG bind to pathogens. C1q (of the C1 complex) recognizes and binds to the Fc portion of these antibodies. C1q also has the ability to bind directly to certain antigens, such as lipoteichoic acid of Gram+ bacteria and C-reactive protein. A conformational change in the C1 complex results, and C1r is activated to cleave C1s, a serine protease that that cleaves C4 into C4a and C4b. C4a is a small soluble product, whereas C4b attaches covalently to the surface of a pathogen via a thioester bond. C4b binds to C2, which is cleaved by C1s to generate C4b2b (attached to pathogen) and C2a (soluble). C4b2b is known as C3 convertase. Antibodies are relatively heat-insensitive, whereas complement proteins are heat-sensitive.

Question 2

lectin pathway

Answer 2

Lectins, produced by the liver during an acute-phase response, act similarly to C1q. They bind to sugars such as mannose on bacterial surfaces. Mannose-binding lectin binds with MASP1 and MASP2, which behave similarly to C1r and C1s, respectively. They result in C3 convertase (C4b2b) bound to the bacterial surface and soluble C4a and C2a.

Question 3

alternative pathway

Answer 3

The alternative pathway occurs in the absence of a specific protein binding. It is initiated by the spontaneous hydrolysis of C3 into C3b (which can covalently bind with repeated structures, such as LPS) and C3a (soluble). C3b binds to factor B, which allows it to be cleaved by factor D, a process regulated by factor P. The result is the generation of C3bBb (attached to pathogen) and Ba (soluble). C3bBb is a C3 convertase.

Question 4

roles of complement system

Answer 4

1. kill pathogens (MAC)
2. induce inflammation
3. opsonization
4. clear immune complexes

Question 5

complement system opsonization

Answer 5

C3b and C4b serve as opsonins for complement receptors (CRs) on macrophages, but C5a is also needed to activate the macrophages

Question 6

complement system immune clearance

Answer 6

C3b or C4b bind to CR1 on erythrocytes

Question 7

complement inhibitors

Answer 7

• C1INH: binds C1
• Factor I: cleaves C3b and C4b
• CD59 (protectin): prevents formation of MAC

Question 8

defects in classical pathway

Answer 8

immune complex disease

Question 9

defects in lectin pathway

Answer 9

repeated childhood infections

Question 10

defects in alternative pathway

Answer 10

Neisseria

Question 11

hereditary angioneurotic edema

Answer 11

defect of C1INH; results in clotting and swelling

Question 12

paroxysmal nocturnal hemoglobinurea

Answer 12

genetic defect in GPI synthesis, causing defective expression of CD59, DAF, and HRF on erythrocytes; results in hemolysis

Question 13

defect of C1INH; results in clotting and swelling

Answer 13

hereditary angioneurotic edema

Question 14

genetic defect in GPI synthesis, causing defective expression of CD59, DAF, and HRF on erythrocytes; results in hemolysis

Answer 14

paroxysmal nocturnal hemoglobinurea