Pathways Of Complement Activaton

Question 1

Step of the alternative pathway

Answer 1

1. Spontaneous breakdown of C3 generating C3a and C3b
2. C3b attaches to microbial surfaces
3. Plasma factor B binds to C3b forming C3bB
4. C3bB is cleaved by factor D which creates Bb (larger attaching to C3b) and Ba (smaller and releases)
5. C3bBb complex forms which is the alternative pathway for C3 convertase (leads to a ton more of C3b and C3a)
6. C3b will then bind to C3bBbC3b which is pathway for C5 convertatse
7. C5a and C5b are created which leads to late stage complement activation (formation of MAC)

Question 2

What happens when C3bBb complex forms on mammalian cells?

Answer 2

It is rapidly degraded. C3bBb can only occur on microbial cells

Question 3

What is the role of Properdin?

Answer 3

A complement regulatory protein that bind to and stabilize the C3bBb complex on microbes

ONLY positive regulator of complement activation

Question 4

Steps in Classical Pathway

Answer 4

1. Binding of C1 to IgG or IgM Ab bound to microbial Ag
2. C1 complex has C1q, C1r, C1s subunits
3. Activated C1s cleaves C4 to generateC4b and C4a (C4b remains attached)
4. C2 is cleaved by C1s giving C2a and C2b
5. C2a (or 2a) binds to C4b on microbial surface to generate C4b2a complex
6. C4b2a is classical pathway for C3 convertase
7. C3b binds to C4b2a creating C4b2aC3b which is the C5 convertase

Question 5

What is mean by the Complment system has amplification?

Answer 5

C3b which is created in the classical pathway can bind to Bb in the alternative pathway and give C3bBb (C3 convertase)

This leads to an net effect of multiple enzymatic steps and leads to 100s-1000s of C3b on the microbe to kill it

Question 6

Steps in the Lectin Pathway

Answer 6

1. Microbial mannose residues bind to plasma mannose binding lectin (MBL)
2. This activates Mannose binding lectin-associated serine protease (MASPs)
3. MASP-2 cleaves C4 and C2
4. This creates C4b2a which is the C3 convertase in lectin pathway

The rest is the same as the classical pathway

Question 7

Steps in late stage Complement activation and formation of the MAC

Answer 7

1. The C5 convertase cleaves C5 to create C5a and C5b
2. C5a creates inflammation and C5b binds to the convertase
3. C6, C7, C8 binds sequentially to convertase
4. Once you get C5b, 6, 7, 8 complex it partially inserts into plasma membrane of microbe
5. C9 molecules then polymerize to form the MAC
6. The poly-C9 creates pores in the microbial membrane and induces cell lysis

Question 8

What is the Complement receptor 1 (CR1)?

Answer 8

Expressed on RBCs, PMNs, Monocytes, Eosinophils, DCs

Promotes: phagocytosis of C3b- and C4b - coated microbes

Clearance of immune complexes from circulation

Acts as a cofactor for cleavage of C3b into inactivated (I)C3b)

Disrupts C3 and C5 converatses

Question 9

Why is opsonization and phagocytosis of microbes an important function of complement system

Answer 9

It’s best for pathogens with thick cell walls of polysaccharide capsules, where MAC is ineffective (pneumococci and meningococci)

It works because C3b or C4b deposition on microbial surface is bound by phagocytes expressing CR1 which leads it to go under phagocytosis and killing of microbes