4: Complement System 🏁

Question 1

How does the complement activation work?

Answer 1

3 pathways: classic (CP), lectin (LP), alternative (AP) all ending in MAC-formation (C5bC6C7C8C9n) and recruitment of other factors by C5a

Question 2

Main facts about the complement system

Answer 2

• part of innate immunity
• can activate adaptive immunity
• recognises PAMPs and DAMPs
• effector molecules existing mainly in precursor state

Question 3

start of the classic pathway

Answer 3

1. C1q recognises Fc part of bound antibodies (IgM and ≥2 IgG)
2. hydrolysis of C4 and C2 into a/b parts
3. Association of C4bC2b (C3 conertase)
4. hydrolysis of C3 by C4bC2b
5. Association of C4bC2bC3b (C5 convertase)
6. further cleavage of C5
7. MAC-formation with C5b

Question 4

start of the lectin pathway

Answer 4

1. lectin (MBL) recognises mannose
2. hydrolysis of C4 and C2 by MASP on MBL
3. hydrolysis of C3 by C4bC2b
   -> further cleavage of C5 and MAC-formation

Question 5

start of the alternative pathway

Answer 5

1. spontaneous hydrolysis of C3 to C3H2O and binding to factor B
2. factor D cleaves B to Bb and Ba
3. C3H2OBb is C3 covertase that cleaves more C3
4. C3b only active if bound to cell surface
5. B bounds to C3b on cell surface and cleaved to Bb by factor D
6. complex gets stabilised by properdin on cell surface
7. C3bBb complex deposits many molecules of C3b on pathogen surface
   -> opsonisation and also further cleavage of C5 and MAC-formation

Question 6

What are the important receptors involved with complement?

Answer 6

C3b recognition:
- CR1 on Erys, Monocytes, Neutro- & Eosinophils, B- & T-cells, follicular DCs
- CR2 on B-cells, activated T-cells, epithelial cells, Basophils, follicular DCs
- CR3 on Monocytes, Neutrophils, NK cells, B1- & T-cells, DCs
- CR4 on Monocytes, Neutrophils, NK cells, activated B-cells, T-cells, DCs

also extra C3aR and C5aR

Question 7

Which fragment mediates opsonisation and immune complex clearance?

Answer 7

C3-fragments
- C3b leads to opsonisation and regulates clearance of immune complex via CR1
- also regulates immune complex localisation in germinal centres on follicular DCs for B cell survival
- C3d increases immunogenicity (1000 fold) of antigen for b cell activation

Question 8

Which diseases are associated with complement deficiency?

Answer 8

Systemic Lupus erythematosous and bacterial infections - C1q, C1s, C4, C2

current bacterial infections, glomerulonephritis - C3

Neisseria infections - C5, C6, C7, C8, C9, factor D, properdin

Fungi infections - MBL

Question 9

Name some Anaphylatoxins/Anaphylactic proteins

Answer 9

• Histamine
• Serotonine
• Prostaglandine
• Chemo-/Cytokines
• C3a and C5a

—> promote pro-inflammatory environment

Question 10

More diseases where complement is involved in pathogenesis

Answer 10

Sepsis, Alzheimers disease, type 2 hypersensitivity reaction
PNH (CPI anchor missing -> no tethering of C regulatory proteins -> MAC formation -> RBC lysis),
Epidermolysis Bullosa (subepidermal blister, C5aR deficiency protects)