Paper I
Question
Role of complement system in inflammation
Answer
The complement system is a group of plasma proteins that, upon sequential proteolytic activation, contribute critically to both innate and adaptive immune responses in inflammation.
Pathways of activation
- Classical pathway: Activated by antigen-antibody (IgG/IgM) complexes binding C1
- Alternative pathway: Activated directly by microbial surfaces (e.g., bacterial cell wall components), without requiring antibody
- Lectin pathway: Activated by mannose-binding lectin binding to microbial carbohydrates
- All three converge on the cleavage of C3, generating C3a and C3b, and ultimately C5, leading to formation of the membrane attack complex
Roles in inflammation
1. Vascular effects (anaphylatoxins)
- C3a and C5a stimulate mast cell degranulation, releasing histamine, which causes vasodilatation and increased vascular permeability
2. Chemotaxis
- C5a is a powerful chemoattractant for neutrophils and monocytes, recruiting them to the site of inflammation
3. Opsonization and phagocytosis
- C3b (and its breakdown product iC3b) coats microbial surfaces (opsonization), enhancing their recognition and phagocytosis by neutrophils/macrophages bearing complement receptors
4. Membrane attack complex (MAC, C5b-9)
- Forms pores in the microbial cell membrane, causing osmotic lysis and direct killing of the pathogen
5. Regulation
- Complement activation is tightly regulated by inhibitory proteins (e.g., C1 inhibitor, decay-accelerating factor) to prevent excessive/uncontrolled activation and host tissue damage
Clinical significance
- Deficiencies in complement components/regulators predispose to recurrent infections (e.g., terminal complement deficiency and Neisseria infections) or, conversely, to uncontrolled complement activation causing tissue injury (e.g., hereditary angioedema from C1 inhibitor deficiency)