C5a

**Generation:** C5 convertase (classical/lectin: C4b2a3b; alternative: C3bBb3b) cleaves C5 into C5a (small soluble fragment, ~11 kDa) and C5b (initiates MAC assembly with C6, C7, C8, C9).

**Functions (high-yield):** - **Chemotaxis:** Most important neutrophil chemotactic complement fragment (along with LTB4, IL-8/CXCL8, bacterial N-formylmethionyl peptides). - **Anaphylatoxin:** C3a, C4a, and C5a (C5a is the most potent) bind receptors on mast cells and basophils, causing degranulation (histamine release), which leads to vasodilation, increased vascular permeability, bronchoconstriction, and smooth muscle contraction. - **Neutrophil activation:** Upregulates adhesion molecules (integrins, such as CD11b/CD18), promotes respiratory burst and degranulation; also activates monocytes/macrophages and endothelium. - **Receptor:** C5aR1 (CD88), a G protein-coupled receptor; C5aR2 (C5L2) also exists.

**Pathophysiology/clinical associations:** - **Sepsis/ARDS/transfusion reactions:** Excess C5a drives neutrophil activation and tissue injury, and contributes to inflammatory organ damage. - **Anaphylatoxin effects:** Hypotension, edema, and bronchospasm, which can resemble type I hypersensitivity (but not IgE-mediated). - **ANCA-associated vasculitis:** C5a primes neutrophils for ANCA-mediated activation (alternative pathway amplification loop). Avacopan, a C5aR1 antagonist, is approved for GPA/MPA. - **Terminal complement deficiencies (C5–C9):** Increased susceptibility to recurrent *Neisseria* infections (meningococcemia, gonorrhea). Note that these deficiencies affect C5b-9 (MAC), not C5a's function per se. - **PNH:** Loss of CD55 (DAF) and CD59 on RBCs leads to complement-mediated intravascular hemolysis. Eculizumab and ravulizumab (anti-C5 monoclonal antibodies) block C5 cleavage, preventing both C5a and MAC formation. This raises the risk of *Neisseria* infections, so meningococcal vaccination is required. Also used in atypical HUS and myasthenia gravis (AChR-Ab positive). - **Regulation:** C5a is rapidly inactivated by serum carboxypeptidase N, which removes the C-terminal arginine to form C5a-desArg (much less active).

**Mnemonic:** "C5a **a**ttracts **a**nd **a**ctivates neutrophils" (C3a, C4a, C5a = anaphylatoxins). C3b = opsonization; C5a = chemotaxis; C5b-9 = lysis.

**Common board pitfall:** Don't confuse C5a (chemotaxis/anaphylatoxin) with C5b-9 (MAC, lysis) or C3b (opsonin).