anaphylatoxin

**Definition:** Anaphylatoxins are low-molecular-weight (~9–10 kDa) fragments released during complement activation: C3a, C4a, and C5a. Potency: C5a > C3a >> C4a (C4a has weak activity and is debated in humans).

**Generation:** - Classical/lectin pathway: C4 cleaved by C1s or MASP-2 → C4a + C4b; C2 cleaved → C2a/C2b; C4b2a = C3 convertase, which cleaves C3 → C3a + C3b. - Alternative pathway: C3bBb = C3 convertase (C3a released). - C5 convertase (C4b2a3b or C3bBb3b) cleaves C5 → C5a (anaphylatoxin, soluble) + C5b (initiates the membrane attack complex, C5b-9).

**Receptors:** C3aR and C5aR1 (CD88) are G protein–coupled receptors (Gq); C5a also binds C5aR2 (C5L2). They are found on mast cells, basophils, neutrophils, monocytes/macrophages, endothelium, and smooth muscle.

**Effects:** - Mast cell/basophil degranulation → histamine release → vasodilation, increased vascular permeability, bronchoconstriction, and smooth muscle contraction. This can mimic IgE-mediated anaphylaxis, which is why they are called anaphylatoxins. - C5a: potent neutrophil chemotaxis and activation, upregulated adhesion molecules, and respiratory burst. - C3a/C5a: promote inflammation, cytokine release, and platelet/endothelial activation.

**Regulation:** Serum carboxypeptidase N removes the C-terminal arginine, producing C3a-desArg and C5a-desArg. C3a-desArg (also called acylation-stimulating protein) loses anaphylatoxin activity. C5a-desArg keeps weak activity and retains some chemotactic activity.

**Clinical correlations:** - Anaphylactoid (non-IgE) reactions: complement activation by radiocontrast media, some drugs, and dialysis membranes. Hypersensitivity type III immune-complex disease (serum sickness, SLE, post-streptococcal GN) generates anaphylatoxins that drive inflammation. - Transfusion reactions (TRALI, anaphylactic reactions) and sepsis/ARDS: C5a contributes to neutrophil dysfunction and organ injury. - Hereditary angioedema (C1 esterase inhibitor deficiency): ↓C4 and ↓C2 with unregulated bradykinin → angioedema without urticaria. This is bradykinin-mediated, not anaphylatoxin-mediated, but C4 is consumed. ACE inhibitors are also a trigger. - Paroxysmal nocturnal hemoglobinuria: deficiency of DAF (CD55) and CD59 on GPI-anchored proteins → complement-mediated hemolysis. Eculizumab (anti-C5) blocks C5 cleavage, so it reduces both C5a and MAC formation. Risk: Neisseria infections, so vaccinate. Avacopan (C5aR antagonist) is used in ANCA-associated vasculitis. - Terminal complement deficiencies (C5–C9): recurrent Neisseria infections.

**High-yield pearls:** - C3a, C4a, C5a = anaphylatoxins; C5a is the most potent. - C5a = chemotaxis of neutrophils; C3b = opsonization; C5b-9 = MAC lysis. - Anaphylatoxin effects are IgE-independent, so they are not blocked by IgE-targeted therapy. Treatment of anaphylaxis is still IM epinephrine first.