C3a

**Generation:** C3 is the most abundant complement protein. C3 convertases cleave it into C3a (small fragment, released) and C3b (large fragment, which deposits on surfaces). The convertases are C4b2a (classical and lectin pathways) and C3bBb (alternative pathway). C3b also joins the convertases to form C5 convertases (C4b2a3b and C3bBb3b), which cleave C5 into C5a and C5b.

**Function:** - C3a is an anaphylatoxin, along with C4a and C5a. In potency, C5a is much greater than C3a, which is greater than C4a. - It binds C3aR, a G protein-coupled receptor, on mast cells, basophils, eosinophils, neutrophils, monocytes/macrophages, and endothelium. - Mast cells and basophils degranulate and release histamine. This causes vasodilation, increased vascular permeability, smooth muscle contraction (bronchoconstriction), and edema. - It has some chemotactic and activating effects on eosinophils and other leukocytes. C5a is the more important chemotactic complement factor for neutrophils. - C3a has both pro-inflammatory and, in some contexts, regulatory roles (for example, in T-cell responses and in neutrophil mobilization from bone marrow).

**Regulation:** Carboxypeptidase N rapidly removes the C-terminal arginine to make C3a-desArg, which is inactive as an anaphylatoxin. (C5a-desArg keeps some chemotactic activity.)

**Clinical correlations:** - **Complement-mediated anaphylactoid reactions** are seen with transfusion reactions, radiocontrast media, and dialysis membranes (complement activation, "complement activation-related pseudoallergy"). - **Hereditary angioedema (C1 esterase inhibitor deficiency):** Uncontrolled C1 activity consumes C4 and C2, so C4 is low. The swelling is mainly bradykinin-mediated, not anaphylatoxin-mediated, so it does not respond to antihistamines or epinephrine. - **C3 deficiency:** Severe recurrent pyogenic (encapsulated organism) infections and increased risk of type III hypersensitivity (immune-complex) disease, such as SLE-like disease and glomerulonephritis. - **C3 nephritic factor** (an autoantibody that stabilizes C3bBb) causes membranoproliferative glomerulonephritis/C3 glomerulopathy, with persistently low C3. - **Factor H or factor I deficiency** causes uncontrolled alternative pathway activation with C3 consumption. It is associated with atypical HUS and C3 glomerulopathy. - **Therapy:** Eculizumab blocks C5 cleavage (so no C5a or MAC). Pegcetacoplan (a C3 inhibitor) blocks C3 cleavage and thus C3a and C3b generation. It is used in PNH.

**High-yield mnemonics and pearls:** - Anaphylatoxins: C3a, C4a, C5a. - C3b is the main opsonin. C5a is the main neutrophil chemotaxin. C3a is mainly an anaphylatoxin. - Anaphylatoxins act through mast cell degranulation, which resembles type I hypersensitivity effects but does not need IgE. - Terminal pathway deficiencies (C5–C9) predispose to Neisseria infections.