Figure 3 Proposed complement-mediated pathways in lupus-associated angioedema. Autoantibodies directed against C1q form immune complexes that may activate (green starburst/arrow) the classical complement pathway and may also promote contact system (kallikrein-kinin) activation. Binding of anti-C1q immune complexes to C1q may activate the C1 complex (C1r/C1s), leading to cleavage of C4 and C2 and formation of the C3 convertase (C4b2a complex) with generation of anaphylatoxins such as C3a, which may augment vascular permeability. In parallel, contact system activation (Factor XII → XIIa) may promote conversion of prekallikrein to kallikrein, which cleaves high-molecular-weight kininogen to generate bradykinin, a major mediator of edema. Plasmin may further amplify these cascades by enhancing complement activation. Because C1-INH normally inhibits (red dash) C1r/C1s, XIIa, kallikrein, and plasmin, dysregulation of these pathways can result in excess bradykinin and complement mediators that could contribute to angioedema. The precise mechanism underlying this phenotype remains incompletely understood.