Abstract
IgG receptors (FcγR) are critical in immune complex (IC)-mediated tissue damage. We performed reverse passive Arthus reactions, a model of IC-mediated cutaneous vasculitis, in normal C57Bl/6 mice and mice genetically deficient in C1q, C4, C3, and Factor B. We hypothesized classical complement pathway (CP) down-regulates while alternative complement pathway (AP) promotes IC binding to activating FcγR; therefore, CP deficiency (C1q-/-, C4-/-, C3-/-) would enhance the IC-induced cutaneous vasculitis, while AP deficiency (FB-/-) would diminish it. Sedated, shaved mice were injected intradermally with 20μl PBS on one side and rabbit anti-BSA IgG 5μg on the opposite. BSA 100μg and 125Iodine-labeled BSA 1.25μg with 1% Evans blue was then injected intravenously. After 4 hours, skin sections were weighed, radioactivity was measured (cpm/gm of tissue), and an Arthus index (AI) was calculated for each mouse (cpm/gm treated skin/control skin cpm/gm). Significant differences in AIs were analyzed by Kruskal-Wallis test, followed by Mann-Whitney tests. Complement absence strongly influenced degree of cutaneous vasculitis (p<0.001). Compared to normal mice (mean 2.5±1.2), C1q-/- (mean 3.6±0.8, p<0.05) and C4-/- (mean 4.7±2.3, p<0.05) exhibited more extensive vasculitis, and C3-/- (mean 3.5±0.5, p=0.05) trended towards greater vasculitis. FB-/- (mean 1.4±0.4, p<0.05) mice exhibited reduced vasculitis. Cutaneous vasculitis is significantly greater in CP-deficient mice and reduced in AP-deficient mice. Our results are first to provide in vivo evidence that complement critically influences IC and FcγR-mediated inflammation. They also refute previous data suggesting complement possesses no role in Arthus-induced vasculitis and may further understanding of why CP-deficient individuals are susceptible to autoimmunity.
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