C4A deficiency and elevated level of immune complexes: The mechanism behind increased susceptibility to systemic lupus erythematosus

Objective. Studies of an Icelandic cohort showed that susceptibility to systemic lupus erythematosus (SLE) in individuals with C4A deficiency was increased only in the presence of increased concentrations of immune complexes. We investigated the interaction of C4A deficiency with elevated concentrations of immune complexes in healthy individuals; i.e., how different levels of C4A affected the activation of C4 and C3 and subsequent binding of increased immune complex load to human red blood cells (RBC). Methods. Forty-five healthy individuals having different levels of C4A were studied, 8 with homozygous C4AQ0, 12 with heterozygous C4A deficiency, and 25 with normal C4A. For comparison to the complement status present after prolonged disease activity, 5 patients with SLE homozygous for C4AQ0 were also studied. Results. The results showed that intact immune complex-RBC binding is dependent on the levels of immune complex-bound Q fragments, which correlate to the levels of IC-bound C4Ad (R = 0.677, p = 0.02), but not on levels of IC-bound total C4d (R = 0.451, p = 0.16). Immune complex binding to RBC was also evaluated in increasing immune complex load. C4A deficient sera had less ability to bind the increased immune complex load to RBC than sera with normal C4A. These results are consistent with the presence of increased amounts of poorly opsonized immune complexes in C4A deficiency, leading to increased precipitation in tissues and initiation of a self-perpetuating cycle. Conclusion. Susceptibility to SLE is increased in individuals with C4A deficiency as C3 opsonization of immune complexes becomes insufficient at elevated immune complex concentrations.