Complement Component C1q is an Immunological Rheostat That Regulates Fc:FcγR Interactions

Abstract

The complement system appears to play a paradoxical role in the pathogenesis of autoimmune diseases. Although the activation of complement contributes to tissue injury and inflammation, individuals with a genetic deficiency in C1q, the first component of the classical complement pathway, have shown to be highly susceptible for developing systemic lupus erythematosus (SLE), which is characterized by the generation of self-reactive antibodies (Abs) and aberrant lymphocyte activation. Research indicates that the development of SLE can be traced back to a breakdown in the clearance of apoptotic cells and the subsequent deposition of immune complexes (ICs). To investigate the role of ICs in autoimmune pathology, circulating immune complexes were physiologically replicated in vitro through the utilization of recombinant immunoglobulin G1 (IgG1) Fc multimers (GL-2045). IC-mediated engagement of FcγRs on NK cells resulted in the upregulation of the cosignaling molecule, 4-1BB (CD137), demonstrating a comparable response to immobilized intravenous immunoglobulin (IVIG), but not to soluble IVIG or recombinant IgG1 Fc monomers (G001). Since the binding sites for C1q and FcγRs on IgG molecules overlap, the extent to which C1q decoration of immune complexes (ICs) influences their ability to engage FcγRs remains unknown. Experimental data demonstrate that C1q engagement of ICs directly and transiently inhibits their interactions with FcγRIII (CD16) on NK cells. This inhibition occurs by C1q engagement alone as well as in concert with other serum factors. Furthermore, the inhibition of CD16 engagement mediated by avid binding of C1q to ICs is directly associated with IC size and dependent on the concentrations of both C1q and Fc multimers present. Functionally, C1q-mediated Fc blockade limits the ability of NK cells to induce CD137 upregulation, and to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Although C1q is traditionally viewed as a soluble effector molecule, we demonstrate that C1q may also take on the role of an “immunologic rheostat,” buffering FcγR-mediated activation of immune cells by circulating ICs. Thus, the unchecked IC-mediated immune activation may be a functional consequence attributed to a genetic deficiency in C1q, leading to the etiopathogenesis of SLE. These data define a novel role for C1q as a regulator of immune homeostasis and add to our growing understanding that complement factors mediate pleiotropic effects.