Anti‐C1q autoantibodies from systemic lupus erythematosus patients enhance CD40–CD154‐mediated inflammation in peripheral blood mononuclear cells in vitro

OBJECTIVES: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease with complex pathogenic mechanisms. Complement C1q has been shown to play a major role in SLE, and autoantibodies against C1q (anti‐C1q) are strongly associated with SLE disease activity and severe lupus nephritis suggesting a pathogenic role for anti‐C1q. Whereas C1q alone has anti‐inflammatory effects on human monocytes and macrophages, C1q/anti‐C1q complexes favor a pro‐inflammatory phenotype. This study aimed to elucidate the inflammatory effects of anti‐C1q on peripheral blood mononuclear cells (PBMCs). METHODS: Isolated monocytes, isolated T cells and bulk PBMCs of healthy donors with or without concomitant T cell activation were exposed to C1q or complexes of C1q and SLE patient‐derived anti‐C1q (C1q/anti‐C1q). Functional consequences of C1q/anti‐C1q on cells were assessed by determining cytokine secretion, monocyte surface marker expression, T cell activation and proliferation. RESULTS: Exposure of isolated T cells to C1q or C1q/anti‐C1q did not affect their activation and proliferation. However, unspecific T cell activation in PBMCs in the presence of C1q/anti‐C1q resulted in increased TNF, IFN‐γ and IL‐10 secretion compared with C1q alone. Co‐culture and inhibition experiments showed that the inflammatory effect of C1q/anti‐C1q on PBMCs was due to a direct CD40–CD154 interaction between activated T cells and C1q/anti‐C1q‐primed monocytes. The CD40‐mediated inflammatory reaction of monocytes involves TRAF6 and JAK3‐STAT5 signalling. CONCLUSION: In conclusion, C1q/anti‐C1q have a pro‐inflammatory effect on monocytes that depends on T cell activation and CD40–CD154 signalling. This signalling pathway could serve as a therapeutic target for anti‐C1q‐mediated inflammation.