INVESTIGATION OF C1Q AND C1S IN CHRONIC INFLAMMATION AND AUTOIMMUNITY

Abstract

Congenital complete C1s deficiency is a strong risk factor associated with the autoimmune disease systemic lupus erythematosus (SLE). How the serine protease C1s protects against autoimmunity is not easily explained by its specific role in cleaving C4 and C2 of the classical complement pathway.

In this study, a novel C1s substrate, high mobility group box 1 (HMGB1), an alarmin with important roles in both infective inflammation and autoimmunity was discovered. Cleavage of HMGB1 by C1s led to a loss of its synergistic pro-inflammatory cytokines response with LPS on monocytes, macrophages and dendritic cells. Of greater significance is that C1 complex treatment of immune complexes formed from SLE autoantibodies and apoptotic cells supernatant led to both cleavage of HMGB1 and reduced its ability to induce IFN-a production from peripheral blood mononuclear cells.

This novel role of C1s cleavage of a non-complement alarmin may help to explain its protective role against autoimmunity.