Autoantibodies against complement component C1q in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is the archetype of a systemic autoimmune disease, but the multifaceted pathogenic mechanisms leading to inflammation and organ damage are not fully understood. Homozygous deficiency of complement C1q, the first component of the classical pathway of complement, is strongly associated with the development of SLE, thus pointing at a primarily protective role of C1q. However, while most SLE patients do not have hereditary C1q deficiency, there is indirect evidence for the importance of C1q in the inflammatory processes of the disease, including hypocomplementemia as a result of activation via the classical pathway, deposition of C1q in affected tissues and the occurrence of autoantibodies against C1q (anti-C1q). The growing body of knowledge on anti-C1q led to the establishment of a biomarker that is used in the routine clinical care of SLE patients. Exploring the binding characteristics of anti-C1q allows to understand the mechanisms, that lead to the expression of relevant autoantigenic structures and the role of genetic as well as environmental factors. Lastly, the analysis of the pathophysiological consequences of anti-C1q is of importance because C1q, the target of anti-C1q, is a highly functional molecule whose downstream effects are altered by the binding of the autoantibody. This review summarises current study data on anti-C1q and their implications for the understanding of SLE.

Keywords: C1q; SLE; anti‐C1q antibodies; complement; systemic lupus erythematosus.

Figure 1

Conceptual model of the origin of anti‐C1q. (a) Physiologically, the clearance of apoptotic cells by professional phagocytes is an anti‐inflammatory process partially mediated by bound C1q. (b) In the context of an altered clearance of apoptotic cells by phagocytes, those phagocytes could induce an immune response, eventually leading to the production of autoantibodies targeting antigens that are exposed on the surface of apoptotic cells, such as many intracellular antigens as well as surface‐bound bridging molecules including C1q. The process of autoantibody generation against C1q seems to be facilitated by the previous infection with the Epstein–Barr virus (EBV) as a result of the presence of preformed antibodies cross‐reacting with EBNA‐1 of EBV and cryptic antigens being expressed on bound C1q.

Figure 2

(a) Secondary effects of anti‐C1q. Once being present, anti‐C1q can enhance complement activation and (b) secondarily enhance the induction of pro‐inflammatory phagocytes with reduced phagocytic activity. These inflammatory cells together with complement activation may trigger further downstream inflammation including T‐cell activation, and lead to the development of proliferative lupus nephritis.