Systemic Lupus Erythematosus (SLE) is the archetype of an autoimmune disease and can involve any organ system eventually leading to comorbidities that can also be observed independently of underlying SLE. The complex pathogenic mechanisms leading to and being involved in this autoimmune-inflammatory syndrome are not well understood. However, complement C1q, the first component of the classical pathway, seems to play a central role. By analysing the role of C1q as well as it’s interaction with autoantibodies targeting C1q (anti-C1q) in SLE, the primary goals of the proposed projects are to elucidate 1) mechanisms being involved in the initiation of autoimmunity, 2) mechanisms of secondary acceleration of inflammation, and 3) processes being associated with comorbidities.With regard to mechanisms being involved in the initiation of SLE, homozygous C1q deficiency is the strongest genetic risk factor for the development of SLE. Vice versa, in SLE patients without primary C1q deficiency, C1q is consumed during disease flares, deposited in affected tissues and becoming a target of autoantibodies (anti-C1q). By the characterisation of structures targeted by anti-C1q we aim to understand mechanisms leading to the development of SLE.Secondly, C1q mediates and modulates the uptake of apoptotic cells, a mechanism that is defective in SLE patients. In the context of a defective clearance, dying cells can become antigenic and trigger the autoimmune response. In previous studies I could show that anti-C1q specifically recognize C1q when being bound to apoptotic cells and that anti-C1q induce a proinflammatory phenotype in macrophages being associated with reduced phagocytic capacity. To explore mechanisms of secondary inflammation, I will further investigate how C1q and anti-C1q interact with other mediators of inflammation.Thirdly, our previous analyses of bone marrow-derived human anti-C1q identified sequence homologies with von Willebrand Factor (vWF). In analogy to anti-C1q, vWF also binds to C1q leading to consecutive platelet rolling and adhesion, thus establishing a novel link between C1q and primary hemostasis. The focus of the third part of our project is to elucidate this link, in particular with regard to comorbidities as observed in SLE. Taken together, the proposed projects will elucidate the role of complement C1q and anti-C1q in interaction with other mediators of inflammation and factors that have been implicated in the pathogenesis of SLE. These data will also improve the understanding of immune-mediated pathology occurring related to but independently of autoimmunity.