Complement, interferon and lupus

The complement pathway was implicated in the immunopathogenesis of lupus and other autoimmune disorders decades ago. The apparent paradox that early complement component (C1q, C2 and C4) deficiencies predispose to lupus has been explained by the beneficial roles of these proteins in promoting the clearance of immune complexes (ICs) and apoptotic cells. Recent findings demonstrate that, in the absence of C1q, instead of ICs binding to monocytes, they preferentially engage plasmacytoid dendritic cells (pDC) so generating interferon (IFN) alpha, the cytokine with potent immune adjuvant properties. C1q opsonized apoptotic cells also exert an immunosuppressive effect through cytokine regulation and the stimulation of additional opsonins by macrophages. C1q was recently reported to impede neutrophil extracellular trap (NET) degradation. NETs are known to promote type I IFN production in SLE by providing a source of antigen for the formation of ICs as well as through direct pDC activation by cathelicidin (LL37). Together, these findings provide both direct and indirect links between two key pathways implicated in lupus pathogenesis: complement and IFN.

► Early classical complement proteins protect against SLE, while late complement proteins promote SLE pathogenesis.
► C1q protects by directly acting as an opsonin for apoptotic cell clearance or through generation of C3 breakdown products.
► C1q also protects by promoting the binding of immune complexes (ICs) to monocytes rather than plasmacytoid dendritic cells.
► C1q binds to DNA released by neutrophils dying by NETosis and may alter susceptibility to DNase degradation.