Systemic lupus erythematosus (SLE) is a complex autoimmune disorder marked by an inappropriate immune response to nuclear antigens. Recent whole genome association and more focused studies have revealed numerous genes implicated in this disease process, including ITGAM, Fc gamma receptors, complement components, C-reactive protein, and others. One common feature of these molecules is their involvement in the immune opsonin pathway and in phagocytic clearing of nuclear antigens and apoptotic debris, which provide excessive exposure of lupus-related antigens to immune cells. Analysis of gene-gene interactions in the opsonin pathway and its relationship to SLE may provide a system-based approach to identify additional candidate genes associated with disease able to account for a larger part of lupus susceptibility. © 2010 Elsevier B.V. All rights reserved.