Systemic lupus erythematosus is a multifactorial autoimmune disease which has been associated with several genetic, hormonal and environmental factors. TLRs are a group of innate immune system receptors and have been linked strongly to SLE development. Several lines of evidence support the significant role of TLR7 in initiation and progression of autoimmunity. The common presence of anti-β2GPI antibodies in SLE patients and the antagonizing effect of these antibodies on the physiologic roles of the β2GPI may suggest a function for this protein in the pathogenesis of SLE. In addition, a recent in vitro report on the role of anti-β2GPI antibodies in translocation and activation of TLR7 raised the suspicion about the possible interactions between TLR7 and β2GPI in development of SLE. By deleting the β2GPI gene from a TLR7-dependent mouse model of SLE, BXSByaa, we have shown that the absence of this protein causes acceleration of the disease development in these mice with presentation of a more severe phenotype including, large lymphadenopathy huge splenomegaly and increased mortality. Histological and serological studies showed that the absence of β2GPI led to formation of a very severe nephritis in BXSByaa mice and production of a high titer of autoantibodies and inflammatory cytokines including BAFF and IFN-I. Flowcytometery analysis also showed a significant proportional increase in the population of the immune cells involved in the pathogenesis of SLE. In vitro experiments did not show any direct inhibitory or enhancing interaction between β2GPI and TLR7. But we have shown that in the absence of β2GPI there is decreased phagocytosis of apoptotic cells by macrophages in vivo. Impaired phagocytosis has been proposed to be one of the main mechanisms involved in the pathogenesis of SLE. As one of the posttranslational modification reactions, oxidization of antigens has been linked to increase in their immunogenecity. Here we have shown that disrupting of the β2GPI gene causes an increase in the serum titer of anti-oxidized RNA antibodies. This observation which can be a reflection of higher titer of oxidized-RNA may imply the protective role of β2GPI in preventing the occurrence of posttranslational modifications of nucleic acid-containing antigens under pathologic conditions like oxidative stress. These findings may open new areas of research to further investigate the possible roles of β2GPI in inflammation and innate immunity and the autoimmune pathologies that may arise upon disruption of its function.