Novel effects of complement activation and the complement receptors 1, 2, and 3 on immune cell regulation

The complement system is comprised of over 30 serum and membrane-bound proteins that function to recognize and eliminate microorganisms as well as mediate inflammation. Regulation of complement activation and execution of complement effector functions occurs at the level of complement receptors. Both C3 and the complement receptors CD21/35 have identified roles in generating proper immune responses, such as antibody production. To better understand the functions for C3 and complement receptors in immune cell regulation we analyzed mice deficient in CD21/35 and C3. We characterized the splenic microenvironment from mice deficient in CD21/35 proteins on B cells and FDCs. Gene expression analysis between naive WT and CD21/35-/- splenocytes indicated a deficiency in CD21/35 proteins within the spleen leads to local inflammation, that we further demonstrate is dependent upon inflammatory cell-infiltrate and complement activation. Consistent with the established role for CD21/35 as a member of the B cell co-receptor complex, a potential modulator of B cell receptor-induced calcium responses is also described. To explain inconsistencies between antibody phenotypes of C3-/- and CD21/35-/- mice, immune receptors on C3-/- B cells were investigated. B cell analysis demonstrates an increase in CR3 surface expression levels, which is further shown to be dependent upon local production of C3 within the splenic follicle. These data demonstrate that the interactions between complement activation products and complement receptors on B cells and FDCs have important, previously undescribed roles in mediating inflammation and immune responses.