The generation of autoantibody and subsequent tissue deposition of immune complexes (IC) is thought to trigger the pathogenic consequences of systemic autoimmune disease, including arthritis, vasculitis and nephritis. Uncoupling IC formation from subsequent effector inflammatory responses seemed unlikely because of the apparent complexity of the IC-triggered inflammatory cascade. However, the disruption of a single gene, which encodes the gamma chain of the Fc receptor (FcR gamma), was found to achieve this uncoupling in a spontaneous model of lupus nephritis, the NZB/NZW (B/W. mouse. Gamma chain-deficient B/W mice generated and deposited IC and activated complement, but were protected from severe nephritis, thus defining another potential pathway for therapeutic intervention in autoimmune disease. The mechanism of this uncoupling will be studied herein, by assessing the contribution of Fc receptor bearing resident and circulating cells to the initiation, recruitment and activation of the IC-triggered inflammatory cascade. The point(s) at which the inflammatory cascade is blocked in B/W gamma -/- mice will be defined by analysis of the component processes in nephritis including the sites of IC deposition, the production of inflammatory cytokines by IC- stimulated resident mesangial cells and the composition of recruited inflammatory cells. Cell transfer experiments using transplantation of either bone marrow or kidneys between FcR gamma +/+ (susceptible) and FcR gamma -/- (resistant) mice will establish whether FcR gamma +/+ resident kidney mesangial cells or circulating hematopoietic cells are necessary and sufficient for B/W Lupus-nephritis. A second, genetic approach using lineage specific promoters to drive FcR transgene expression in either the monocyte on neutrophil compartment, will establish whether monocyte or neutrophil FcR expression is sufficient to reconstitute the inflammatory response.
| Bergtold, Amy; Gavhane, Anamika; D'Agati, Vivette et al. (2006) FcR-bearing myeloid cells are responsible for triggering murine lupus nephritis. J Immunol 177:7287-95 |
