Cell Mediated Renal Injury In Lupus

Brigham And Women'S Hospital, Boston MA

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Abstract

Macrophages (M0) are integral in the pathogenesis of renal disease. Activated M0 induce apoptosis in resident renal cells. M0 rich infiltrates are characteristic of renal disease in the MRL-Fas'pr strain with features that are similar to human lupus. Autoimmunerenal disease in MKL-Fasipr mice is spontaneous, rapid and lethal, and is accompanied by a profound systemic illness. Thus, identifying molecules that regulate M0 numbers and functions in MRL-Faslpr kidneys is central to the pathogenesis of nephritis. Colony Stimulating Factor 1 (CSF-1) is a primary regulator of the M0, responsible for survival, differentiation, and proliferation. There are three distinct CSF-1 isoforms; a cell surface glycoprotein, and two secreted isoforms; a glycoprotein and proteoglycan. Studies in transgenic mice that each only express an individual CSF-1 isoform indicates that there are distinct functions for each CSF-1 isoform during normal development. In light of the importance of CSF-1 in M0 mediated renal disease, it is critical to identify the local sites of CSF- 1 synthesis, and functions of these CSF-1isoforms during lupus nephritis. The actions of CSF-1are exclusively mediated via the CSF-1 receptor (CSF-1R), principally on mononuclear phagocytes. However, CSF-IRs are on intrinsic renal cells, the tubularepithelialcell (TEC). Since TECs are a major source of CSF- 1 during renal inflammation, we suggest that CSF-1 mediated TEC mechanisms are pivotal in the pathogenesis of autoimmune renal disease. We hypothesize that CSF-1 isoforms have shared and unique roles in the pathogenesis of lupus nephritis. To test this hypothesis we propose to use novel genetically constructed mouse strains. The specific aims are: 1) To determine whether CSF-1, and certain individual CSF-1 isoforms, promote lupus nephritis, and the systemic illness in MRL-Fas''"' mice; and 2) To determine the role and location (renal, non-renal) of CSF-1, individual CSF-1isoforms, and the CSF-lR's in the pathogenesis of lupus nephritis, and the systemic illness in MRL-Fas''"" mice. Taken together, the proposed experiments will identify the potential role of CSF-1 isoforms in the pathogenesis of human lupus nephritis and the systemic illness.