- A long-term goal of the principal investigator's laboratory is to understand the immune circuits and pathogenetic mechanisms leading to the initiation and progression of renal and vascular disease in murine SLE. For these purposes, novel genetically autoimmune-prone MRL/lpr mice that are either B- or T-cell deficient have been developed. Genetic complementation and cellular and humoral reconstitution of these mice will be used to examine the role(s) of B cells, T cells, and autoAbs in causing renal and vascular disease. Initial characterization of these mice has revealed that both B and T cells are absolutely required for expression of disease. Particularly surprising was the absence of interstitial and vascular disease in B-less MRL/lpr mice, as these lesions had been considered to be T-cell-mediated. A clue to this puzzle may be recent preliminary data suggesting that spontaneous T cell activation is inhibited in B-less MRL/lpr mice, revealing a previously unsuspected immunoregulatory role of B cells in autoimmune pathogenesis. These new models, along with additional knockout and transgenic mice described below, provide a powerful means to elucidate the pathogenesis of nephritis and vasculitis. This proposal will exploit these mice to address two related questions: 1) What is the mechanism by which spontaneous expansion and activation of peripheral T cells inhibited in B-less MRL/lpr mice and what is the significance of these T cells? It is hypothesized that autoreactive B cells, through cognate Ag-specific interactions, play a critical role in development of autoreactive, spontaneously activated peripheral T cells. This question will be addressed by: a) phenotypic and functional characterization of T cells in B-less and B-sufficient MRL/lpr mice; b) transfer of T cells from these mice to T-less MRL/lpr mice, to determine their in vivo functional capacity; and c) assessment of the costimulatory requirements for elicitation of these T cells by analyzing T cell phenotypes and function in MRL/lpr mice with mutations in Class II, CD40, and B7.2. 2) Why and how does the absence of B cells prevent interstitial nephritis and vasculitis? It is hypothesized that lack of B cell APC function (vs. autoAb secretion) prevents renal infiltration of T cells, thereby preventing these lesions. Question 2 will be addressed by: a) assessment of renal disease in novel MRL/lpr mice which have IgM-expressing B cells that cannot secrete Ab; b) analysis of renal pathology in T-less MRL/lpr mice reconstituted of with all components necessary to cause disease except T cells and c) analysis of renal pathology in the MRL/lpr knockout mice developed above. Results, the investigator believes, should considerably enhance knowledge of how autoreactive T cells are activated and the relative pathogenic roles of T and B cells.
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