T Cell Activation in Lupus Proteomic Characterization

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is characterized by IgG autoantibodies to ubiquitous intracellular components. Several inbred mouse strains also develop spontaneous lupus, with the same spectrum of autoantibodies. Certain of these specificities are pathogenic, including those directed against chromatin that induces immune-complex glomerulonephritis. Such autoantibodies in lupus appear to arise as a consequence of autoantigen-specific CD4 + T cell help. While the mechanisms of tolerance escape for T cells responsive to ubiquitous self peptides are unknown, central (thymic) T cell tolerance appears intact in spontaneous lupus; thus, a peripheral defect(s) presumably leads to activation of autoreactive T cells in this disorder. The hypothesis to be addressed in this proposal is that naive CD4 + T cells from lupus-prone MRL mice have intrinsic (genetic) defects that, compared to non-autoimmune T cells, render them hyperresponsive after T cell receptor (TCR)-CD3 complex contact with self-peptides, a defect(s) that contributes to tolerance loss with expansion of autoreactive T cells in secondary lymphoid organs. This hypothesis is based upon published work that naive T cells from Fas (CD95)-intact, lupus-prone MRL (MRL/+ FaS/lpr) mice are hyper-proliferative after TCR stimulation in vitro, compared to T cells from nonautoimmune mice, and that such T cells avoid peripheral tolerance induction in vivo. This data suggests that these differences are integral to the lupus phenotype, rather than reflective of differences in strains, a belief bolstered in part by the finding that T cells from humans with SLE have a similar hyper- proliferative phenotype after TCR engagement in vitro. In this proposal, the biochemical mechanisms responsible for the hyper-proliferative phenotype of CD4 + T cells in lupus will be addressed using state of- the art proteomic analysis to determine if the observed phenotypic differences in CD4 + T cell activation are associated with alterations in protein expression compared to control cells.