A central focus of the immune response in systemic lupus erythematosus is the U1 small nuclear ribonucleoprotein particle (U1 snRNP). Both anti-Sm and anti-U1 RNP antibodies, markers for the diagnosis of SLB, target this snRNP. Antibodies of the same specificity also arise in lupus that occurs spontaneously in MRL/Mp-lpr/lpr (or in MRL/Mp-+/+) mice. One hypothesis to explain the induction of these autoantibodies in humans and mice with lupus is that snRNP-specific autoreactive T cells provide help for their production, and that such T cells are triggered by peptides of self-snRNP proteins presented by class II MHC molecules. To address this hypothesis, this proposal will investigate mechanisms of presentation of snRNP peptides by class II heterodimers to CD4+ T cells, and the role of snRNP specific T cells in autoantibody amplification. Support for the hypothesis that self snRNPs are directly involved in autoreactive T cell activation and anti-snRNP antibody production is based in part upon the recent observation that self-reactive CD4+ T cells can be generated in normal mice to intact, self (murine) snRNPs. In this model, the mechanism for tolerance abrogation is the generation of cross-reactive B cells, initially primed by foreign (human) snRNPs (molecular mimics), which can bind, process, and present self snRNPs, with the subsequent activation, of autoreactive T cells. Additionally, it appears that such autoreactive T cells can drive autoantibody production to multiple proteins of self snRNPs. This model provides support for the notion that autoreactive T cells are present in the normal murine repertoire, and that they can be activated by self snRNPs after immunization of mice with molecular mimics, with the resultant production of anti-snRNP autoantibodies. Activation of autoreactive T cells in spontaneous lupus, followed by autoantibody production, would also presumably require a source of self snRNP peptides. Thus, in the current proposal, mechanisms whereby snRNP peptides may be presented to CD4+ T cells by class II MHC molecules will be explored. snRNP-specific autoreactive T cells will also be generated and fully characterized, and their ability to amplify autoantibody production determined.
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