Systemic lupus erythematosus (SLE) is characterized by diverse clinical and laboratory findings and multiple, frequently antithetic cellular and cytokine aberrations. It has been established that the T cell receptor (TCR) chain is decreased in SLE T patients independently of disease activity and treatment. Additional discoveries made recently include: First, the _ chain homologous FcsRI 3, (FcR_,)chain was found upregulated and to become part of the TCR; second, signaling molecules, including the FcR,/, were found to be components of preformed rafts on the SLE T cell membrane; and third, it was found that defects at three distinct levels were responsible for the decreased expression of _ chain in SLE T cells, that is decreased transcription, decreased half life of the _ chain mRNA and increased proteolytic degradation of _ chain. Prior studies and preliminary data have lead to the hypothesis that altered antigen receptor signaling in SLE T cells is the result of altered expression of signaling chains that compose the TCR and the signal-mediating rafts. The hypothesis will be tested in the following aims: 1. Define the mechanisms that are involved in the decreased expression of chain in SLE patients, i. Define the role of defective expression of the TCR _ chain enhancer Elf-1 in the decreased expression of _ chain, ii. Define the role of the repressor cAMP response element modulator in the suppression of _ chain gene transcription, iii. Study the TCR _ chain mRNA stability in SLE T cells, iv. Define the extent to which ubiquitination contributes to the degradation of _ chain in SLE T cells. 2. Study the composition and kinetics of rafts on the surface membrane of SLE T cells. 3. Characterize the transcriptional requirements for the increased expression of FcR3, chain. The findings of these studies will reveal biochemical and molecular defects that underwrite the aberrant lymphocyte function and lymphokine production in patients with SLE. Abnormal steps can be reversed with drugs and have the potential to complement existing therapeutic modalities.
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