Systemic lupus erythematosus (SLE) is characterized by diverse clinical and laboratory findings and multiple, frequently opposing cellular and cytokine aberrations. The T cell receptor (TCR) 6 chain is decreased in SLE T patients because of limited promoter activity, instability of an alternatively spliced TCR 6 mRNA missing crucial AU response elements and increased degradation by caspase 3. Its pace in the CD3 complex is taken by the FcR3 chain which signals through Syk. Lipid rafts form aggregates on the surface of T cells and together with the rewired TCR account for the aberrant signaling process in SLE T cells. In the lipid aggregates the adhesion molecule is present in increased amounts, which signal through ezrin. CD44 and phosphorylated ezrin positive cells are found in the kidneys of patients with lupus nephritis. It is hypothesized that altered cell surface membrane-mediated signaling in SLE T cells results in aberrant T cell function including inappropriate expression of adhesion molecules and homing to inflamed tissues. The objective of the proposed studies is to explore the role of TCR rewiring (FcR3 ->CD36) in effector SLE T cell function and establish the central role of Syk-mediated signaling in the expression of the SLE T cell phenotype and disease pathology. In addition, the contribution of cell membrane-mediated signaling in upregulating the expression of the adhesion molecule CD44 that results in inappropriate homing of T cells to the kidney will be studied. The proposed studies suggest the presence of molecular targets that can be modulated with gene transfer or drugs and have the potential to complement existing therapeutic modalities. In addition, they will identify several potential T cell based biomarkers. The long term goal of the ongoing and proposed research is the establishment of a "molecular signature" for each patient, or subgroups of SLE patients that will help the diagnosis and personalized treatment.
Systemic lupus erythematosus afflicts more than one million Americans most of whom are women in the child bearing age. Current treatment is based primarily on indiscriminate immunosuppression. This application will explore the presence of molecular targets that can be modulated with gene transfer or drugs and have the potential to complement existing therapeutic modalities.
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