Systemic lupus erythematosus (SLE) represents the prototype systemic autoimmune disease, in which the human immune system fails to regulate immune reactivity to chromatin and other well-characterized self antigens. The T helper (Th) cell, the central immunoregulatory cell in the normal immune system, mediates the hypergammaglobulinemia and autoantibody formation that result in tissue damage in SLE. CD40 ligand (C40L), a member of the TNF gene family, mediates the Th cell signals that drive B cell activation and differentiation. Several new observations regarding the regulation of CD40L expression on lymphocytes from patients with SLE represent the important preliminary data for the proposed studies: 1) Baseline expression of CD40L is increased in patients with active SLE; 2) Expression of CD40L is prolonged following treatment of SLE T lymphocytes with PMA and ionomycin, a stimulus that bypasses TCR signaling events; 3) Soluble CD40L circulates in SLE and is readily detectable in serum samples from patients. The proposed experiments will investigate potential mechanisms and functional consequences of altered regulation of CD40L expression in SLE. The hypothesis to be pursued is that in SLE, impaired regulation of T cell activation results in excessive Th cell function, autoantibody formation, inflammation, and disease. CD40L is both a marker and mediator of this abnormal T cell help.
The specific aims of the project are: I. To Study the Regulation of CD40L Expression in Human T Cells. We will investigate the T cell stimuli required for induction of CD40L mRNA and protein expression, the biochemical pathways that mediate induction of CD40L, the regulation of soluble CD40L production, and the effect of cytokines on expression of cell surface and soluble CD40L. II. To Study the Regulation of CD40L Expression in SLE. We will characterize the baseline activation status of SLE T cells, study the effects of costimulatory molecules and cytokines on induction of CD40L expression in SLE, study transcription and post-transcriptional regulation of CD40L mRNA in SLE, and assess cleavage and clearance of cell surface CD40L in SLE. III. To Study the Functional Properties of Cell Surface and Soluble CD40L in SLE. We will characterize the functional properties of T cell subpopulations expressing CD40L in SLE, and study the functional effects of soluble CD40L on target cell populations. These studies should elucidate disease pathogenesis and identify new targets for therapy in SLE.
