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 defined self antigens. The T helper (Th) cell, the formation that result in tissue damage in SLE. CD40 ligand (CD40L), 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 of lymphocytes from patients with SLE represent the important preliminary data for the proposed studies: 1) Baseline expression of CD40L is increased in active lupus patients and the kinetics of expression of CD40L after in vitro activation is prolonged in SLE. 2) CD40L expression is observed on CD8 plus T cell populations in SLE. 3) Soluble CD40L circulates in SLE and is readily detectable in serum samples from patients. The planned experiments will continue the investigation of the mechanisms and regulation of normal T cell help and will characterize the impaired regulation of Th cell function in systemic autoimmunity. 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. a. To characterize the t cell stimuli required for induction of CD40L mRNA and protein expression. b. To characterize the biochemical pathways that mediate induction of CD40L. c. To study the regulation of soluble CD40L production. d. To investigate the effect of cytokines on expression of cell surface and soluble CD40L. II. To Study the Functional Properties of Cell Surface and Soluble CD40L in SLE. a. To characterize the functional properties of T cell subpopulations expressing CD40L in SLE. b. To study the functional effects of soluble CD40L on target cell populations. c. To investigate the hypothesis that CD40L can transduce T cell activating signals. III. To Study the Molecular Mechanisms that Mediate Increased and Prolonged Expression of Cell Surface and Soluble CD40L in SLE. a. To study costimulatory molecule expression on SLE antigen presenting cells. b. To characterize the activation status of SLE T cells. c. To study the regulation of CD40L transcription in SLE. It is anticipated that these studies will elucidate disease pathogenesis and will identify new targets for therapeutic modulation of immune function in disorders of systemic autoimmunity.
| Vakkalanka, R K; Woo, C; Kirou, K A et al. (1999) Elevated levels and functional capacity of soluble CD40 ligand in systemic lupus erythematosus sera. Arthritis Rheum 42:871-81 |
