Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by pathogenic autoantibodies that are dependent on T lymphocyte interactions with autoantibody producing B lymphocytes. This interaction is reliant on CD40-ligand (CD154), which is expressed on the surface of activated CD4 T cells and which engages its cognate cell surface receptor, CD40, on B cells. Because of its critical and pleiotropic role in the immune system, CD154 expression is normally tightly regulated. Several recent reports have described dysregulated (increased and prolonged levels) expression of CD154 in patients with SLE relative to normal controls. Similar findings have been made in lupus-prone mice, and treatment of these mice with a neutralizing anti-CD154 monoclonal antibody delays and reduces the incidence of glomerulonephritis, a hallmark of SLE. However, similar approaches in humans have not proven efficacious due to unanticipated side-effects involving coagulation. The expression of CD154, like that of other T cell cytokine genes, is controlled at the level of gene transcription and mRNA stability. Therefore, understanding the cis-acting (DNA and RNA regulatory) elements and trans-acting (transcription factor and RNA binding) proteins that control CD154 expression will be critical to understanding both the normal and perturbed regulation of the gene. The initial goal of this study is to establish if transcriptional and/or post-transcriptionally-mediated increases in CD154 mRNA contribute to the increased expression of CD154 in SLE. Potential regulatory cis-elements will be tested for transcriptional or mRNA stabilizing activity in SLE and normal human T cells using reporter genes. Next, transcription factors and/or RNA binding proteins that are involved in the overexpression of CD154 in SLE will be studied. Elucidating the molecular mechanisms that regulate CD154 expression in both normal controls and SLE patients will lead to a greater understanding of the pathogenesis of SLE and to potential new approaches for intervention. Moreover, because of the contributory role of CD154 to other autoimmune diseases, information relevant to the pathology and treatment of arthritis and other autoimmune disorders will also be obtained. Defining the major regulatory regions of the CD154 gene will have potential relevance to any process in which CD154 plays a role. For example, such knowledge may allow for the development of better gene therapy for deficiencies of CD154 and other activation-dependent genes, or more selective immunosuppression of graft rejection.
NIH ExPorter
NIH ExPorter