Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by profound T cell effector dysfunction. The fundamental molecular mechanisms underlying T cell dysfunction remain largely unknown. Infection-related morbidity and mortality rates are high among patients with SLE and attributed to disease activity, the use of immunosuppressive drugs and deficient cell-mediated cytotoxic responses that are associated with decreased expression of interleukin-2 (IL-2). Besides the contribution to the increased rate of infections, decreased IL-2 production is involved in the defective activation-induced cell death that is important for the elimination of autoreactive T cells and the generation of T regulatory cells, which are believed to be decreased in SLE patients. Evidence suggests that the production of IL-2 is controlled at the gene transcription level. Specifically, it has been documented that SLE T cells have increased amounts of serine/threonine phosphatase 2A (PP2Ac) which limits the amounts of the phosphorylated (p) cAMP responsive element binding protein (CREB), a transcriptional enhancer. The increased expression of PP2Ac appears to be controlled at the transcriptional level through a CpG motif and single nucleotide polymprphisms (SNPs) located throughout the gene. In addition, certain regulatory B subunits of the PP2A trimolecular complex are aberrantly expressed in SLE T cells and account for specific T cell malfunction. Finally, a novel mouse over expressing PP2Ac in T cells produces increased amounts of IL-17 and is prone to glomerulonephritis. The hypothesis that PP2Ac represents a main contributor in the immunopathogenesis of SLE will be tested by determining genetic and epigenetic mechanisms that control the expression of PP2A in human SLE T cells; establishing the aberrant expression of B regulatory subunits in human SLE T cells and determining how each one of them contributes to a specific abnormal T cell function, and using the Cd2-Pp2ac mouse to establish the contribution of increased expression of PP2Ac in the autoimmune response and pathology. This line of research will generate novel information on the origin of T cell malfunction in SLE patients and will identify novel approaches to correct IL-2 production which will help decrease the rate of infections by restoring immune cell function.
Systemic lupus erythematosus (SLE) is an autoimmune disorder of indeterminate etiology characterized by profound T cell effector dysfunction. Infection-related morbidity and mortality rates are high among patients with SLE and it is attributed to disease activity, the use of immunosuppressive drugs and deficient cell- mediated cytotoxic responses that are associated with decreased expression of interleukin-2. Understanding the molecular mechanisms that account for the decreased production of interleukin-2 will generate novel information which will guide approaches to correct its production and help decrease the rate of infections by restoring immune cell function.
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