Class II MHC antigens regulate the immune response by presenting antigen to CD4+ T cells, leading to their activation. The expression of class II MHC genes is regulated by a non-DNA binding protein, class II transactivator (CIITA) the """"""""master control factor"""""""" for class II MHC transcription. Appropriate constitutive and inducible expression of class II MHC antigens is essential for normal immune function, while aberrant expression has been correlated with autoimmune diseases, including multiple sclerosis. The costimulatory molecule, CD40, upon interaction with its cognate ligand CD154 on T cells, promotes the expression of numerous cytokines/chemokines by the CD40 expressing cells. In the inflamed CNS, class II MHC and CD40 molecules are aberrantly expressed by microglia and macrophages, allowing them to function as antigen presenting cells. This leads to activation of autoreactive CD4+ T cells, and subsequent inflammation and demyelination. IFNgamma is the most potent inducer of class II MHC and CD40 expression, and plays a pivotal role in the initiation of intracerebral immune responses. We hypothesize that aberrant CIITA, class II MHC and CD40 expression in microglia/macrophages results in detrimental immunologic activities in the CNS. As a corollary, we propose that downregulation of these molecules will result in a reduction of immune responsiveness in the CNS. Restricting expression of class II MHC and CD40 molecules in the CNS can be achieved by a new family of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS proteins function as negative regulators of cytokine signaling, especially those such as IFNgamma that utilizes the JAK/STAT pathway. Currently, there is no information regarding the expression or function of SOCS proteins within the CNS. In this study, we will examine the ability of microglia/macrophages to express SOCS proteins, both constitutive and cytokine-inducible expression (AIM 1). Next, SOCS gene expression in MS brain will be examined (AIM 2). We will determine the cellular localization of SOCS proteins within the CNS, the disease specificity of SOCS expression, and the extent of SOCS expression in different stages of MS lesions. Lastly, the ability of SOCS proteins to modulate IFNgamma-induction of class II MHC and CD40 in microglia/macrophages will be tested by stable transfection of SOCS-1 and SOCS-3 proteins in these cells (AIM3). Our studies will provide the first biological assessment of SOCS production and function in cells of the CNS, thereby setting the foundation for future therapeutic manipulations of these critical immunoregulatory proteins.
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