Under normal steady state conditions, dying cells are removed by the immune system and an active immune response against cellular constituents is prevented. On the other hand, if dying cells are not efficiently removed, they may provoke autoimmunity. A large number of factors determine the outcome of the dying cell / phagocyte interaction. Amongst these factors are the efficiency of opsonization of apoptotic cells by serum components, especially early components of the classical complement (CCC) pathway; active immunosuppression of the phagocyte, the state of maturation of dendritic cells (DCs) and the cytokines in the milieu. In the first Aim, using purified components and component deficient serum, we will test the hypothesis that CCC are the dominant ligands responsible for immunosuppression of antigen presenting cells (ARC) that have ingested opsonized apoptotic cells. We will also determine how C-reactive protein (CRP) exerts its immunosuppressive effect on ARC and whether the suppressive effects exerted by these pathways can attenuate inflammatory properties of SLE blood cells. Using a defined T cell transgenic system and pseudo self antigen, the second Aim will determine how ingestion of apoptotic cells tolerize CD4+ T cells under steady state conditions. Having discovered novel alterations in DC populations that have ingested apoptotic cells, we will investigate whether suppressive changes fail to be initiated in lupus models that are accelerated by DCs that have ingested apoptotic cells. We have previously shown that maturation of DCs breaks tolerance to intracellular antigens but does not induce clinical disease in normal mice. In the third Aim we will determine what additional factors are required to produce pathogenic autoantibodies. Specifically the roles of type 1 interferons and regulatory T cells will be examined. Successful completion of these specific aims will lead to improved understanding of the mechanisms responsible for low complement and low CRP leading to SLE, for understanding how apoptotic cells attenuate T cell responses to self and will elucidate what specific immunological abnormalities need to be dysregulated in order to change what is normally a tolerizing signal in the immune system into a potent source of self antigen for autoimmunization. ? ? ? ?
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