Autoimmunity is the consequence of conspiring effects of genetic predisposition and environmental stimuli. Strong evidence indicates that infection can be involved in initiation of autoimmunity. In what is perhaps the best example of this association, Epstein Barr Virus infection appears to predispose to development of Systemic Lupus Erythematosus. How infection prompts the loss of immune tolerance is unknown. It seems likely that infection somehow undermines mechanisms responsible for the silencing of autoreactive cells. Three such mechanisms are operative in silencing of autoreactive B cells;receptor editing, clonal deletion and anergy. Anergic B cells are the most obvious targets of environmental contributions to autoimmunity because these cells uniquely persist in peripheral organs for a period of time where they are exposed to infectious agents and innate immune mediators that could reawaken them. It is unclear how the antigen unresponsiveness of anergic cells is maintained biochemically or whether infectious agents or innate signals can restore or complement their response to autoantigen. Our recent studies indicate that maintenance of B cell anergy requires chronic antigen receptor (BCR) occupancy and transduction of signals. Preliminary findings indicate that these "anergy maintenance" signals mediated by biased BCR activation of inhibitory feedback signaling circuitry in which the SH2 domain- containing phosphatidylinositol 5-phosphatase SHIP-1 is a primary mediator. We hypothesize that SHIP-1 mediates the unresponsiveness of anergic B cells to antigen as well as to the survival factor BAFF, and propose to test this possibility in aim 1. Studies proposed in aim 2 will address the effect on anergy of gamma herpes virus infections and TLR signals known to be associated with autoimmunity. Do these agents target anergic B cells and mediate their effects by disrupting anergy maintenance signaling or by bypassing this circuitry. Do these agents prompt departure of cells from the anergy and drive them to make autoantibodies, and do they enable them to be recruited into ongoing responses to autoantigen-mimicking foreign immunogens. The proposed studies will employ immunoglobulin transgenic models of B cell anergy as well as naturally occurring anergic B cells derived from normal mice. These models will be used in conjunction with biochemical and molecular genetic approaches to define regulatory signaling circuitry, and elucidate the effect of MgHV infection, as well as innate immune and T helper signals on anergic cell function. The proposed studies should advance our understanding of the genesis of autoimmunity by defining circumstances in which immunologic tolerance is broken by infectious agents and by mutations that disable molecular regulatory mechanisms critical for maintenance of anergy.
The development of autoimmune diseases, such as systemic lupus erythematosus (Lupus), is often proceeded by infection with specific viruses and bacteria. These associations suggest that certain infections disrupt mechanisms that silence B cells specific for self antigens. We propose to define the molecular mechanisms by which gamma herpesvirus infections, e.g. EBV in human and gHV68 in mouse, re-awaken anergic B cells thereby leading to autoimmunity. Results of these studies may provide new strategies for prevention, diagnosis and treatment of autoimmunity.
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