In contrast to its role in central tolerance (nonresponsiveness toward abundantly expressed self antigens), the contribution of the thymus to peripheral tolerance (tolerance to self antigens that are only minimally expressed and/or are expressed by only one or a few organs) is not well understood. Thus the long-term objective of the proposed research is to determine if reduction or loss of intrathymic expression of self antigens contributes to failure of peripheral tolerance and induction of autoimmune disease. As an initial step towards this objective we will focus our efforts on a unique animal model, i.e. Iupus-prone BW mice that express a human C- reactive protein (CRP) transgene as a neo-self antigen. Despite recent reports that CRP-transgenic (CRPtg) mice tolerate human CRP due to thymic expression of the transgene, aged CRPtg/BW mice express high titers of serum anti-human CRP autoantibodies. This mimics the situation seen in patients with SLE. We hypothesize that in BW mice the loss of tolerance to CRP and other 'organ-specific' peripheral antigens is accelerated due to compromised thymic expression. To test this hypothesis we will focus our efforts on three specific aims. 1) We will determine the time-course of thymic expression of peripheral autoantigens in autoimmune versus normal mice. Thymic expression of the candidate autoantigens CRP, myelin basic protein (MBP), Fas ligand (FasL), and thyroglobulin will be quantitated for female mice of various ages. Thymic expression in autoimmune CRPtg/BW versus nonautoimmune CRPtg strains (CRPtg/NZW and CRPtg/B6) will be compared. 2) We will determine if intra and extrathymic expression of peripheral autoantigens are differentially regulated. Constitutive and induced hepatic versus thymic expression of CRP and serum amyloid P-component will be compared for CRPtg BW, NZW, and B6 mice. Endotoxin, IL-6, and testosterone will be used for inductions. 3) We will determine if development of autoimmunity coincides with compromised thymic expression of antigens. The time-course of serum CRP expression, development of the anti-CRP auto-antibody response, and T-cell responsiveness to human CRP will be determined for CRPtg/BW mice. Thymic expression of human CRP will be induced experimentally in aged CRPtg/BW mice to determine if this delays the anti-CRP response. These studies provide a unique opportunity to document the spontaneous loss of tolerance to a peripheral self-antigen normally tolerated via intrathymic expression. Inadequate levels of expression of tissue-specific genes in the thymus, causing impaired self tolerance, might be a common mechanism of disease.
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