Apoptotic Cells As Immunogens In SLE

University Of Washington, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies to nucleoprotein antigens. We have shown that complement and certain acute phase proteins are deposited on the surface of apoptotic cells and facilitate phagocytosis of the dying cell. Based on the clinical observations that patients with deficiencies of the early complement components develop SLE, that mice deficient in Clq or SAP develop lupus-like autoimmunity and that Clq deficient mice have increased numbers of apoptotic cells in their kidneys, we propose that autoantibodies in SLE arise through failure to process and clear dying cells, particularly at sites of inflammation. To test this idea, we will perform the following studies: In Aim 1, we will define how complement is activated on the surface of dying cells and how pentraxins modulate this process. In Aim 2, we will determine which receptors on macrophages are engaged by different opsonins on the dying cells and will determine the consequences of receptor engagement in terms of anti- or pro-inflammatory cytokine production. In Aim 3, uptake and processing of dying cells will be examined in vivo using two different experimental systems under baseline and inflammatory conditions. The responses will be compared between wild type and mice deficient in opsonins (Aim 1) or receptors (Aim 2) implicated in phagocytosis of dying cells. These studies should elucidate whether the hypothesis proposed is correct. If correct, it will provide the solid scientific background from which to define the molecular basis of human SLE.