Hypothesis-Apoptosis-inducing molecules mediate the autologous monocyte/macrophage (Mphi) killing caused by CD4+ lupus T cells, and target cell killing by this mechanism can lead to the generation of autoantibodies (autoAbs). Introduction.-Increased apoptosis of monocytes/macrophages (Mphi) occurs in lupus (SLE), and CD4+ T cells from SLE patients kill autologous Mphi. In addition, autoreactive murine CD4+ T cells kill Mphi in vitro and induce anti-DNA Abs in vivo, suggesting that this killing might contribute to the autoantibody response by providing a source of antigenic DNA. We have reported that Fas- Ligand (FasL), TRAIL (Apo 2-Ligand) and TWEAK (Apo 3-Ligand) are involved in Mphi killing induced by murine CD4+ lymphocytes. We intend to determine the pathways involved in Mphi apoptosis induced by CD4+ T cells in SLE. We will also test whether it is possible to inhibit the development of autoimmunity in an SLE animal model, by blocking the apoptotic pathways involved in Mphi killing by autoreactive CD4+ T cells. Finally, the role of apoptosis in triggering or augmenting autoimmunity will be investigated. Methods A) By flow cytometry, expression of death-receptor ligands will be compared in T cells from SLE patients, patients with other autoimmune diseases and healthy controls. B) With cytotoxicity assays, we will determine whether these pathways mediate the APC apoptosis induced by CD4+ T cells in SLE patients. C) We will determine if inhibition of molecules downstream of the 'death-receptors'-apoptotic cascade (FADD/caspases) can decrease/abolish Mphi apoptosis in vitro. D) In vivo studies will be performed to characterized whether the blockade of Mphi apoptosis- inducing molecules by monoclonal Abs or fusion proteins, can inhibit the development of a murine SLE model, and whether the elimination of tissue Mphi per se (with clodronate liposomes in vivo) is sufficient to induce autoimmunity in an animal model. Significance- The results of the studies proposed may characterized mechanisms involved in the generation of autoantigens in SLE. This could lead to the development of novel therapeutic interventions designed to rever5se these abnormalities and abrogate or block the onset and/or severity of this disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Center Core Grants (P30)
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University of Michigan Ann Arbor
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