Role of Bone Marrow T Cells, Transendothelial Migratory T Cells and Anti-Endothelial Cell Antibodies in the Pathogenesis of Autoimmunity.

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1. MRL-lpr/lpr mouse has defect in apoptosis due to abnormal Fas gene and develops autoimmune diseases. Ceramide is an important mediator of intracellular signal transduction from Fas-Fas ligand interaction, and the cell membrane-permeable form C2-ceramide induced apoptosis in CD3+CD4-CD8-(DN) T cells from MIRL-lprllpr mice. FTY72O is a novel immunosuppressive agent resembling sphingosine in chemical structure. Oral administration of FTY72O as well as C2-ceramide reduced the number of DN T cells in lymph nodes and spleen of MRL-lpr/lpr mice, and significantly prolonged the survival at nine months.2. A monoclonal antibody (4C8) was established, which inhibits the transendothelial migration of T cells without interfering their adhesion to endothelial cells. The 4C8 molecule also acts as the second signal of T cell activation.3. Significantly elevated level of anti-endothelial cell antibody was found in SLE patients associated with pulmonary hypertension. One of the antigen recognized by anti-endothelial cell antibodies was identified as ribosomal P0 protein. Anti-ribosomal PG protein antibodies were found in sera from the patient with systemic lupus erythematosus(SLE). Positive anti-ribosomal P0 protein antibodies were associated with central nervous system involvement in SLE.A close temporal relationship of liver disease to anti-ribosomal P0 protein antibodies and central nervous system disease was also found in SLE patients.