title: Regulation of apoptosis of synovial fibroblasts.
abstract: In 1992, the first gene to cause systemic autoimmune disease in mice was identified as the Fas gene that is mutated in lymphoproliferative (lpr mice). These mice exhibited a defect in activation-induced cell death of T cells and B cells in vivo. This leads to the failure of proper clearance and removal of immune cells and defective downmodulation of an immune response. This then leads to the speculation that apoptosis defects, including defects in Fas, Fas ligand and Fas apoptosis signaling, may play a role in defective downmodulation of the hyperimmune response observed in human autoimmune diseases. Over the past 7 years, many scientists have analyzed different proapoptotic genes such as Fas, Fas ligand, Bcl-X, caspases as well as antiapoptosis pathways including defects in Fas and Fas ligand, Bcl-2 and caspase inhibitors. Potential genetic defects have been analyzed at the RNA, protein and functional level in humans with autoimmune disease. Somewhat surprisingly, most studies indicate that there is excessive apoptosis of PBMCs in autoimmune disease and human autoimmune disease suggesting that human autoimmune disease is not due to defective apoptosis of immune cells. Some studies indicate that there is decreased apoptosis of parenchymal cells such as RASF that undergo hyperplasia. Gene therapy and other modulators of apoptosis, such as wortmannin, can be used to faciliate apoptosis of RASF.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham Veterans Administration Medical Center, Birmingham, Ala., USA. John.Mountz@ccc.uab.edu
authors.forename: J D
authors.initials: JD
authors.lastname: Mountz
authors.forename: H G
authors.initials: HG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D051379:Mice; D013583:Synovial Membrane / Q000166:cytology*