Related Experiment Videos
Regulation of apoptosis of synovial fibroblasts
1Division 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
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.
Insights
Defects in apoptosis, or programmed cell death, are not the cause of human autoimmune diseases. Studies show excessive immune cell death and decreased parenchymal cell death, suggesting new therapeutic targets.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- The Fas gene mutation in lpr mice causes autoimmune disease due to defective T and B cell apoptosis.
- This defect leads to immune cell accumulation and impaired immune response regulation.
- This suggested a potential role for apoptosis defects in human autoimmune diseases.
Purpose of the Study:
- To investigate the role of apoptosis defects in human autoimmune diseases.
- To analyze proapoptotic and antiapoptotic pathways in patients with autoimmune conditions.
- To determine if immune cell apoptosis defects contribute to autoimmune disease pathogenesis.
Main Methods:
- Analysis of proapoptotic genes (Fas, Fas ligand, Bcl-X, caspases) and antiapoptotic pathways.
- Examination of genetic defects at RNA, protein, and functional levels in human autoimmune disease patients.
- Assessment of peripheral blood mononuclear cells (PBMCs) and synovial cells (RASF) apoptosis.
Main Results:
- Most studies indicate excessive apoptosis of PBMCs in human autoimmune diseases.
- This finding suggests that defective immune cell apoptosis is not the primary cause of human autoimmune disease.
- Some evidence points to decreased apoptosis in parenchymal cells like RASF, which exhibit hyperplasia.
Conclusions:
- Human autoimmune diseases are not caused by defective apoptosis of immune cells.
- Therapeutic strategies may need to focus on promoting apoptosis in specific cell types, such as RASF.
- Modulators of apoptosis, including gene therapy and compounds like wortmannin, show potential for treating conditions involving RASF hyperplasia.