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Novel Fas (CD95/APO-1) mutations in infants with a lymphoproliferative disorder
1Department of Pediatrics, School of Medicine, Kanazawa University, Ishikawa, Japan.
Insights
Fas receptor mutations disrupt immune cell apoptosis in children with a lymphoproliferative disorder. This highlights the critical role of Fas-mediated apoptosis in maintaining immune system homeostasis and preventing disease.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- The Fas receptor (also known as CD95 or APO-1) is crucial for regulating immune system homeostasis through apoptosis.
- Lymphoproliferative disorders can arise from defects in immune cell regulation.
Observation:
- Three Japanese children from two families presented with a lymphoproliferative disorder, exhibiting symptoms like lymphadenopathy, hepatosplenomegaly, pancytopenia, and hypergammaglobulinemia.
- Activated T cells, B cells, and granulocytes from these patients showed defective apoptosis when induced by anti-Fas monoclonal antibody (mAb).
Findings:
- Two siblings had a truncated Fas receptor due to a point mutation in the intron 7 splice region, lacking the death domain.
- The third patient had a homozygous point mutation in the intron 3 splice acceptor of the Fas gene, leading to exon 4 skipping and complete loss of Fas expression.
- Patients exhibited decreased soluble Fas levels and increased soluble Fas ligand levels in their sera.
Implications:
- These findings underscore the essential role of Fas-mediated apoptosis in maintaining immunological homeostasis in humans.
- Defects in Fas signaling are directly linked to lymphoproliferative disorders, emphasizing its importance in clonal deletion of immune cells.
Abstract:
Fas is an apoptosis-signaling receptor important for homeostasis of the immune system. In this study, Fas-mediated apoptosis and Fas mutations were analyzed in three Japanese children from two families with a lymphoproliferative disorder characterized by lymphadenopathy, hepatosplenomegaly, pancytopenia, hypergammaglobulinemia and an increase in TCR alphabeta+ CD4- CD8- T cells. Apoptosis induced by anti-Fas mAb was defective in both activated T cells and B cells, and granulocytes from these patients. Truncated Fas receptor lacking the cytoplasmic death domain caused by a point mutation in the splice region of intron 7 were demonstrated in two siblings. A homozygous point mutation in the splice acceptor of intron 3 was found in the Fas gene of the third patient, which resulted in the skipping of exon 4 and complete loss of Fas expression. Corresponding to these mutations, soluble Fas concentrations were decreased and reciprocally soluble Fas ligands were increased in patients' sera. Interestingly, co-stimulation by immobilized anti-Fas mAb in T cells from the two siblings was comparable to that seen in normal T cells. These results suggest that Fas-mediated apoptosis plays a pivotal role in immunological homeostasis in vivo, especially regarding clonal deletion of immune cells in humans.