Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation
| Autor: | Cécile Daussy, Gérard Michel, Aude Magerus-Chatinet, Filomeen Haerynck, Sophie Cluet-Dennetiere, Capucine Picard, Serge Romana, Alain Fischer, Nina Lanzarotti, Frédéric Rieux-Laucat, Christine Bole-Feysot, Catherine Schaffner, Mohammed Zarhrate, Isabelle Radford-Weiss, Marie-Claude Stolzenberg, Bénédicte Neven, Peter D. Arkwright |
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| Rok vydání: | 2011 |
| Předmět: |
EXPRESSION
Adult Male Heterozygote Adolescent FEATURES LYMPHOCYTE APOPTOSIS Loss of Heterozygosity Lymphocytes Null Penetrance Biology medicine.disease_cause FAMILIES DISEASE Loss of heterozygosity Young Adult Germline mutation Medicine and Health Sciences medicine Humans fas Receptor Allele Germ-Line Mutation SOMATIC FAS MUTATIONS Autoimmune disease Mutation Models Genetic Chromosomes Human Pair 10 Autoimmune Lymphoproliferative Syndrome Genetic Variation General Medicine Middle Aged Uniparental Disomy INTERLEUKIN-10 medicine.disease Uniparental disomy Pedigree Protein Structure Tertiary Autoimmune lymphoproliferative syndrome Immunology T-CELLS Commentary Female CD8 Research Article Signal Transduction |
| Zdroj: | JOURNAL OF CLINICAL INVESTIGATION |
| ISSN: | 0021-9738 |
| Popis: | Autoimmune diseases develop in approximately 5% of humans. They can arise when self-tolerance checkpoints of the immune system are bypassed as a consequence of inherited mutations of key genes involved in lymphocyte activation, survival, or death. For example, autoimmune lymphoproliferative syndrome (ALPS) results from defects in self-tolerance checkpoints as a consequence of mutations in the death receptor-encoding gene TNF receptor superfamily, member 6 (TNFRSF6; also known as FAS). However, some mutation carriers remain asymptomatic throughout life. We have now demonstrated in 7 ALPS patients that the disease develops as a consequence of an inherited TNFRSF6 heterozygous mutation combined with a somatic genetic event in the second TNFRSF6 allele. Analysis of the patients' CD4(-)CD8(-) (double negative) T cells--accumulation of which is a hallmark of ALPS--revealed that in these cells, 3 patients had somatic mutations in their second TNFRSF6 allele, while 4 patients had loss of heterozygosity by telomeric uniparental disomy of chromosome 10. This observation provides the molecular bases of a nonmalignant autoimmune disease development in humans and may shed light on the mechanism underlying the occurrence of other autoimmune diseases. |
| Databáze: | OpenAIRE |
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