title: Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation.
abstract: 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.
authors.affiliation: INSERM U768, Université Paris Descartes, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Aude
authors.initials: A
authors.lastname: Magerus-Chatinet
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Neven
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Stolzenberg
authors.forename: Cécile
authors.initials: C
authors.lastname: Daussy
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Nina
authors.initials: N
authors.lastname: Lanzarotti
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaffner
authors.forename: Sophie
authors.initials: S
authors.lastname: Cluet-Dennetiere
authors.forename: Filomeen
authors.initials: F
authors.lastname: Haerynck
authors.forename: Gérard
authors.initials: G
authors.lastname: Michel
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.forename: Mohammed
authors.initials: M
authors.lastname: Zarhrate
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford-Weiss
authors.forename: Serge P
authors.initials: SP
authors.lastname: Romana
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
mesh_terms: D000293:Adolescent; D000328:Adult; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics* / Q000276:immunology; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008215:Lymphocytes, Null / Q000276:immunology; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D024182:Uniparental Disomy; D055815:Young Adult; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor