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Article Dans Une Revue Journal of Clinical Investigation Année : 2011

Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation

Aude Magerus-Chatinet
  • Fonction : Auteur
Bénédicte Neven
  • Fonction : Auteur
Marie-Claude Stolzenberg
  • Fonction : Auteur
Cécile Daussy
  • Fonction : Auteur
Peter Arkwright
  • Fonction : Auteur
Nina Lanzarotti
  • Fonction : Auteur
Catherine Schaffner
  • Fonction : Auteur
Sophie Cluet-Dennetiere
  • Fonction : Auteur
Filomeen Haerynck
  • Fonction : Auteur
Gérard Michel
  • Fonction : Auteur
Christine Bole-Feysot
  • Fonction : Auteur
Mohammed Zarhrate
  • Fonction : Auteur
Isabelle Radford-Weiss
  • Fonction : Auteur
Serge Romana
  • Fonction : Auteur
Capucine Picard
  • Fonction : Auteur
Alain Fischer
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-04457090 , version 1 (14-02-2024)

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Aude Magerus-Chatinet, Bénédicte Neven, Marie-Claude Stolzenberg, Cécile Daussy, Peter Arkwright, et al.. Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation. Journal of Clinical Investigation, 2011, 121 (1), pp.106-112. ⟨10.1172/JCI43752⟩. ⟨hal-04457090⟩

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