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Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation
Aude Magerus-Chatinet, … , Alain Fischer, Frédéric Rieux-Laucat
Aude Magerus-Chatinet, … , Alain Fischer, Frédéric Rieux-Laucat
Published December 22, 2010
Citation Information: J Clin Invest. 2011;121(1):106-112. https://doi.org/10.1172/JCI43752.
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Onset of autoimmune lymphoproliferative syndrome (ALPS) in humans as a consequence of genetic defect accumulation

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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

Aude Magerus-Chatinet, Bénédicte Neven, Marie-Claude Stolzenberg, Cécile Daussy, Peter D. Arkwright, Nina Lanzarotti, Catherine Schaffner, Sophie Cluet-Dennetiere, Filomeen Haerynck, Gérard Michel, Christine Bole-Feysot, Mohammed Zarhrate, Isabelle Radford-Weiss, Serge P. Romana, Capucine Picard, Alain Fischer, Frédéric Rieux-Laucat

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Figure 3

Impact of TNFRSF6 mutations on FAS protein expression by lymphocyte subsets.

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Impact of TNFRSF6 mutations on FAS protein expression by lymphocyte subs...
FAS expression by CD4, CD8, and DN T cells was determined by FACS analysis (A) for patients 1 to 3 carrying a germline TNFRSF6 mutation and a somatic TNFRSF6 mutation in the second allele; (B) for patients 4 to 7 carrying a germline heterozygous TNFRSF6 mutation and exhibiting LOH on the second allele; and (C) for 3 ALPS patients carrying germline ICD TNFRSF6 mutations. Analysis was also performed for 3 MPRs (patient 2’s mother, patient 3’s father, and patient 4’s father). Patients 2 and patient 4 to 6 and their respective MPRs were analyzed in parallel in the same experiment, using an ARIA II cytometer. Patient 1, patient 3, and all patients with ICD mutations were processed in distinct experiments in parallel with different healthy controls, using an ARIA II cytometer. Numbers on histograms indicate the percentage of cells in the depicted FAS-negative gates, and numbers in bold type indicate the mean fluorescence of FAS intensity in the whole population.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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