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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Research Article

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

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 1

Family tree of 7 ALPS patients with germ­line heterozygous TNFSFR6 mutations and additional somatic mutations in patients 1, 2, and 3.

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Family tree of 7 ALPS patients with germ­line heterozygous TNFSFR6 mutat...
(A) Family trees of 7 ALPS patients with a germline ECD TNFRSF6 mutation. Asymptomatic mutated relatives are indicated by vertical gray bars. Subjects with ALPS are marked in black (arrows). The range of values determined for the 4 ALPS markers, i.e., apoptosis of activated T cells (control > 75%), plasma IL-10 concentration (control < 20 pg/ml), plasma FAS-L concentration (control < 0.2 ng/ml), and the percentage of DN T cells (< 2% of TCRαβ cells) are shown for these patients and their relatives. Apoptosis values depicted in bold were obtained in an assay performed at the same time for patients’ cells and relatives’ cells. P1, patient 1. (B) Localization of the 2 mutations in the TNFRSF6 alleles (9 exons) for patients 1, 2, and 3. The oblique gray bars in exon 6 and the dark section in exon 9 represent the transmembrane domain and the death domain, respectively.