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.

Sometimes double negative is positive

“…Holzelova et al reported 6 patients with a sporadic form of ALPS, all of whom had somatic heterozygous mutations of Fas (24). In some patients who carry the mutation, the phenotype is rather mild or absent, and this may imply partial clinical penetrance of the Fas mutation (25). Additional rare mutations in the Fas ligand and caspase 10 have also been described (26,27).…”

Diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency in adults

“…Olivier Lambotte, 1-2 Bénédicte Neven, [3][4][5] Lionel Galicier, 6,7 Aude Magerus-Chatinet, 3 Nicolas Schleinitz, 8,9 Olivier Hermine, 4,10 Isabelle Meyts, 11 Capucine Picard, 4,[12][13][14] Bertrand Godeau, 15-17 Alain Fischer, [3][4][5]12 and Frédéric Rieux-Laucat A diagnosis of autoimmune lymphoproliferative syndrome caused by FAS deficiency during adulthood is unusual. We analyzed 17 cases of autoimmune lymphoproliferative syndrome caused by FAS deficiency diagnosed during adulthood in French reference centers for hereditary immunodeficiencies and for immune cytopenias.…”

“…This type of mutation is often associated with a secondary somatic event affecting the second FAS allele. 6 In 2 patients (P2.2 and 2.5), molecular screening of DNA extracted from sorted DN T cells revealed the loss of the wild-type allele and duplication of the mutated allele.…”

“…Lastly, when germline FAS heterozygous mutations lead to haploinsufficiency, 5 combinations of germline and somatic modifications of the FAS gene have been observed. 6 A FAS-mediated apoptosis defect may be assessed in vitro in patients carrying germline mutations but not in those affected by somatic mutations. Plasma biomarkers are now routinely assayed in the pre-diagnosis of ALPS-FAS and include soluble FAS ligand (sFASL), interleukin-10 (IL-10), IL-18 and vitamin B12.…”

Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia

“…We still include analysis of DNT in the initial screening, but mainly to quantify the surface FAS expression of these cells, which can be helpful to identify patients with somatic second-hit mutations. 19,20 The combination of vitamin B12 and sFASL helps to identify patients with germline mutations as well as those with somatic FAS mutations and possibly also patients with as yet unknown mutations in the FAS pathway ('ALPS by biomarkers'). Moreover, it can identify FAS mutations as highly unlikely in a large proportion of patients with lymphoproliferation and autoimmunity.…”