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

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.