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

Autoimmune diseases develop m 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 m lymphocyte activation, survival, or death For example, autoimmune lymphoproliferative syndrome (ALPS) results from defects m self-tolerance checkpoints as a consequence of mutations m 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 m these cells, 3 patients had somatic mutations m 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