Onset of Autoimmunity In ALPS as a Consequence of Genetic Defects Accumulation

• Published in: Blood 2010-11, Vol.116 (21), p.278-278
• Main Authors: Magerus-Chatinet, Aude, Neven, Benedicte, Stolzenberg, Marie-Claude, Daussy, Cecile, Arkwright, Peter, Cavazzana-Calvo, Marina, Picard, Capucine, Fischer, Alain, Rieux-Laucat, Frederic
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V116.21.278.278

Abstract 278 Autoimmune diseases develop in about 5% of human beings and arise with a delayed stochastic penetrance when lymphocytes directed towards self components, such as chromatin in lupus or insulin-producing cells in diabetes, are generated. This occurs when self-tolerance checkpoints of the immune system are bypassed as a consequence of inherited mutations of key genes involved in activation, survival or death of lymphocytes. The autoimmune lymphoproliferative syndrome (ALPS) is a model of self-tolerance checkpoints defects as autoimmune manifestations occur in 2/3 of ALPS patients. Mutations in the TNFRSF6 gene (encoding FAS, also known as the CD95 receptor) is the most common cause of ALPS. Patients carrying a homozygous TNFRSF6 mutation have an early-onset, severe phenotype, whereas subjects with heterozygous TNFRSF6 mutations present ALPS of variable intensity. T cells from patients with homozygous or heterozygous TNFRSF6 mutations respectively exhibit a complete or partial functional impairment in an in vitro FAS-induced apoptosis assay. Moreover, we recently described somatic heterozygous mutations in TNFRSF6 in patients with a clinical ALPS phenotype in which activated T cells showed normal sensitivity to FAS-induced apoptosis in vitro. The inability to detect an apoptosis defect was due to spontaneous in vitro apoptosis of the mutant T cells. However, more than 80% of these patients' DN T cells were mutated. These patients displayed mosaic expression of a somatic TNFRSF6 mutation, which provided the affected cells a selective advantage and accounted for the observed lymphoproliferation and autoimmunity. Heterozygous germline TNFRSF6 mutations are not always associated with clinical expression (partial clinical penetrance) since some mutation-positive relatives (MPRs) remain asymptomatic despite an in vitro FAS-induced apoptosis impairment on their T cells. This observation led us to postulate that a second event is necessary for disease expression in patients with TNFRSF6 mutations when an incomplete penetrance is observed. We analyzed double-negative (DN) T lymphocytes from seven ALPS patients with low penetrance mutations for FAS expression and defects in the second TNFRSF6 allele and compared with data from healthy, mutation-positive relatives and controls. Missense mutations (in three patients) and loss of heterozygosity (LOH, in four patients) were found in the second TNFRSF6 allele. The LOH observed in 4 of our patients with germline