Immune dysregulation diseases are characterized by heterogeneous clinical manifestations and may have severe disease courses.The identification of the genetic causes of these diseases therefore has critical clinical i...Immune dysregulation diseases are characterized by heterogeneous clinical manifestations and may have severe disease courses.The identification of the genetic causes of these diseases therefore has critical clinical implications.We performed whole-exome sequencing of patients with immune dysregulation disorders and identified two patients with previously undescribed mutations in LRRC32,which encodes glycoprotein A repetitions predominant(GARP).These patients were characterized by markedly reduced numbers and frequencies of regulatory T cells(Tregs).Tregs with mutated LRRC32 exhibited strongly diminished cell-surface GARP expression and reduced suppressor function.In a model of conditional Garp deficiency in mice,we confirmed increased susceptibility to inflammatory diseases once GARP expression on Tregs was decreased.Garp deficiency led to an unstable Treg phenotype due to diminished Foxp3 protein acetylation and stability.Our study reinforces the understanding of the immunological mechanisms of immune dysregulation and expands the knowledge on the immunological function of GARP as an important regulator of Treg stability.展开更多
基金supported by the Deutsche Forschungsgemeinschaft,grants SK59/4-1,SK59/9-1,Schu 786/8-1,and Schu 1683/10-1by the Verbundantrage"ArthroMark"(projects 1 and 7,OIEC100913),"lmpam"(project 10,OIEC1008H),and"GAIN"(project 8,01GM1910C),all by the Federal Ministry of Education and Research of Germanyby the FoFoLe program of the medical faculty of the LMU Munich.
文摘Immune dysregulation diseases are characterized by heterogeneous clinical manifestations and may have severe disease courses.The identification of the genetic causes of these diseases therefore has critical clinical implications.We performed whole-exome sequencing of patients with immune dysregulation disorders and identified two patients with previously undescribed mutations in LRRC32,which encodes glycoprotein A repetitions predominant(GARP).These patients were characterized by markedly reduced numbers and frequencies of regulatory T cells(Tregs).Tregs with mutated LRRC32 exhibited strongly diminished cell-surface GARP expression and reduced suppressor function.In a model of conditional Garp deficiency in mice,we confirmed increased susceptibility to inflammatory diseases once GARP expression on Tregs was decreased.Garp deficiency led to an unstable Treg phenotype due to diminished Foxp3 protein acetylation and stability.Our study reinforces the understanding of the immunological mechanisms of immune dysregulation and expands the knowledge on the immunological function of GARP as an important regulator of Treg stability.
