Hou, TZ; Olbrich, P; Soto, JML; Sanchez, B; Moreno, PS; Borte, S; Stauss, HJ; ... Neth, O; + view all Hou, TZ; Olbrich, P; Soto, JML; Sanchez, B; Moreno, PS; Borte, S; Stauss, HJ; Burns, SO; Walker, LSK; Pan-Hammarström, Q; Hammarström, L; Sansom, DM; Neth, O; - view fewer (2018) Study of an extended family with CTLA-4 deficiency suggests a CD28/CTLA-4 independent mechanism responsible for differences in disease manifestations and severity. Clinical Immunology , 188 pp. 94-102. 10.1016/j.clim.2018.01.001.

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Abstract

The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.

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