%0 Journal Article
%A Hou, Tie Zheng
%A Olbrich, Peter
%A Soto, Jose Manuel Lucena
%A Sanchez, Berta
%A Moreno, Paula Sanchez
%A Borte, Stephan
%A Stauss, Hans J
%A Burns, Siobhan O
%A Walker, Lucy S K
%A Pan-Hammarström, Qiang
%A Hammarström, Lennart
%A Sansom, David M
%A Neth, Olaf
%T Study of an extended family with CTLA-4 deficiency suggests a CD28/CTLA-4 independent mechanism responsible for differences in disease manifestations and severity.
%D 2018
%U http://hdl.handle.net/10668/11974
%X 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.
%K Autoimmunity
%K CD28
%K CTLA-4
%K Immunodeficiency
%K Mutation
%K Regulatory T cells
%~