ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity.
This study demonstrates the feasibility of antibody-mediated inhibition of Orai1 function and, more broadly, reveals the possibility of targeting ion channels with biologics for the treatment of autoimmunity and other diseases.
Patients with autosomal recessive mutations in the CRAC channel gene ORAI1, its activator stromal interaction molecule 1 (STIM1), and mice with targeted deletion of Orai1, Stim1, and Stim2 genes reveal important roles for CRAC channels in adaptive and innate immune responses to infection and in autoimmunity.
Mutations in ORAI1 and STIM1 genes in human patients that lead to expression of non-functional ORAI1 or complete lack of ORAI1 or STIM1 protein are associated with a unique clinical phenotype that is characterized by immunodeficiency, muscular hypotonia and anhydrotic ectodermal dysplasia, as well as, in the case of STIM1 deficiency, autoimmunity and lymphoproliferative disease.