JAK3-DEFICIENT SEVERE COMBINED IMMUNODEFICIENCY

Abstract

Severe combined immunodeficiency (SCID) comprises a heterogeneous group of genetic disorders, with numerical and functional defects of both T and B lymphocytes. The most common form of SCID in humans, accounting for about 40% to 50% of all cases, is characterized by lack of circulating T (and usually also NK) cells, with a normal or increased number of B lymphocytes (T − B + SCID). 5,47 Most patients with T − B + SCID are men, reflecting the occurrence of X-linked SCID (SCIDX1), a disorder caused by mutations of the IL2RG gene, 31,38,39 encoding for the common gamma chain (γ c ), shared by receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15. 25,48 In all these receptors, γ c is associated with the intracellular tyrosine kinase JAK3, whereas the unique receptor transducing subunit (as the β chain in the case of the IL-2 receptor, IL-2Rβ) binds to another JAK kinase, JAK1. 29 JAK1 and JAK3 are strictly required for cytokine-mediated signaling. Mutations of the IL2RG gene that affect interaction between the γ c and JAK3 also cause SCID. 42 Based on these data, it was hypothesized and then demonstrated in three unrelated patients, that mutations of the JAK3 gene are responsible for autosomal recessive T − B + SCID in humans. 27,43 Disruption of the Jak3 gene in mice also results in a form of murine SCID , that is indistinguishable by that of γ c −/y mice. 32,36,49 During recent years, additional patients with SCID caused by JAK3 deficiency have been identified 3,11 ; this has allowed better definition of the clinical and immunologic spectrum of the disease, its biochemical basis, and evaluation of prognostic and therapeutic implications of this disorder. Finally, the potential for gene therapy to correct this disorder has been successfully investigated in the murine knock-out model 7,8 and through in vitro biochemical correction of JAK3-deficient human cell lines. 10