JAK3-DEFICIENT SEVERE COMBINED IMMUNODEFICIENCY - 04/09/11

Doi : 10.1016/S0889-8561(05)70136-3

Luigi D. Notarangelo, MD ^a, Fabio Candotti, MD ^b

^a Istituto di Medicina Molecolare “Angelo Nocivelli,” Department of Pediatrics, University of Brescia, Brescia, Italy (LDN)

^b Clinical Gene Therapy Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland (FC)

Résumé

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 Buckley R.H., Schiff R.I., Schiff S.E. , et al. Human severe combined immunodeficiency: Genetic, phenotypic, and functional diversity in 108 infants J Pediatr 1997 ; 130 : 378 [cross-ref]

Cliquez ici pour aller à la section Références, 47 Stephan J.L., Vlekova V., Le Deist F. , et al. A retrospective single-center study of clinical presentation and outcome in 117 patients with severe combined immunodeficiency Immunodeficiency 1993 ; 4 : 87

Cliquez ici pour aller à la section Références} 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 Noguchi M., Yi H., Rosenblatt H.M. , et al. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans Cell 1993 ; 73 : 147 [cross-ref]

Cliquez ici pour aller à la section Références, 38 Puck J.M., de Saint Basile G., Schwarz K. , et al. IL2RG base: A database of γ_c chain defects causing human X-SCID Immunol Today 1996 ; 17 : 507 [cross-ref]

Cliquez ici pour aller à la section Références, 39 Puck J.M., Deschenes S.M., Porter J.C. , et al. The interleukin-2 receptor γ chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1 Hum Mol Genet 1993 ; 2 : 1099

Cliquez ici pour aller à la section Références} 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 Leonard W.J., Noguchi M., Russell S.M. , et al. The molecular basis of X-linked severe combined immunodeficiency: The role of the interleukin-2 receptor gamma chain as a common gamma chain, γ_c Immunol Rev 1994 ; 138 : 61 [cross-ref]

Cliquez ici pour aller à la section Références, 48 Sugamura K., Asao H., Kondo M. , et al. The common γ chain for multiple cytokine receptors Adv Immunol 1995 ; 59 : 225

Cliquez ici pour aller à la section Références} 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 Miyazaki T., Kawahara A., Fujii H. , et al. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits Science 1994 ; 266 : 1045

Cliquez ici pour aller à la section Références} 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 Russell S.M., Johnston J.A., Noguchi M. , et al. Interaction of IL-2R β and γ_c chains with Jak1 and Jak3: Implications for XSCID and SCID Science 1994 ; 266 : 1042

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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 Macchi P., Villa A., Giliani S. , et al. Mutations of JAK3 gene in patients with autosomal severe combined immune deficiency (SCID) Nature 1995 ; 377 : 65 [cross-ref]

Cliquez ici pour aller à la section Références, 43 Russell S.M., Tayebi N., Nakajima H. , et al. Mutation of Jak3 in a patient with SCID: Essential role of Jak3 in lymphoid development Science 1995 ; 270 : 797

Cliquez ici pour aller à la section Références} 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 Nosaka T., van Deursen J.M., Tripp R.A. , et al. Defective lymphoid development in mice lacking Jak3 Science 1995 ; 270 : 800

Cliquez ici pour aller à la section Références, 36 Park S.J., Saijo K., Takahashi T. , et al. Developmental defects of lymphoid cells in JAK3 kinase–deficient mice Immunity 1995 ; 3 : 771 [cross-ref]

Cliquez ici pour aller à la section Références, 49 Thomis D.C., Gurniak C.B., Tivol E. , et al. Defects in B-lymphocyte maturation and T-lymphocyte activation in mice lacking Jak3 Science 1995 ; 270 : 794

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During recent years, additional patients with SCID caused by JAK3 deficiency have been identified^{3 Bozzi F., Lefrano G., Villa A. , et al. Molecular and biochemical characterization of JAK3 deficiency in a patient with severe combined immunodeficiency over 20 years after bone marrow transplantation: Implications for treatment Br J Haematol 1998 ; 102 : 1363

Cliquez ici pour aller à la section Références, 11 Candotti F., Oakes S.A., Johnston J.A. , et al. Structural and functional basis for JAK3-deficient severe combined immunodeficiency Blood 1997 ;

Cliquez ici pour aller à la section Références}; 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 Bunting K.D., Flynn K.J., Riberdy J.M. , et al. Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency Proc Natl Acad Sci USA 1999 ; 96 : 232 [cross-ref]

Cliquez ici pour aller à la section Références, 8 Bunting K.D., Sangster M.Y., Ihle J.N. , et al. Restoration of lymphocyte function in Janus kinase 3–deficient mice by retroviral-mediated gene transfer Nat Med 1998 ; 4 : 58 [cross-ref]

Cliquez ici pour aller à la section Références} and through in vitro biochemical correction of JAK3-deficient human cell lines.^{10 Candotti F., Oakes S., Johnston J.A. , et al. In vitro correction of JAK3-deficient severe combined immunodeficiency by retroviral-mediated gene transduction J Exp Med 1996 ; 183 : 2687 [cross-ref]

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Plan

THE BIOLOGY OF JAK3

CLINICAL AND IMMUNOLOGIC FEATURES OF PATIENTS WITH JAK3 DEFICIENCY

MOLECULAR DEFECTS IN SEVERE COMBINED IMMUNE DEFICIENCY CAUSED BY JAK3 DEFICIENCY

MODELING JAK3-DEFICIENT SEVERE COMBINED IMMUNE DEFICIENCY IN VITRO AND IN VIVO

THERAPEUTIC OPTIONS FOR JAK3-DEFICIENT SCID

SUMMARY

Address reprint requests to Luigi D. Notarangelo, MD, Istituto di Medicina, Molecolare “Angelo Nocivelli”, Department of Pediatrics, University of Brescia, Spedali Civili, 25123 Brescia, Italy
This work was partially supported by NATO (Grant CRG.CRG 973041), Telethon (Grant E.668), and Progetto Finalizzato Biotechnologie, Consiglio Nazionale delle Ricerche. This article is, in part, US government work. There are no restrictions on its use.