Severe combined immunodeficiencies (SCIDs) are inherited diseases that represent the most severe forms of primary immunodeficiencies, affecting approximately 1 child out of every 80,000 live births. These diseases are characterized by profound defects in cellular and humoral immunity. As a result, affected individuals typically die within the first year of life because of recurrent opportunistic infections, unless they receive successful bone marrow transplants. SCID is most appropriately described as a syndrome with diverse genetic origins. Because of advances made in genetics and molecular biology, it has become possible to identify the genes responsible for many forms of SCID, although approximately 30% of cases have unknown causes.<sup>6 Buckley R.H., Schiff R.I., Schiff S.E. , y al. Human severe combined immunodeficiency: Genetic, phenotypic, and functional diversity in 108 infants J Pediatr 1997 ;  130 : 378  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 20 Fischer A., Cavazzana Calvo M., De Saint Basile G. , y al. Naturally occurring primary deficiencies of the immune system Annu Rev Immunol 1997 ;  15 : 93  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 45 Leonard W.J. The molecular basis of X-linked severe combined immunodeficiency: Defective cytokine receptor signaling Annu Rev Med 1996 ;  47 : 229

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In this article, SCID refers to cases of inherited immunodeficiency characterized by a marked decrease in T cells, as previously defined.<sup>20 Fischer A., Cavazzana Calvo M., De Saint Basile G. , y al. Naturally occurring primary deficiencies of the immune system Annu Rev Immunol 1997 ;  15 : 93  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> Patients with other inherited immunodeficiencies, such as those resulting from mutations in the T-cell receptor (TCR)–associated chains, CD3γ or CD3ε, or in the TCR-associated tyrosine kinase ZAP-70, may have normal or decreased numbers of T cells, but typically do not develop life-threatening infections in the first months of life.<sup>20 Fischer A., Cavazzana Calvo M., De Saint Basile G. , y al. Naturally occurring primary deficiencies of the immune system Annu Rev Immunol 1997 ;  15 : 93  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> Patients with SCID then can be classified into four groups according to their basic immunologic phenotypes (Table 1). In all four groups, T cells are almost uniformly decreased in numbers; however, the levels of B and natural killer (NK) cells are more variable. In the first group, T, B, and NK cells are all diminished (T⁻B⁻NK⁻ SCID). The most severe form in this group is reticular dysgenesis, a disease in which the lymphoid and myeloid systems are affected.<sup>18 De Vall O.M., Seynheve V. Reticular dysgenesis Lancet 1959 ;  2 : 1123

Haga clic aquí para ir a la sección de Referencias</sup> The responsible gene for this form of SCID has not been identified. Adenosine deaminase (ADA) deficiency is less severe, but still also is characterized by a profound block in lymphocyte maturation.<sup>30 Hirschorn R. Adenosine deaminase deficiency Immunodeficiency 1990 ;  5 : 141

Haga clic aquí para ir a la sección de Referencias</sup> Mutations in the ADA gene result in the accumulation of dATP in cells, therefore inhibiting cell division. The major impact of ADA deficiency is in the immune system. In the second group, T and B cells are diminished but NK cells are not (T⁻B⁻NK⁺ SCID). Approximately 20% of all patients with SCID have such a block in T- and B-lymphocyte differentiation because of a defect in the recombination process.<sup>83 Stephan J.L., Vlekova V., Le Deist F. , y al. Severe combined immunodeficiency: A retrospective single-center study of clinical presentation and outcome in 117 patients J Pediatr 1993 ;  123 : 564  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> This group can be divided in two subgroups: one with a normal cell radiosensitivity, resulting from mutations in the RAG1 or RAG2 genes, which are responsible for the initiation of the V(D)J rearrangement process,<sup>1 Abe T., Tsuge I., Kamachi Y. , y al. Evidence for defects in V(D)J rearrangements in patients with severe combined immunodeficiency J Immunol 1994 ;  152 : 5504

Haga clic aquí para ir a la sección de Referencias, 80 Schwarz K., Gauss G.H., Ludwig L. , y al. RAG mutations in human B-cell–negative SCID Science 1996 ;  274 : 97  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> and the other with an increased cell radiosensitivity, in which the involved gene(s) have not been identified.<sup>11 Cavazzana-Calvo M., Le Deist F., De Saint Basile G. , y al. Increased radiosensitivity of granulocyte macrophage colony-forming units and skin fibroblasts in human autosomal recessive severe combined immunodeficiency J Clin Invest 1993 ;  91 : 1214  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> The third and fourth groups are characterized by the presence of B cells (T⁻B⁺ SCID); however, the B cells are usually nonfunctional, in part because of an absence of T-cell help.<sup>13 Conley M.E. Molecular approaches to analysis of X-linked immunodeficiencies Annu Rev Immunol 1992 ;  10 : 215  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> The third group is characterized by the absence of NK cells (T⁻B⁺NK⁻ SCID). The most frequent form of SCID in this group—and indeed the most common overall form of SCID is X-linked SCID (XSCID). In XSCID, which accounts for almost 50% of cases of SCID, patients have profoundly diminished numbers of T cells and NK cells, but normal or increased numbers of B cells.<sup>45 Leonard W.J. The molecular basis of X-linked severe combined immunodeficiency: Defective cytokine receptor signaling Annu Rev Med 1996 ;  47 : 229

Haga clic aquí para ir a la sección de Referencias, 47 Leonard W.J., Noguchi M., Russell S.M. , y al. The molecular basis of X-linked severe combined immunodeficiency: The role of the interleukin-2 receptor γ chain as a common γ chain, γc Immunol Rev 1994 ;  138 : 61  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> XSCID was found to result from mutations in the gene encoding the γ chain of the interleukin-2 (IL-2) receptor.<sup>61 Noguchi M., Yi H., Rosenblatt H.M. , y al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans Cell 1993 ;  73 : 147  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> As discussed below, IL-2Rγ is now denoted as the common cytokine receptor γ chain, γ_c, because it is shared by the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15.<sup>24 Giri J.G., Ahdieh M., Eisenman J. , y al. Utilization of the β and γ chains of the IL-2 receptor by the novel cytokine IL-15 EMBO J 1994 ;  13 : 2822

Haga clic aquí para ir a la sección de Referencias, 36 Kimura Y., Takeshita T., Kondo M. , y al. Sharing of the IL-2 receptor γ chain with the functional IL-9 receptor complex Int Immunol 1995 ;  7 : 115

Haga clic aquí para ir a la sección de Referencias, 38 Kondo M., Takeshita T., Higuchi M. , y al. Functional participation of the IL-2 receptor γ chain in IL-7 receptor complexes Science 1994 ;  263 : 1453

Haga clic aquí para ir a la sección de Referencias, 39 Kondo M., Takeshita T., Ishii N. , y al. Sharing of the interleukin-2 (IL-2) receptor γ chain between receptors for IL-2 and IL-4 Science 1993 ;  262 : 1874

Haga clic aquí para ir a la sección de Referencias, 60 Noguchi M., Nakamura Y., Russell S.M. , y al. Interleukin-2 receptor γ chain: A functional component of the interleukin-7 receptor Science 1993 ;  262 : 1877

Haga clic aquí para ir a la sección de Referencias, 61 Noguchi M., Yi H., Rosenblatt H.M. , y al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans Cell 1993 ;  73 : 147  [cross-ref]

Haga clic aquí para ir a la sección de Referencias, 75 Russell S.M., Johnston J.A., Noguchi M. , y al. Interaction of IL-2Rβ and γc chains with Jak1 and Jak3: Implications for XSCID and XCID Science 1994 ;  266 : 1042

Haga clic aquí para ir a la sección de Referencias, 76 Russell S.M., Keegan A.D., Harada N. , y al. Interleukin-2 receptor γ chain: A functional component of the interleukin-4 receptor Science 1993 ;  262 : 1880

Haga clic aquí para ir a la sección de Referencias, 87 Takeshita T., Asao H., Ohtani K. , y al. Cloning of the γ chain of the human IL-2 receptor Science 1992 ;  257 : 379

Haga clic aquí para ir a la sección de Referencias</sup> The XSCID phenotype also has been found in patients with an autosomal recessive form of SCID, and it was hypothesized that this form of SCID could result from mutations in the gene coding for the tyrosine kinase Jak3,<sup>75 Russell S.M., Johnston J.A., Noguchi M. , y al. Interaction of IL-2Rβ and γc chains with Jak1 and Jak3: Implications for XSCID and XCID Science 1994 ;  266 : 1042

Haga clic aquí para ir a la sección de Referencias</sup> which associates with γ_c and is activated by IL-2, IL-4, IL-7, IL-9, and IL-15.<sup>48 Leonard W.J., O'Shea J.J. JAKs and STATs: Biological implications Annu Rev Immunol 1998 ;  16 : 293  [cross-ref]

Haga clic aquí para ir a la sección de Referencias</sup> Finally, the fourth group of SCID consists of patients with a selective T-cell defect (T⁻B⁺NK⁺ SCID). One of the genetic causes for this syndrome is defective expression of IL-7R⍺,<sup>70 Puel A., Ziegler S.F., Buckley R.H. , y al. Defective IL7R expression in T−B+NK+ severe combined immunodeficiency Nat Genet 1998 ;  20 : 394

Haga clic aquí para ir a la sección de Referencias</sup> which is the principal focus of this article.