Severe combined immunodeficiency disease (SCID) refers to a heterogeneous group of rare (1/100,000 live births), lethal, congenital disorders that result in the inability of T cells to respond to mitogens, alloantigens, and specific antigens and B cells to produce specific antibodies.1 Rosen F.S., Cooper M.D., Wedgewood R.J.P. The primary immunodeficiencies N Engl J Med 1995 ; 333 : 431-440 [cross-ref]
Cliquez ici pour aller à la section Références Before the early 1990s, patients with this disorder were characterized primarily by the phenotype and function of their circulating lymphocytes, mode of inheritance, and presence or absence of enzyme deficiencies known to be associated with SCID, such as adenosine deaminase. In this original classification, three main types of SCID were described2 Rosen F.S., Aiuti F., Hitzig W. , et al. Meeting report: Primary immunodeficiency disease Clin Immunol Immunopathol 1983 ; 28 : 450-475 [cross-ref]
Cliquez ici pour aller à la section Références and include the following: (1) classical SCID, characterized by T and B lymphopenia, with or without natural killer (NK) cells, and agammaglobulinemia, (2) the more common SCID with B lymphocytes, and (3) SCID secondary to adenosine deaminase (ADA) deficiency, which may present with either of the preceding lymphoid phenotypes.3 Giblett E.R., Anderson J.E., Cohen F. , et al. Adenosine deaminase deficiency in two patients with severely impaired cellular immunity Lancet 1972 ; 2 : 1067-1069 [cross-ref]
Cliquez ici pour aller à la section Références, 4 Hershfield M.S. Adenosine deaminase deficiency: Clinical expression, molecular basis, and therapy Semin Hematol 1998 ; 35 : 291-293
Cliquez ici pour aller à la section Références Less often, children with SCID present with Omenn's syndrome,5 Omenn G. Familial reticuloendotheliosis N Engl J Med 1965 ; 273 : 427-432 [cross-ref]
Cliquez ici pour aller à la section Références in which affected infants have scaling erythroderma, leukocytosis, eosinophilia, hepatosplenomegaly, and lymphadenopathy with replacement of nodal architecture by Langerhans and reticulum cells,6 Ruco L.P., Stoppacciaro A., Pezzella F. , et al. The Omenn syndrome: Histological, immunohistochemical, and ultrastructural evidence for a partial T-cell deficiency evolving in an abnormal proliferation of T-lymphocytes and S-100+/T6+ Langerhans-like cells Virchow's Archive 1985 ; 407 : 69-82 [cross-ref]
Cliquez ici pour aller à la section Références reticular dysgenesis,7 DeVaal O.M., Seynhaeve V. Reticular dysgenesis Lancet 1959 ; 2 : 1123-1125 [cross-ref]
Cliquez ici pour aller à la section Références in which SCID is associated with severe neutropenia and often bilateral sensorineural deafness,8 Small T.N., Wall D.A., Kurtzberg J. , et al. Association of reticular dysgenesis (thymic alymphoplasia and congenital aleukocytosis) with bilateral sensorineural deafness J Pediatr 1999 ; 135 : 387-389 [cross-ref]
Cliquez ici pour aller à la section Références or SCID with short-limbed dwarfism and ectodermal dysplasia.9 Gatti R.A., Platt N., Pomerance H.H. , et al. Hereditary lymphopenic agammaglobulinemia associated with a distinctive form of short-limbed dwarfism and ectodermal dysplasia J Pediatr 1969 ; 75 : 675-684 [cross-ref]
Cliquez ici pour aller à la section Références Multiple variants of SCID have been described in which patients have nonfunctional T cells that demonstrate capping defects,10 Gelfand E.W., Oliver J.M., Schuurman R.K. , et al. Abnormal lymphocyte capping in a patient with severe combined immunodeficiency disease N Engl J Med 1979 ; 301 : 1245-1249 [cross-ref]
Cliquez ici pour aller à la section Références lack CD711 Jung L.K.L., Fu S.M., Hara T. , et al. Defective expression of T-cell associated glycoprotein in severe combined immunodeficiency J Clin Invest 1986 ; 77 : 940-946 [cross-ref]
Cliquez ici pour aller à la section Références or possess abnormal CD3 subunit expression,12 Alarcon B., Regueiro J.R., Arnaiz-Villena A. , et al. Familial defect in the surface expression of the T-cell receptor-CD3 complex N Engl J Med 1988 ; 319 : 1203-1208 [cross-ref]
Cliquez ici pour aller à la section Références or have CD8 deficiency with nonfunctional CD4+ cells.13 Roifman C.M., Hummel D., Martinez-Valdez H. , et al. Depletion of CD8+ cells in human thymic medulla results in selective immune deficiency J Exp Med 1989 ; 170 : 2177-2182 [cross-ref]
Cliquez ici pour aller à la section Références, 14 Monafo W.J., Polmar S.H., Neudorf S. , et al. A hereditary immunodeficiency characterized by CD8+ T lymphocyte deficiency and impaired lymphocyte activation Clin Exp Immunol 1992 ; 90 : 390-393
Cliquez ici pour aller à la section Références Despite this phenotypic heterogeneity, the distribution of SCID phenotypes reported in four separate studies performed in Europe and the United States was surprisingly similar.15 Fischer A., Landais P., Friedrich W. , et al. European experience of bone-marrow transplantation for severe combined immunodeficiency Lancet 1990 ; 336 : 850-854 [cross-ref]
Cliquez ici pour aller à la section Références, 16 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 : 378-87 [cross-ref]
Cliquez ici pour aller à la section Références, 17 Dror Y., Gallagher R.M., Wara D.W. , et al. Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, TCD haploidentical bone marrow transplantation Blood 1993 ; 2021-2030
Cliquez ici pour aller à la section Références, 18 O'Reilly R.J., Friedrich W., Small T.N. Hematopoietic cell transplantation for immunodeficiency disorders Hematopoietic Cell Transplantation Malden, MA: Blackwell Science (1999).
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Cliquez ici pour aller à la section Références Approximately 40% of patients presented as SCID with B cells, 25% as classical SCIDs (B−T−), 15% with ADA deficiency, 10% as SCIDs with nonfunctional T cells, and 2% to 3% with reticular dysgenesis. Inheritance of these disorders are either autosomal recessive (ADA deficiency,4 Hershfield M.S. Adenosine deaminase deficiency: Clinical expression, molecular basis, and therapy Semin Hematol 1998 ; 35 : 291-293
Cliquez ici pour aller à la section Références, 19 Parkman R., Gelfand E.W., Rosen F.S. , et al. Severe combined immunodeficiency and adenosine deaminase deficiency N Engl J Med 1975 ; 14 : 714-719 [cross-ref]
Cliquez ici pour aller à la section Références short-limbed dwarfism,9 Gatti R.A., Platt N., Pomerance H.H. , et al. Hereditary lymphopenic agammaglobulinemia associated with a distinctive form of short-limbed dwarfism and ectodermal dysplasia J Pediatr 1969 ; 75 : 675-684 [cross-ref]
Cliquez ici pour aller à la section Références Omenn's syndrome,5 Omenn G. Familial reticuloendotheliosis N Engl J Med 1965 ; 273 : 427-432 [cross-ref]
Cliquez ici pour aller à la section Références capping defects,10 Gelfand E.W., Oliver J.M., Schuurman R.K. , et al. Abnormal lymphocyte capping in a patient with severe combined immunodeficiency disease N Engl J Med 1979 ; 301 : 1245-1249 [cross-ref]
Cliquez ici pour aller à la section Références CD8 deficiency,13 Roifman C.M., Hummel D., Martinez-Valdez H. , et al. Depletion of CD8+ cells in human thymic medulla results in selective immune deficiency J Exp Med 1989 ; 170 : 2177-2182 [cross-ref]
Cliquez ici pour aller à la section Références, 14 Monafo W.J., Polmar S.H., Neudorf S. , et al. A hereditary immunodeficiency characterized by CD8+ T lymphocyte deficiency and impaired lymphocyte activation Clin Exp Immunol 1992 ; 90 : 390-393
Cliquez ici pour aller à la section Références or as either an X-linked or autosomal recessive disorder (classical SCID, SCID with B cells, reticular dysgenesis).14 Monafo W.J., Polmar S.H., Neudorf S. , et al. A hereditary immunodeficiency characterized by CD8+ T lymphocyte deficiency and impaired lymphocyte activation Clin Exp Immunol 1992 ; 90 : 390-393
Cliquez ici pour aller à la section Références, 20 Ownby D.R., Pizzo S., Blackmon L. , et al. Severe combined immunodeficiency with leukopenia (reticular dysgenesis) in siblings: Immunologic and histopathologic findings J Pediatr 1976 ; 89 : 382-387 [cross-ref]
Cliquez ici pour aller à la section Références
Although first trimester diagnosis of adenosine deaminase deficiency has been possible for many years by measurement of enzyme activity in cultured amniocytes or chorionic villi samples,21 Dooley T., Fairbanks L.D., Simmonds H.A. , et al. First trimester diagnosis of adenosine deaminase deficiency Prenat Diagn 1987 ; 7 : 561-565 [cross-ref]
Cliquez ici pour aller à la section Références children with ADA+ SCID, until recently, required fetal blood sampling to ascertain the presence or absence of T cells.22 Durandy A., Dumez Y., Guy-Grand D. , et al. Prenatal diagnosis of severe combined immunodeficiency disease J Pediatr 1982 ; 101 : 995-997 [cross-ref]
Cliquez ici pour aller à la section Références The elucidation of many of the genetic mutations which give rise to SCID, such as X-linked SCID (IL-2R gamma chain),23 Noguchi M., Yi H., Rosenblatt H.M. , et al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans Cell 1993 ; 73 : 147-57 [cross-ref]
Cliquez ici pour aller à la section Références, 24 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 : 1099-104
Cliquez ici pour aller à la section Références, 25 Puck J.M., Pepper A.E., Henthorn P.S. , et al. Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency Blood 1997 ; 89 : 1968-77
Cliquez ici pour aller à la section Références autosomal recessive SCID with B cells (JAK-3),26 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 : 797-800
Cliquez ici pour aller à la section Références, 27 Macchi P., Villa A., Gillani S. , et al. Mutations of Jak-3 gene in patients with autosomal severe combined immunodeficiency disease (SCID) Nature 1995 ; 377 : 65-68 [cross-ref]
Cliquez ici pour aller à la section Références classic SCID, Omenn's syndrome28 Schwarz K., Gauss G.H., Ludwig L. , et al. RAG mutations in human B cell–negative SCID Science 1996 ; 274 : 97-99 [cross-ref]
Cliquez ici pour aller à la section Références, 29 Mombaerts P., Iacomini J., Johnson R.S. , et al. RAG-1–deficient mice have no mature B and T lymphocytes Cell 1992 ; 68 : 869-877 [cross-ref]
Cliquez ici pour aller à la section Références, 30 Villa A., Santagata S., Bozzi F. , et al. Partial V(D)J recombination activity leads to Omenn syndrome Cell 1998 ; 93 : 885-896 [cross-ref]
Cliquez ici pour aller à la section Références, 31 Villa A., Santagata S., Bozzi F. , et al. Omenn syndrome: A disorder of Rag1 and Rag2 genes J Clin Immunol 1999 ; 19 : 87-97 [cross-ref]
Cliquez ici pour aller à la section Références (recombinase defects (RAG-1, RAG-2), and CD8 deficiency with nonfunctional T-cells (ZAP-70),32 Arpaia E., Shahar M., Dadi H. , et al. Defective T-cell–receptor signaling and CD8+ thymic selection in humans lacking Zap-70 kinase Cell 1994 ; 76 : 947-958 [cross-ref]
Cliquez ici pour aller à la section Références, 33 Elder M.E., Lin D., Clever J. , et al. Human severe combined immunodeficiency due to a defect in ZAP-70, a T-cell tyrosine kinase Science 1994 ; 264 : 1596-1599
Cliquez ici pour aller à la section Références, 34 Chan A.C., Kadlecek T.A., Elder M.E. , et al. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency Science 1994 ; 264 : 1599-1601
Cliquez ici pour aller à la section Références has increased the proportion of infants who can be diagnosed by amniocentesis or chorionic villus sampling (CVS).35 Puck J.M., Middelton L., Pepper A.E. Carrier and prenatal diagnosis of X-linked severe combined immunodeficiency: Mutation detection methods and utilization Hum Genet 1997 ; 628-633 [cross-ref]
Cliquez ici pour aller à la section Références, 36 Schumacher R.F., Mella P., Lalatta F. , et al. Prenatal diagnosis of JAK3 deficient SCID Prenat Diagn 1999 ; 19 : 653-656
Cliquez ici pour aller à la section Références Better prenatal diagnosis, earlier postnatal diagnosis, because of heightened awareness of immunodeficiency disorders resulting from the AIDS epidemic, in conjunction with advances in anti-microbial therapy, have reduced the number of children presenting to bone marrow transplant (BMT) with a life-threatening infection.
Successful correction of SCID by BMT was first reported by Gatti et al using bone marrow derived from an HLA-matched sibling.37 Gatti R.A., Meeuwissen H.J., Allen H.D. , et al. Immunological reconstitution of sex-linked lymphopenic immunological deficiency Lancet 1968 ; 2 : 1366-1369 [cross-ref]
Cliquez ici pour aller à la section Références Since that report, over 500 curative transplants for this disorder have been performed,38 Buckley R.H. Bone marrow reconstitution in primary immunodeficiency Clinical Immunology: Principles and Practice 1995 ; 2 : 1813-1830
Cliquez ici pour aller à la section Références the majority using T-cell–depleted haploidentical parental bone marrow. Within the last 5 years, advances in unrelated bone marrow39 Filipovich A.H. Stem cell transplantation from unrelated donors for correction of primary immunodeficiencies Organ and bone marrow transplantation 1996 ; 16 : 393-377
Cliquez ici pour aller à la section Références and cord blood transplantation40 Rubinstein P., Carrier C., Scaradavou A. , et al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors N Engl J Med 1998 ; 339 : 1565-1577 [cross-ref]
Cliquez ici pour aller à la section Références and successes with in utero stem cell transplants41 Flake A.W., Zanjani E.D. In utero hematopoietic stem cell transplantation: Ontogenic opportunities and biologic barriers Blood 1999 ; 94 : 2179-2191
Cliquez ici pour aller à la section Références have expanded the options available to infants with SCID, particularly those lacking an HLA-matched sibling. In this article, the results and continued controversies of stem cell transplantation for SCID are reviewed.
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