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]
Cliccare qui per andare alla sezione Riferimenti 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. , e al. Meeting report: Primary immunodeficiency disease Clin Immunol Immunopathol 1983 ; 28 : 450-475 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti 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. , e al. Adenosine deaminase deficiency in two patients with severely impaired cellular immunity Lancet 1972 ; 2 : 1067-1069 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 4 Hershfield M.S. Adenosine deaminase deficiency: Clinical expression, molecular basis, and therapy Semin Hematol 1998 ; 35 : 291-293
Cliccare qui per andare alla sezione Riferimenti 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]
Cliccare qui per andare alla sezione Riferimenti 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. , e 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]
Cliccare qui per andare alla sezione Riferimenti reticular dysgenesis,7 DeVaal O.M., Seynhaeve V. Reticular dysgenesis Lancet 1959 ; 2 : 1123-1125 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti in which SCID is associated with severe neutropenia and often bilateral sensorineural deafness,8 Small T.N., Wall D.A., Kurtzberg J. , e al. Association of reticular dysgenesis (thymic alymphoplasia and congenital aleukocytosis) with bilateral sensorineural deafness J Pediatr 1999 ; 135 : 387-389 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti or SCID with short-limbed dwarfism and ectodermal dysplasia.9 Gatti R.A., Platt N., Pomerance H.H. , e al. Hereditary lymphopenic agammaglobulinemia associated with a distinctive form of short-limbed dwarfism and ectodermal dysplasia J Pediatr 1969 ; 75 : 675-684 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti 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. , e al. Abnormal lymphocyte capping in a patient with severe combined immunodeficiency disease N Engl J Med 1979 ; 301 : 1245-1249 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti lack CD711 Jung L.K.L., Fu S.M., Hara T. , e al. Defective expression of T-cell associated glycoprotein in severe combined immunodeficiency J Clin Invest 1986 ; 77 : 940-946 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti or possess abnormal CD3 subunit expression,12 Alarcon B., Regueiro J.R., Arnaiz-Villena A. , e al. Familial defect in the surface expression of the T-cell receptor-CD3 complex N Engl J Med 1988 ; 319 : 1203-1208 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti or have CD8 deficiency with nonfunctional CD4+ cells.13 Roifman C.M., Hummel D., Martinez-Valdez H. , e al. Depletion of CD8+ cells in human thymic medulla results in selective immune deficiency J Exp Med 1989 ; 170 : 2177-2182 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 14 Monafo W.J., Polmar S.H., Neudorf S. , e al. A hereditary immunodeficiency characterized by CD8+ T lymphocyte deficiency and impaired lymphocyte activation Clin Exp Immunol 1992 ; 90 : 390-393
Cliccare qui per andare alla sezione Riferimenti 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. , e al. European experience of bone-marrow transplantation for severe combined immunodeficiency Lancet 1990 ; 336 : 850-854 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 16 Buckley R.H., Schiff R.I., Schiff S.E. , e al. Human severe combined immunodeficiency: Genetic, phenotypic, and functional diversity in 108 infants J Pediatr 1997 ; 130 : 378-87 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 17 Dror Y., Gallagher R.M., Wara D.W. , e al. Immune reconstitution in severe combined immunodeficiency disease after lectin-treated, TCD haploidentical bone marrow transplantation Blood 1993 ; 2021-2030
Cliccare qui per andare alla sezione Riferimenti, 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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Cliccare qui per andare alla sezione Riferimenti 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
Cliccare qui per andare alla sezione Riferimenti, 19 Parkman R., Gelfand E.W., Rosen F.S. , e al. Severe combined immunodeficiency and adenosine deaminase deficiency N Engl J Med 1975 ; 14 : 714-719 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti short-limbed dwarfism,9 Gatti R.A., Platt N., Pomerance H.H. , e al. Hereditary lymphopenic agammaglobulinemia associated with a distinctive form of short-limbed dwarfism and ectodermal dysplasia J Pediatr 1969 ; 75 : 675-684 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti Omenn's syndrome,5 Omenn G. Familial reticuloendotheliosis N Engl J Med 1965 ; 273 : 427-432 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti capping defects,10 Gelfand E.W., Oliver J.M., Schuurman R.K. , e al. Abnormal lymphocyte capping in a patient with severe combined immunodeficiency disease N Engl J Med 1979 ; 301 : 1245-1249 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti CD8 deficiency,13 Roifman C.M., Hummel D., Martinez-Valdez H. , e al. Depletion of CD8+ cells in human thymic medulla results in selective immune deficiency J Exp Med 1989 ; 170 : 2177-2182 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 14 Monafo W.J., Polmar S.H., Neudorf S. , e al. A hereditary immunodeficiency characterized by CD8+ T lymphocyte deficiency and impaired lymphocyte activation Clin Exp Immunol 1992 ; 90 : 390-393
Cliccare qui per andare alla sezione Riferimenti 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. , e al. A hereditary immunodeficiency characterized by CD8+ T lymphocyte deficiency and impaired lymphocyte activation Clin Exp Immunol 1992 ; 90 : 390-393
Cliccare qui per andare alla sezione Riferimenti, 20 Ownby D.R., Pizzo S., Blackmon L. , e al. Severe combined immunodeficiency with leukopenia (reticular dysgenesis) in siblings: Immunologic and histopathologic findings J Pediatr 1976 ; 89 : 382-387 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti
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. , e al. First trimester diagnosis of adenosine deaminase deficiency Prenat Diagn 1987 ; 7 : 561-565 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti 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. , e al. Prenatal diagnosis of severe combined immunodeficiency disease J Pediatr 1982 ; 101 : 995-997 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti 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. , e al. Interleukin-2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans Cell 1993 ; 73 : 147-57 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 24 Puck J.M., Deschenes S.M., Porter J.C. , e 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
Cliccare qui per andare alla sezione Riferimenti, 25 Puck J.M., Pepper A.E., Henthorn P.S. , e al. Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency Blood 1997 ; 89 : 1968-77
Cliccare qui per andare alla sezione Riferimenti autosomal recessive SCID with B cells (JAK-3),26 Russell S.M., Tayebi N., Nakajima H. , e al. Mutation of Jak3 in a patient with SCID: Essential role of Jak3 in lymphoid development Science 1995 ; 270 : 797-800
Cliccare qui per andare alla sezione Riferimenti, 27 Macchi P., Villa A., Gillani S. , e al. Mutations of Jak-3 gene in patients with autosomal severe combined immunodeficiency disease (SCID) Nature 1995 ; 377 : 65-68 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti classic SCID, Omenn's syndrome28 Schwarz K., Gauss G.H., Ludwig L. , e al. RAG mutations in human B cell–negative SCID Science 1996 ; 274 : 97-99 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 29 Mombaerts P., Iacomini J., Johnson R.S. , e al. RAG-1–deficient mice have no mature B and T lymphocytes Cell 1992 ; 68 : 869-877 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 30 Villa A., Santagata S., Bozzi F. , e al. Partial V(D)J recombination activity leads to Omenn syndrome Cell 1998 ; 93 : 885-896 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 31 Villa A., Santagata S., Bozzi F. , e al. Omenn syndrome: A disorder of Rag1 and Rag2 genes J Clin Immunol 1999 ; 19 : 87-97 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti (recombinase defects (RAG-1, RAG-2), and CD8 deficiency with nonfunctional T-cells (ZAP-70),32 Arpaia E., Shahar M., Dadi H. , e al. Defective T-cell–receptor signaling and CD8+ thymic selection in humans lacking Zap-70 kinase Cell 1994 ; 76 : 947-958 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti, 33 Elder M.E., Lin D., Clever J. , e al. Human severe combined immunodeficiency due to a defect in ZAP-70, a T-cell tyrosine kinase Science 1994 ; 264 : 1596-1599
Cliccare qui per andare alla sezione Riferimenti, 34 Chan A.C., Kadlecek T.A., Elder M.E. , e al. ZAP-70 deficiency in an autosomal recessive form of severe combined immunodeficiency Science 1994 ; 264 : 1599-1601
Cliccare qui per andare alla sezione Riferimenti 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]
Cliccare qui per andare alla sezione Riferimenti, 36 Schumacher R.F., Mella P., Lalatta F. , e al. Prenatal diagnosis of JAK3 deficient SCID Prenat Diagn 1999 ; 19 : 653-656
Cliccare qui per andare alla sezione Riferimenti 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. , e al. Immunological reconstitution of sex-linked lymphopenic immunological deficiency Lancet 1968 ; 2 : 1366-1369 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti 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
Cliccare qui per andare alla sezione Riferimenti 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
Cliccare qui per andare alla sezione Riferimenti and cord blood transplantation40 Rubinstein P., Carrier C., Scaradavou A. , e al. Outcomes among 562 recipients of placental-blood transplants from unrelated donors N Engl J Med 1998 ; 339 : 1565-1577 [cross-ref]
Cliccare qui per andare alla sezione Riferimenti 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
Cliccare qui per andare alla sezione Riferimenti 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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