Severe combined immunodeficiency: new advances in diagnosis and treatment

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Severe combined immunodeficiency: new advances in diagnosis and treatment Jennifer M. Puck

Published online: 11 July 2007  Humana Press Inc. 2007

Abstract Severe combined immunodeficiency (SCID) is a condition characterized by lack of cellular and humoral immunity. Uniformly fatal before 1968, SCID was first cured by allogeneic bone marrow transplantation (BMT). Despite improvements in BMT, particularly for cases in which there is no matched related donor, difficulties in SCID treatment persist. Because of incomplete reconstitution and transplant-related complications, gene therapy has been pioneered in SCID with success, but also adverse events in the form of leukemic proliferations related to retroviral insertional mutagenesis. Infectious complications are a major limitation to effective treatment. Early diagnosis of SCID in the pre-symptomatic period could be achieved by population-based newborn screening. Keywords Severe combined immunodeficiency (SCID)  Newborn screening  Gene therapy  Bone marrow transplantation  IL2RG  Common gamma chain  X-linked inheritance  T-cell receptor excision circle (TREC)  Retrovirus  Leukemia

Severe combined immunodeficiency (SCID) is the name given to a collection of disorders characterized by profound impairment of both T-cell and B-cell immunity. Affected individuals are usually healthy at birth, but begin to suffer from excessive infections coincident with the waning of transplacentally acquired maternal IgG between 2 and 4 months of age. Infections characteristically fail to respond standard treatments. Chronic diarrhea and growth delay, upper and lower respiratory infections and systemic infections are caused by a common and opportunistic pathogens. Infections cause fatality in infancy unless the patient can be provided with adaptive immunity, either through allogeneic bone

Presented at the First Robert A Good Society Symposium, St. Petersburg, FL 2006. J. M. Puck (&) Department of Pediatrics, University of California, HSE 301A, 513 Parnassus Avenue, San Francisco, CA 94143-0519, USA e-mail: [email protected]

Immunol Res (2007) 38:64–67

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marrow transplantation from a healthy donor; enzyme replacement (in the case of ADA deficiency); or, in exciting recent clinical trials, gene therapy in which autologous hematopoietic cells are corrected by genomic integration of retroviruses bearing a correct copy of the patient’s mutated gene. All patients with SCID have absent or very few T-cells. They also have absent or nonfunctional B-cells, while NK cells may be present or absent. As of 2006, there are over a dozen known SCID genotypes. The most common is the X-linked form, due to defects in the common gamma chain (cc) of cytokine receptors encoded by IL2RG, [1]. Autosomal recessive forms include genes encoding other cytokine activation and T-cell antigen receptor proteins. While either X-linked inheritance, with affected males related through phenotypically normal females, or autosomal recessive inheritance, with affected siblings of either sex, can be observed in