This article is an excerpt from:
Marina Cavazzana-Calvo and Alain Fischer
Journal of Clinical Immunology 2007
SCIDs comprise a number of rare, monogenic disorders whose common characteristic is the occurrence of a block in T cell differentiation together with a direct or indirect impairment of B cell immunity. The overall frequency of SCIDs is estimated at between 1:50,000 and 1:100,000 live births. This could be a slight underestimate, as early death may prevent correct diagnosis in some cases. Studies of patterns of inheritance, immunological characteristics, and, more recently, genotypes have led to the identification of at least 11 distinct SCID conditions
Four main mechanisms of these diseases have been described: (a) Premature cell death caused by the accumulation of purine metabolites, as seen in adenosine deaminase (ADA) deficiency. (b) Defective cytokine-dependent survival signaling in T cell precursors (and sometimes NK cell precursors). This mechanism accounts for more than 50% of cases of SCID. Deficiency in expression or function of the common (c) cytokine receptor subunit shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 causes the X-linked form of SCID (SCID-X1), characterized by the complete absence of both T and NK lymphocytes. Deficiency in JAK3, which is normally associated with the cytoplasmic region of c, results in an identical phenotype. (c) Defective V(D)J rearrangements of the TCR and B cell receptor genes. In our experience, this group accounts for 30% of SCID cases. Deficiency in either RAG1 or RAG2 (the lymphoid-specific recombination–initiating elements) or Artemis (a factor involved in the nonhomologous end-joining repair pathway) leads to defective V(D)J rearrangements and thereby thymocyte and pre–B cell death. (d) Defective pre-TCR and TCR signaling. Pure T cell deficiencies are caused by defects in either a CD3 subunit (such as CD3, CD3, or CD3) or in the CD45 tyrosine phosphatase, key proteins involved in pre-TCR and/or TCR signaling at the positive selection stage.
Some researchers include other T cell immunodeficiencies in the SCID group, such as ZAP-70 deficiency, CD3 deficiencies, HLA class II expression deficiency, purine nucleoside phosphorylase deficiency, ligase IV or Cernunnos deficiency, and Omenn syndrome. However, since these conditions are characterized by the presence of mature (though functionally defective) T cells, they raise very distinct issues as far as therapy is concerned (see below) and so are not considered in this review.
The clinical presentation of the different SCID conditions is fairly uniform and is characterized by the early onset of infections (usually in the respiratory tract and the gut). Common opportunistic organisms such as Pneumocystis carinii and Aspergillus and intracellular organisms such as Cytomegalovirus can cause recurrent infections and a failure to thrive. The severity of these clinical manifestations makes SCID a medical emergency that, in the absence of treatment, leads to death within the first year of life.
Article URL: http://www.jci.org/cgi/content/full/117/6/1456