Severe combined immunodeficiency (SCID) spans a constellation of genetically distinct syndromes, all having in common impaired development of mature T lymphocytes and/or B lymphocytes and defects in both humoral and cell-mediated immunity. Affected infants present with thrush (oral candidiasis), severe diaper rash, and failure to thrive. Some infants develop a generalized rash shortly after birth because maternal T cells are transferred across the placenta and attack the fetus, causing GVHD. Children with SCID are extremely susceptible to recurrent, severe infections by a wide range of pathogens, including Candida albicans, Pneumocystis jiroveci, Pseudomonas, cytomegalovirus, varicella, and a whole host of bacteria. Without HSC transplantation, death occurs within the first year of life. The overall prevalence of the disease is approximately 1 in 65,000 to 1 in 100,000, but it is 20 to 30 times more frequent in some Native American populations.
Despite the common clinical manifestations, of different forms of SCID the underlying defects are quite varied.
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Fig. 5.36 Primary immune deficiency diseases. Shown are the principal pathways of lymphocyte development and the blocks in these pathways in selected primary immune deficiency diseases. The affected genes are indicated in parentheses for some of the disorders. ADA, Adenosine deaminase; CD40L, CD40 ligand (also known as CD154); CVID, common variable immunodeficiency; SCID, severe combined immunodeficiency.
Often, the defect resides in the T-cell compartment, with a secondary impairment of humoral immunity. Two major forms are described next.
X-linked SCID. Approximately half of the cases of SCID are X-linked; these are caused by mutations in the gene encoding the common γ (γc) chain shared by the receptors for the cytokines IL-2, IL-4, IL-7, IL-9, and IL-15. Of these cytokines, defective IL-7 signaling is the most important underlying basis of SCID because this cytokine is responsible for stimulating the survival and expansion of immature B and T cell precursors in the generative lymphoid organs.
Autosomal recessive SCID. Another 40% to 50% of SCID cases follow autosomal recessive pattern of inheritance, with approximately half of these caused by mutations in adenosine deaminase (ADA), an enzyme involved in purine metabolism. ADA deficiency results in accumulation of adenosine and deoxyadenosine triphosphate metabolites, which inhibit DNA synthesis and are toxic to lymphocytes. Other autosomal recessive forms of SCID result variously from defects in another purine metabolic pathway, primary failure of class II MHC expression, or mutations in genes encoding the recombinase responsible for the rearrangement of lymphocyte antigen-receptor genes.