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Chapter 99 : Approach to the Diagnosis of Severe Combined Immunodeficiency
Central to the adaptive immune system, T cells protect the host from intracellular pathogens by mediating cytolytic activity and releasing Th1 cytokines. In addition, through release of soluble mediations such as interleukin 4 (IL-4) and IL-10 and interactions with antigen-presenting cells and B cells, T cells regulate the production of antibody against protein antigens. Nevertheless, a profound selective deficiency in the T-cell lineage such as in CD3δ deficiency is sufficient to produce a full phenotype of severe combined immunodeficiency (SCID) with extreme susceptibility to microbes of even low pathogenicity. Genetic and immunological features of SCID have been discussed in this chapter. However, a significant proportion of SCID patients has normal or near normal number of circulating lymphocytes (Omenn’s syndrome, major histocompatibility complex class II deficiency, and ZAP-70 deficiency). Flow cytometry analysis will help decipher these cases and will aid in pinpointing the molecular defect by providing insight into the number of B cells and NK cells. It is therefore recommended that all infants with a putative diagnosis of SCID have their lymphocyte subsets analyzed. Finally, since the genes responsible for many forms of SCID have already been identified, it is important to perform mutation analysis.
Simplified scheme of the block in T-cell, NK-cell, and B-cell development caused by aberrations in genes which cause SCID. The symbol “⊥” represents complete block, while the symbol “⊥” represents partial block. Stem cells which originate in the bone marrow mature into putative lymphoid progenitor cells which either populate the thymus gland and become T-lineage precursors or develop into NK or B cells. The TCR complex consists of the α and β or γ and δ variant chains, paired as mutually exclusive heterodimers in association with the invariant chains CD3 γ, δ, ɛ, and ζ. After rearrangements of the δ and then γ genes, some thymocytes develop into a distinct population of γδ TCR+ T cells. Precursors of the αβ T-cell lineage undergo three major stages of maturation, defined by the expression of CD4 and CD8. The earliest precursors are designated double negative, expressing neither CD4 nor CD8. They progress to a stage of dual expression of CD4 and CD8 (double positive) before committing to the expression of either CD4 or CD8 alone (single positive) and leaving the thymus. A rearrangement of TCR(3 occurs at the double-negative stage and precedes the rearrangement of TCRα. Transition from the double-negative stage to CD4+ CD8+ double positivity requires the surface expression of TCRβ and precursor TCRα (pTα) forming the pre-TCR, whereas the maturation from double-positive to single-positive CD4 or CD8 cells is dependent on the surface expression of the αβ TCR complex.
Step-by-step laboratory evaluation of patients who present within the first year of life with typical manifestations of SCID (see Table 2 ) and after secondary causes, such as human immunodeficiency virus infection and medications, have been excluded.
Genetic and immunological features of SCID a
Clinical presentation of SCID