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Chapter 111: Severe Combined Immunodeficiency (SCID)

Jennifer Jenks; Kari Nadeau

BACKGROUND

Severe combined immunodeficiency (SCID) is a fatal primary immune condition characterized by the absence of both humoral and cellular immunity with severe lymphopenia. Patients with SCID have reduced numbers and function of both T and B lymphocytes (and in some cases, natural killer [NK] cells) and hypogammaglobulinemia. If left untreated, babies with SCID most often die within 1 to 2 years of life because of severe, recurrent infections.

Since SCID was initially described over 50 years ago, 15 specific genetic mutations that contribute to disease development have been identified. The most common type is X-linked SCID (SCID-X1), which accounts for approximately 46% of cases in the United States (Figure 111-1). SCID can also be inherited as an autosomal recessive disease that results from deficiencies in adenosine deaminase (ADA), Janus kinase 3 (JAK3), interleukin 7 receptor α chain (IL7R), recombination activating genes (RAG1 or RAG2), Artemis gene, CD45, and others (Table 111-1).

Table 111-1Classification of Severe Combined Immunodeficiency (SCID)
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Table 111-1Classification of Severe Combined Immunodeficiency (SCID)
Lymphocyte Profile Disease Genetic Mutation Inheritance Chromosome Band
T Cells B Cells Natural Killer (NK) Cells
– – – Adenosine deaminase deficiency Adenosine deaminase (ADA) AR 20q13.2-q13.11
– – – Reticular digenesis AK2 AR 1q35
– – + Artemis gene deficiency Artemis gene (DCLRE1C) AR 10p13
– – + Omenn syndrome RAG1 or RAG2 AR 11p13.41
– – + DNA protein kinase catalytic subunit (DNA-PKcs) PRKDC AR 8q11
– + – X-linked SCID Common γ chain receptor (IL-2Rg) XL Xq13.1
– + – JAK3 deficiency JAK3 AR 19q13.1
– + + Interleukin (IL) 7 α-chain receptor deficiency Interleukin (IL) 7 α-chain receptor (CD127) AR 5p13
– + + CD3 deficiency CD3δ, CD3ε, or CD Ζ AR 11q23
– + + Actin-regulating protein coronin 1A (CORO1A) deficiency CORO1A AR 16p11
CD45– + + CD45 deficiency CD45 tyrosine phosphatase (PTPRC) AR 1q31
CD4+ + + ZAP70 kinase deficiency ZAP70 tyrosine kinase AR 2q12
CD8+ + + p56lck deficiency p56lck AR 1p35
CD8+ B+DR + Major histocompatibility complex (MHC) II deficiency RFXAP CIITA RFXANK RFX5

AR

AR

AR

AR

13q13.3

16p13

19p13

1q21

Abbreviations: AR, autosomal recessive; XL, X linked.

Numerous genetic mutations contributing to X-linked and autosomal recessive SCID have been identified in humans. They have differential effects on T-, B-, and NK-cell populations and functions.

FIGURE 111-1

The relative frequencies of particular genetic mutations were evaluated in 174 consecutive cases of human severe combined immunodeficiency (SCID) evaluated at Duke University over 30 years. The most common type is X-linked SCID, which disables common gamma (γc) signaling. ADA, adenosine deaminase; JAK3, Janus kinase 3; IL7R, interleukin 7 receptor α chain; RAG1 or RAG2, recombination activating genes 1 or 2. (Reproduced with permission ...

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