What is the role of genetics in the pathophysiology of severe combined immunodeficiency (SCID)?

Updated: Apr 28, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD  more...
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SCID results from mutations in any of more than 15 known genes. These molecular defects interfere with lymphocyte development and function, blocking the differentiation and proliferation of T cells and, in some types, of B cells and NK cells. Antibody production is severely impaired even when mature B cells are present, because of the lack of T-cell help. NK cells, a component of innate immunity, are variably affected. Sequencing and other techniques may reveal the actual genetic defects in these patients. [5] Ideally, SCID can be detected in a newborn before the onset of infections, with one well-documented example by screening of T-cell–receptor excision circles. [6]

SCID can be broadly classified into 2 groups: SCID with B cells (70% of patients with SCID) and SCID without B cells. Beyond this basic grouping, SCID may be categorized according to phenotypic lymphocyte profiles that include both B-cell status (B+ or B) and NK-cell status (NK+ or NK) in addition to T-cell status (T, because there is always a T-cell deficiency in SCID).

The most common genetic condition responsible for SCID is a mutation of the common γ chain of the interleukin (IL) receptors shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 (T B+ NK). [7] This protein is encoded on the X chromosome; therefore, this variant of SCID is X-linked (and is sometimes referred to as X-linked SCID [XL-SCID]). These patients account for approximately 50% of all patients with SCID. A novel pathogenic mutation on the interleukin-7 receptor has been described in a newborn. [8]

In X-linked SCID, loss of IL-2 receptor (IL-2R) function leads to the loss of a lymphocyte proliferation signal. Loss of IL-4R function leads to the inability of B cells to class switch. Loss of IL-7R function leads to the loss of an antiapoptotic signal, resulting in a loss of T-cell selection in the thymus. Loss of IL-7R function is also associated with the loss of a T-cell receptor (TCR) rearrangement. Loss of IL-15R function leads to the ablation of NK-cell development. [7, 9, 10]

Autosomal recessive SCID (formerly known as Swiss-type agammaglobulinemia) includes the following deficiencies:

  • Janus-associated kinase 3 (JAK3) deficiency (T B+ NK) [9, 10, 11, 12]

  • Adenosine deaminase (ADA) deficiency (T B NK+/–) [13]

  • Bare lymphocyte syndrome (a somewhat milder SCID) [14, 15, 16]

  • ζ chain–associated protein (ZAP)-70 deficiency [17]

  • Reticular dysgenesis

  • IL-7R α chain deficiency

  • Deficiency of the recombination-activating genes RAG1 and RAG2 (T B NK+) [18]

  • Ligase 4 deficiency (T B NK+) [19]

  • CD45 deficiency [20]

JAK3 is a protein tyrosine kinase (PTK) that associates with the common γ chain of the IL receptors. Deficiency of this protein results in the same clinical manifestations as those of XL-SCID. [11, 12]

ADA is an enzyme that breaks down purines. When it is absent, deoxyadenosine triphosphate (dATP) builds up and inhibits the enzymes necessary for lymphocyte proliferation. It causes B-, T-, and NK-cell deficiency. [13]

Bare lymphocyte syndrome is a deficiency of major histocompatibility complex (MHC). MHC type II is decreased on mononuclear cells. MHC type I levels may be decreased, or MHC type I may be absent entirely. The defect occurs in a gene regulating expression of MHC type II. [14, 15]

In ZAP-70 deficiency, a mutation occurs in the gene coding for this tyrosine kinase, which is important in T-cell signaling and is critical in positive and negative selection of T cells in the thymus. A selective absence of CD8+ T cells and an abundance of nonfunctioning CD4+ T cells occur. ZAP-70 is apparently needed in the selection of CD8+ T cells and is necessary for T cell functioning—hence the nonfunctioning CD4+ cells. [17]

Reticular dysgenesis is a rare variant of SCID arising from the lack of appropriate stem cell development and characterized by agranulocytosis in addition to a lack of both B cells and T cells in the adaptive immune system. Mutations in mitochondrial adenylate kinase 2 have been revealed in patients with reticular dysgenesis. [21] Cartilage-hair hypoplasia is also classified as SCID, although a significant proportion of patients have a less severe form not requiring stem cell reconstitution.

Several deficiencies of the CD3 complex (CD3γ, ε, δ, and ζ) are associated with SCID. [22, 23] Omenn syndrome results from mutations that impair the function of Ig and TCR recombinase genes. These include the Artemis mutation [24] (an enzyme that opens DNA hairpin during variable diversity joining [VDJ] rearrangement) and RAG1 and RAG2 deficiencies. [18, 25, 26]

Purine nucleotide phosphorylase (PNP) deficiency and IL-2 deficiency are severe enough in nature to be classified as SCID, and other defects are identified every year. [27] The exact molecular defect involved in IL-2 production deficiency is unknown, but this defect is often associated with other cytokine production defects.

These are the most common and best characterized forms of SCID, but not all of the genetic conditions leading to SCID are well characterized. Infants with SCID usually present with infections that are secondary to the lack of T-cell function (eg, Pneumocystis jiroveci (carinii) pneumonia [PCP], systemic candidiasis, generalized herpetic infections, severe failure to thrive secondary to gut infections or diarrhea). Graft versus host disease (GVHD) from nonirradiated blood products is an important cause of morbidity.

Most patients with SCID have atrophic thymuses populated by few lymphocytes and decreased or absent Hassall corpuscles. Peripheral lymphoid tissue is usually absent or severely decreased. In some circumstances, poorly functioning activated oligoclonal lymphocytes develop, perhaps because of increased antigen stimulation that may occur due to failure of clearing antigens appropriately.

Human phosphoglucomutase 3 mutations cause a congenital severe immunodeficiency disorder associated with skeletal dysplasia. [28]


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