Etiology

SCID develops as a result of specific genetic mutations that severely impair lymphocyte development and function.[3] The following molecular defects can occur depending on which gene is affected:[16][17]

  • Apoptosis of lymphocytes due to accumulation of toxic metabolites (e.g., due to adenosine deaminase deficiency)

  • Defects in DNA recombination and repair mechanisms (e.g., RAG1 or RAG2 deficiency, Artemis/DNA cross-link repair 1C [DCLRE1C] SCID, DNA ligase IV deficiency, Cernunnos/XLF deficiency)

  • Defects in signal transduction pathways of specific cytokine receptors (e.g., due to common gamma chain [γ-c] deficiency, Janus kinase 3 deficiency, or interleukin-7 receptor alpha chain deficiency)

  • Defects in T-cell receptor (TCR) or pre-TCR signal transduction pathways (e.g., due to CD3 deficiency or CD45 deficiency).

In approximately 6.5% to 8% of infants with SCID, the genetic cause remains unknown.[8][18]

Pathophysiology

SCID is caused by specific genetic mutations that severely impair the development and function of lymphocytes. T cells are significantly decreased in most forms of SCID; however, the absence and/or presence of B cells and natural killer (NK) cells varies depending on the gene defect.[2][3] Although the presence of B cells may appear normal in certain types of SCID, they are not producing antibody responses, in part due to a lack of T-cell help. 

T-B+NK-:

  • X-linked SCID is caused by genetic mutations in the common gamma chain (γ-c) (used by receptors for interleukin [IL]-2, IL-4, IL-7, IL-9, IL-15, and IL-21). Mutation in γ-c leads to defects in the signal transduction pathways of specific cytokine receptors, and blocks the development of both T cells and NK cells.

  • Autosomal-recessive T-B+NK- SCID is due to genetic mutations in Janus kinase 3 (JAK3). JAK3 binds γ-c and activates downstream signaling pathways. JAK 3 mutations result in a similar presentation to X-linked SCID.

T-B+NK+:

  • IL-7 receptor mutations result in a similar clinical presentation to X-linked SCID and JAK3 mutations, but laboratory findings reveal measurable numbers of NK cells (not present in X-linked SCID and JAK3 mutations).

  • Mutations in any of the component proteins of the CD3 complex result in defects in the T-cell receptor (TCR) or pre-TCR signal transduction pathways, which impairs T-cell development.

T-B-NK+:

  • Mutations in genes involved in DNA repair and recombination (e.g., recombination activating genes [RAG1 or RAG2], Artemis/DNA cross-link repair 1C [DCLRE1C], DNA ligase IV, and Cernunnos/XLF) result in SCID, as they are essential for the generation of T-cell and B-cell receptors, and the development of these lymphocyte populations.[16]

T-B-NK-:

  • Reticular dysgenesis can result from genetic mutations in adenylate kinase 2, although the underlying pathophysiology remains unclear.[19][20] It is characterized by agranulocytosis in addition to lymphopenia.

  • Adenosine deaminase (ADA) deficiency (caused by mutations in the ADA gene) results in the accumulation of toxic metabolites in lymphocytes.

Severe immunodeficiency leads to increased susceptibility to opportunistic and recurrent infections, which can be unusually severe. Respiratory and gastrointestinal infections are most common. These infections can be debilitating, and can lead to organ damage (e.g., acute kidney injury, respiratory failure) and death if untreated.[4]

Classification

International Union of Immunological Societies phenotypic classification for primary immunodeficiencies[2][3]

Clinical and immunological classification of SCID is based on the absence or presence of B cells (B- or B+) and natural killer (NK) cells (NK- or NK+), in addition to the absence of T cells (T-), in the peripheral blood as determined by flow cytometry. Certain types of SCID usually (but not always) have a specific lymphocyte phenotype, for example:

T-B-NK-:

  • Adenosine deaminase deficiency

  • Reticular dysgenesis (adenylate kinase-2 deficiency)

T-B-NK+:

  • Recombination activating gene (RAG1 or RAG2) deficiency

  • Artemis/DNA cross-link repair 1C (DCLRE1C) or Athabascan SCID

  • DNA ligase IV deficiency

  • DNA-dependent protein kinase, catalytic subunit (DNA PKcs) deficiency

  • Cernunnos/XRCC4-like factor deficiency

T-B+NK+:

  • Interleukin-7 receptor alpha chain deficiency

  • Mutation in CD3 delta

  • Mutation in CD3 epsilon

  • Mutation in CD3 gamma

  • Coronin 1A deficiency

  • CD45 deficiency

  • LAT deficiency

T-B+NK-:

  • Common gamma chain (y-c) deficiency

  • Janus kinase 3 deficiency

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