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Severe Combined Immune Deficiency (SCID): Genetics

  1. A Fischer

Published Online: 27 JAN 2006

DOI: 10.1038/npg.els.0005941

eLS

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How to Cite

Fischer, A. 2006. Severe Combined Immune Deficiency (SCID): Genetics. eLS. .

Author Information

  1. Hôpital Necker, Paris, France

Publication History

  1. Published Online: 27 JAN 2006

This is not the most recent version of the article. View current version (15 NOV 2011)

Introduction

  1. Top of page
  2. Introduction
  3. Purine Metabolism Deficiency – Premature Apoptosis of Lymphocyte Precursors
  4. γc-Dependent Cytokine Receptor Pathway Deficiencies
  5. V(D)J Recombination Deficiencies
  6. CD45 Deficiency
  7. Atypical SCID Phenotypes
  8. See also
  9. References
  10. Further Reading
  11. Web Links

Severe combined immunodeficiency (SCID) consists of a group of rare inherited diseases characterized by a block in T-lymphocyte development. The overall frequency is estimated to one in 75000–100000 births (Buckley et al., 1997). Eight different conditions fulfilling the definition of SCID have been described both at the molecular level and phenotype (Figure 1). In addition, a small number of SCID phenotypes have so far not received a molecular definition. Identification of the developmental block in T-lymphocyte differentiation provides information on basic aspects of lymphocyte development as well as the medical consequences, that is, molecular diagnosis, genetic counseling and new therapeutics (Fischer, 2001).

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Figure 1. SCID diseases and mechanisms. HSC with self renewal capacity can generate lymphocyte precursors such as putative CLP. The latter give rise to NK, T and B lymphocytes. Arrows indicate block in lymphocyte development caused by indicated gene mutations and resulting in a SCID ADA: adenosine deaminase; PNP: purine nucleoside phosphorylase; Rag-1/-2: recombination activating gene 1/2; IL-7R: interleukin-7 receptor α chain; JAK-3: janus kinase 3; HSC: hematopoietic stem cell; CLP: common lymphoid progenitor; NK: natural killer.

The absence of mature functional T cells, that is, a lack of adaptive immunity, carries devastating clinical consequences caused by multiple infections of different origins: bacterial, mycobacterial, fungal, protozoal and viral organisms can spread and provoke protracted infections or an acute fatal attack within the first year of life. In addition, live vaccines, such as BCG, can also cause a disseminated fatal infection. Circulating maternal T lymphocytes are very frequently detected in the blood of SCID patients. In most cases, the maternal T-cell count is low and there are no clinical consequences. However, maternal T cells can, in some instances, expand (up to several thousands per microliter of blood) and cause immunological attack to the skin, gut and liver. However, only a small number of maternal T-cell clones do expand.

As discussed below, the description of SCID conditions relies on several parameters including immunological phenotype, inheritance pattern, gene identification and mechanism when available (Buckley, 2000). SCID conditions represent intrinsic defects of lymphocyte differentiation and should thus be distinguished from faulty development of T cells caused by environmental defects as observed in the DiGeorge syndrome or the rare nude phenotype in which the thymic epithelial component is missing.

Purine Metabolism Deficiency – Premature Apoptosis of Lymphocyte Precursors

  1. Top of page
  2. Introduction
  3. Purine Metabolism Deficiency – Premature Apoptosis of Lymphocyte Precursors
  4. γc-Dependent Cytokine Receptor Pathway Deficiencies
  5. V(D)J Recombination Deficiencies
  6. CD45 Deficiency
  7. Atypical SCID Phenotypes
  8. See also
  9. References
  10. Further Reading
  11. Web Links

The first SCID condition to be characterized at the molecular level was adenosine deaminase (ADA) deficiency. ADA is an enzyme involved in purine metabolism, and transforms adenosine and deoxyadenosine (dado) into inosine and deoxynosine respectively. Deoxyadenosine is phosphorylated into deoxyadenosine triphosphate (dATP) in immature lymphocytes; accumulation of dATP results in a block in synthesis of deoxyribonucleic acid (DNA) and also induces chromosomal breaks. A complete deficiency of ADA leads to almost total disappearance of T, B and natural killer (NK) lymphocytes. Partial deficiency results in an incomplete block in lymphocyte differentiation. ADA deficiency also leads to primary bone, lung and liver abnormalities. The immunodeficiency resulting from adenosine deaminase (ADA) gene mutations can be cured by allogeneic hematopoietic stem cell transplantation (HSCT) but can also be alleviated in part by enzymatic supplementation. Gene therapy is being tested in this setting.

Another defect in purine metabolism, that is, purine nucleoside phosphorylase (PNP) deficiency, also causes T-cell immunodeficiency because of the toxicity of accumulating deoxyguanosine triphosphate.

γc-Dependent Cytokine Receptor Pathway Deficiencies

  1. Top of page
  2. Introduction
  3. Purine Metabolism Deficiency – Premature Apoptosis of Lymphocyte Precursors
  4. γc-Dependent Cytokine Receptor Pathway Deficiencies
  5. V(D)J Recombination Deficiencies
  6. CD45 Deficiency
  7. Atypical SCID Phenotypes
  8. See also
  9. References
  10. Further Reading
  11. Web Links

Lymphocyte precursors do actively proliferate once they receive signals through appropriate cytokine receptors (Figure 1). Among them, interleukin-7 (IL-7), produced by both bone marrow stromal cells and thymic epithelial cells, provides survival as well as proliferative signals to T-lymphocyte progenitor cells while IL-15 acts similarly for NK lymphocyte progenitors. IL-7 and IL-15 receptors share with the IL-2, IL-4, IL-9 and IL-21 receptors a common cytokine receptor subunit named γc which is expressed at the surface of lymphocyte precursors. Upon cytokine binding, the tyrosine kinase JAK-3 (janus kinase 3) associates with the cytoplasmic domain if γc is activated and phosphorylates a downstream mediator, that is, the signal transduction activator of the transcription (STAT) 5 molecule. The most common form of SCID consists of a block in development of both T and NK lymphocytes. Its inheritance pattern is either recessive X-linked or autosomal recessive. The X-linked form of SCID (SCID-X1) accounts for more than half of all SCID cases. It is caused by mutations of the gene encoding γc. Multiple distinct mutations have been described, leading to the same phenotype. This observation illustrates the important role of the cytokine-dependent phase of T/NK lymphocyte development. Surprisingly, B-cell differentiation occurs normally despite defective IL-7 signaling. Actually, in most patients the peripheral B-cell counts is even increased. These B lymphocytes are at least partially functional in vitro as well as in vivo following HSCT in some cases; γc-negative B cells have been shown to undergo class-switch recombination and produce protective antibodies following physiological activation.

Deficiency in JAK-3 accounts for the autosomal recessive form of T(−), NK(−), B(+) SCID demonstrating that γc-dependent signals require JAK-3 activation (Macchi et al., 1995). Recently, six SCID patients were shown to exhibit deleterious mutations in the gene encoding the IL-7 receptor (IL-7R) α chain. IL-7Rα associates with γc to form IL-7R. IL-7Rα deficiency results in a selective block in T-lymphocyte development, demonstrating the crucial role of IL-7 in a very early step of T-cell differentiation (Puel et al., 1998). It is actually unknown whether or not this step precedes thymus homing of precursors.

V(D)J Recombination Deficiencies

  1. Top of page
  2. Introduction
  3. Purine Metabolism Deficiency – Premature Apoptosis of Lymphocyte Precursors
  4. γc-Dependent Cytokine Receptor Pathway Deficiencies
  5. V(D)J Recombination Deficiencies
  6. CD45 Deficiency
  7. Atypical SCID Phenotypes
  8. See also
  9. References
  10. Further Reading
  11. Web Links

A subset of SCID is typically characterized phenotypically by an absence of both mature T and B lymphocytes while NK cells are spared. It accounts for approximately 20% of cases. Inheritance is autosomal recessive. This condition has turned out to be genetically heterogeneous. This SCID condition is reminiscent of the scid mouse model, a natural mutant in which the V(D)J recombination process of the T- and B-cell receptor genes is impaired, due to a deficiency in the DNA-dependent protein kinase activity within the nonhomologous end-joining (NHEJ) repair process. It was therefore reasoned that this form of SCID also results from defective V(D)J recombination.

T(−), B(−) SCID can be divided into two subsets according to cell radiosensitivity. In approximately half of the cases, patients' cells exhibit a normal cell sensitivity to ionizing radiation while in the other half, as in murine scid, cells are abnormally radiosensitive.

The first phenotype is accounted for by deficiencies in recombination activating gene 1 or 2 proteins (Rag-1 or Rag-2) (Schwartz et al., 1996). These elements, which are lymphocyte specific, initiate V(D)J recombination by creating site-specific DNA breaks at recombination signal sequences flanking coding elements of the variable part of T-cell receptors (TCRs) and B-cell receptors (BCRs). Complete defects result in an absence of mature T and B lymphocytes.

The second phenotype, associating defective V(D)J recombination and defective repair of DNA double-strand breaks (dsb), has been shown to be the consequence of mutations of the gene encoding the artemis protein (DNA cross-link repair 1C (PSO2 homolog, S. cerevisiae) (DCLRE1C)) (Moshous et al., 2001). It appears that this ubiquitously expressed protein is involved in the NHEJ process required for both TCR and BCR gene rearrangements and dsb DNA repair. The artemis sequence has some homology with proteins involved in repair of DNA lesions caused by inter-DNA strand bonds, but its exact function remains unknown. Artemis deficiency accounts for the SCID observed in the Athabascan-speaking Native Americans, where it is the most frequent inherited disease (about one in 1000 live births).

CD45 Deficiency

  1. Top of page
  2. Introduction
  3. Purine Metabolism Deficiency – Premature Apoptosis of Lymphocyte Precursors
  4. γc-Dependent Cytokine Receptor Pathway Deficiencies
  5. V(D)J Recombination Deficiencies
  6. CD45 Deficiency
  7. Atypical SCID Phenotypes
  8. See also
  9. References
  10. Further Reading
  11. Web Links

Finally, a CD45 deficiency was found to be responsible in two patients of a SCID phenotype consisting of absence of TCRαβ+ T cells. CD45, a membrane-associated phosphatase, plays a major role in pre-TCR/TCR-induced signaling by removing an inhibitory phosphate in the CD4/CD8 associated src kinase p56 Lck.

Atypical SCID Phenotypes

  1. Top of page
  2. Introduction
  3. Purine Metabolism Deficiency – Premature Apoptosis of Lymphocyte Precursors
  4. γc-Dependent Cytokine Receptor Pathway Deficiencies
  5. V(D)J Recombination Deficiencies
  6. CD45 Deficiency
  7. Atypical SCID Phenotypes
  8. See also
  9. References
  10. Further Reading
  11. Web Links

Residual activities of mutated proteins associated with SCID can attenuate the severity of the phenotype. This has been known for more than a decade for ADA deficiency. It has also been shown for Rag-1 and Rag-2, as residual activities of either product can be associated with a unique phenotype known as Omenn syndrome (Notarangelo et al., 1999). Omenn syndrome consists of consequences of a massive oligoclonal T-cell expansion. These T cells infiltrate the skin, the gut and sometimes organs, they exhibit a TH2 phenotype and cause severe disease with diffuse erythroderma and protracted diarrhea. While it can be understood that residual productive TCR gene rearrangements account for the development of a small number of T-cell clones, it is not clear why such T cells expand and behave as autoimmune clones especially at mucosal sites. There is an overlap between Rag-1/Rag-2 mutations causing absence of T and B lymphocytes and Omenn syndrome, suggesting that additional factor(s) might be involved.

Partial phenotypes have also been described in association with γc or JAK-3 mutations. While in some cases, partial T/NK cell development and function can be explained by γc/JAK-3 residual expression and function, in other instances, the phenotype is not well understood. For instance, in at least one case, a mutation leading to a truncated γc protein unable to bind JAK-3 was found associated with the progressive development over time of partially functioning T cells. Of interest, in one case, a partial T-cell deficiency associated with a deleterious γc mutation actually resulted from a spontaneous reverse mutation event that occurred in a T-cell precursor. For 5 years this child exhibited a mild T-cell lymphopenia with a somewhat diverse repertoire. This observation indicates the tremendous ability of T-cell precursors to proliferate prior to TCR gene rearrangement.

Other characterized genetic defects induce partial deficiencies of T-cell development. There are several examples including CD3γ and ε defects, ZAP-70 kinase deficiency, which, in humans, lead to an impairment in CD8 T-cell development and defective activation of CD4 T cells and expression deficiency of HLA class II molecules which prevents CD4 T-cell development, at least in part. More complex genetic diseases with multiple associated features can also impair T-cell development to some extent, as observed in DNA ligase 4 deficiency and the Nijmegen breakage syndrome caused by NBS/nibrin deficiency. DNA ligase 4 is involved in ligation of the ends of dsb DNA at the end of the NHEJ process. Its partial deficiency is compatible with life but results in microcephaly, a variable T-cell immunodeficiency and susceptibility to cytotoxic drugs. NBS/nibrin is part of a heterotrimeric protein complex with MRE-11 and Rad 50, which bind to DNA dsb and probably act as sensors of the DNA lesion.

Identification of the various genetic defects associated with impairment of T-cell development is of major importance, not only for basic science but also in medicine as it provides accurate tools for disease diagnosis and genetic counseling. In addition, it may pave the way for genetic treatment, as illustrated by the successful gene therapy of SCID-X1 (γc deficiency) (Cavazzana-Calvo et al., 2000).

Finally, the molecular basis of a few SCID phenotypes has not yet been characterized. This is the case of the very rare so-called reticular dysgenesis syndrome characterized not only by partially faulty development of T, NK and B lymphocytes, but also by a block in development of phagocytic cells. Associated deafness has been found in several cases. The yet unknown gene product should play a major role in the early steps of hematopoiesis. In some instances, a pure T-cell deficiency is observed without known etiology. Any gene product with a selective role in early steps of T-cell differentiation could be involved. There are also a number of more complex and somewhat ill-defined partial T-cell deficiencies – also termed combined immunodeficiencies – for which no molecular mechanisms are known. It is likely that further study of these phenotypes will delineate the role of yet unknown proteins in T-cell differentiation and function.

References

  1. Top of page
  2. Introduction
  3. Purine Metabolism Deficiency – Premature Apoptosis of Lymphocyte Precursors
  4. γc-Dependent Cytokine Receptor Pathway Deficiencies
  5. V(D)J Recombination Deficiencies
  6. CD45 Deficiency
  7. Atypical SCID Phenotypes
  8. See also
  9. References
  10. Further Reading
  11. Web Links

Further Reading

  1. Top of page
  2. Introduction
  3. Purine Metabolism Deficiency – Premature Apoptosis of Lymphocyte Precursors
  4. γc-Dependent Cytokine Receptor Pathway Deficiencies
  5. V(D)J Recombination Deficiencies
  6. CD45 Deficiency
  7. Atypical SCID Phenotypes
  8. See also
  9. References
  10. Further Reading
  11. Web Links