Severe Combined Immune Deficiency (SCID): Genetics

Abstract

Severe combined immunodeficiency consists of an array of genetically determined blocks in T‐lymphocyte development. Characterisation of genetic defects contributes to a better understanding of lymphocyte differentiation pathways. Seventeen distinct defects have now been characterised that affect multiple steps of T lymphocytes ontogenesis, from defective survival of several haematopoietic lineage precursors, premature cell death of lymphocyte precursors, defective interleukin‐7‐dependent survival/proliferation of T‐lymphocyte precursors, defective recombination of T‐cell receptor (TCR) genes, defective (pre) TCR signalling and defective egress of the thymus. These disorders are life threatening because of the early onset of various infections notably caused by opportunistic agents, hence stressing the importance of T cell adaptive immunity in longevity. These disorders can be cured by allogeneic haematopoietic stem cell transplantation, some by gene therapy while neonatal screening is being developed.

Key Concepts:

  • Severe combined immunodeficiencies are rare inherited diseases caused by defective development of the T lymphocyte lineage.

  • Clinical consequences are devastating leading to death within the first year of life in the absence of treatment.

  • Allogeneic transplantation of haematopoietic stem cells or in some cases gene therapy can be life saving by restoring T‐cell development.

  • Seventeen different genetic defects have been found to cause SCID, they are classed in six groups as based on pathophysiology.

  • SCID variants – defined by the presence of residual T cells – are relatively frequent as a consequence of hypomorphic mutation or reversion.

Keywords: severe combined immunodeficiencies; haematopoietic stem cells; T lymphocytes; B lymphocytes; NK lymphocytes; lymphocyte differentiation

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, haematopoietic stem cell; CLP, common lymphoid progenitor; NK, natural killer.

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Further Reading

Bassing CH, Swat W and Alt FW (2002) The mechanism and regulation of chromosomal V(D)J recombination. Cell 109: S45–S55.

Fischer A (2001) Primary immunodeficiency diseases: an experimental model for molecular medicine. Lancet 357: 1863–1869.

Leonard WJ (2001) Cytokines and immunodeficiency diseases. Nature Reviews Immunology 1: 200–208.

Notarangelo LD, Fischer A, Geha RS et al. (2009) Primary immunodeficiencies: 2009 update. Journal of Allergy and Clinical Immunology 124: 1161–1178.

Reith W and Mach B (2001) The bare lymphocyte syndrome and the regulation of MHC expression. Annual Review of Immunology 19: 331–373.

Rooney S, Sekiguchi J, Zhu C et al. (2002) Leaky SCID phenotype associated with defective V(D)J coding end processing in artemis‐deficient mice. Molecular Cell 10: 1379–1390.

Villa A, Santagata S, Bozzi F et al. (1998) Partial V(D)J recombination activity leads to Omenn syndrome. Cell 93: 885–896.

Web Links

Adenosine Deaminase (ADA); MIM Number: 102700. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?102700

DNA Cross‐link Repair 1C (PSO2 S. cerevisiae) (DCLRE1C); MIM Number: 605988. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?605988

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Fischer, A(Nov 2011) Severe Combined Immune Deficiency (SCID): Genetics. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005941.pub2]