Severe Combined Immunodeficiency Disease

Severe combined immunodeficiencies (SCID – Severe Combined Immunodeficiency Diseases) are the most severe primary immunodeficiencies. They represent a group of heterogeneous genetic diseases that affect both the cellular and antibody component of the immune system. Affected individuals are extremely sensitive to a wide range of pathogens (especially intracellular), including opportunistic microorganisms (eg Candida albicans, Pneumocystis carinii). Vaccination with a live vaccine (BCG vaccine) can be a serious complication. Severe, chronic infections are the first and most serious manifestation of these diseases, which end up being lethal, by one year of age without adequate treatment (currently only bone marrow transplantation; gene therapy is still in the experimental stage) . Despite the same manifestations, the cause of various types of severe combined immunodeficiency is different, caused by different mutations of the human genome. However, 50-60% of the mutations are located on the X chromosome, resulting in a much higher percentage of men among patients with severe combined immunodeficiency.

Types of SCID

SCID is caused by adenosine deaminase deficiency

(SCID T-, B-, NK- OMIM: 102700)

This is a form with an autosomal recessive inheritance, which is found in approximately 15% of patients diagnosed with SCID (and in approximately one-third of patients with autosomal recessive inherited SCID). Adenosine deaminase (ADA) is an enzyme involved in purine metabolism that is encoded by a gene on chromosome 20 (20q13.11). The exact mechanism of action is not yet known, it is assumed that the alternative metabolites (2-deoxyadenosine and its derivatives) have a toxic effect on developing lymphocytes, especially T-type. The main and most serious manifestation is therefore severe lymphopenia. Other associated manifestations include various bone deformities, especially chest abnormalities and various defects in osteochondral connections.

Early-onset forms are more common, but forms with delayed or even late-onset are also known, in which ADA activity may be partially preserved.

SCID T-, B-, NK+

(OMIM: 601457) This form of severe combined immunodeficiency is characterized by the absence of both T and B-lymphocytes and the presence of NK cells (TB-NK +). The disease has an autosomal recessive inheritance, caused by a mutation in the RAG1 (RAG1 - Recombination activating gene-1; localization 11p13) or RAG2 (RAG2 - Recombination activating gene-2; localization 11p13) gene. Recombinases produced by these genes activate the V (D) J recombination process (rearrangement of V, J or D gene segments) and are therefore responsible for the production of TCR (T cell receptors) and BCR (B cell receptors).

Radiation-sensitive SCID

(SCID T-, B-, NK+ sensitive to ionizing radiation, RS-SCID, Athabaskan SCID OMIM: 602450) This, relatively recently described, a form of severe combined immunodeficiency is an autosomal recessive inherited disease caused by an Artemis gene mutation (localization 10p; the product is DCLRE1C - DNA cross link-repair protein 1C). Cells (especially fibroblasts and bone marrow stem cells) from patients with this mutation show increased sensitivity to ionizing radiation. The reason is the inability to repair a DNA double helix break (such a break also occurs in V (D) J recombination, when DNA splicing occurs).

X-linked SCID

(SCIDX1, SCID T-, B+, NK- OMIM: 300400)

In this most common X-linked form of SCID, we find a mutation in the gamma chain of the interleukin-2 receptor gene. This gene is called IL2RG and is located in the Xq13.1 region. This chain has also been shown to be common to receptors for other interleukins (namely IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21). The defect in the IL-7 receptor appears to be the most serious, as this interleukin is important in humans for the development of lymphocyte cells but especially T-cell precursors. A result is a minimal number of T-lymphocytes, and although the number of B-lymphocytes is mostly normal, their function is limited by the absence of T-lymphocytes.

SCID caused by JAK3 kinase deficiency

(SCID T-, B+, NK- OMIM: 600802) This form of SCID is phenotypically very similar to the previous X-linked form (low or even no T and NK cells, B cells are present). However, this form is autosomal recessively inherited and caused by a mutation in the JAK3 gene (19p13.1), encoding the Janus kinase 3. This enzyme is a protein kinase that is responsible for biosignal transmission and realization upon binding of an appropriate signalling molecule to a receptor, which includes a gamma chain of cytokine receptors (it is associated with JAK3 kinase activity, which explains the phenotypic similarity of this form with the above-described mutation of the IL2RG gene).

SCID T-, B+, NK+

(OMIM: 608971) It is an autosomal recessively inherited form of SCID, which differs from the two above-mentioned variants by the preserved presence of NK cells. It can be caused by mutations in various genes - eg mutations in the interleukin-7 receptor gene (IL-7R, localization 5q17), for CD45 antigen (LCA, localization 1q31-q32) and for CD3 delta (CD3D, localization 11q23) or CD3 epsilon antigen (CD3E, localization 11q23).

References

Related articles

• CVID
• Reticular dysgenesis
• Primary immunodeficiency

Source

• ŠÍPEK, Antonín. Geneticky podmíněné poruchy imunitního systému [online]. The last revision 9. 6. 2006, [cit. 16. 12. 2009]. <http://www.genetika-biologie.cz/primarni-imunodeficience>.

Literature

• BARTŮŇKOVÁ, Jiřina. Imunodeficience. 1. edition. Praha : Grada, 2002. 228 pp. ISBN 80-247-0244-4.