Severe combined Immunodefciency (overwiew)

SCID is the acronym for Severe Combined Immunodeficiency. SCID is a collective term for severe congenital immunodeficiencies in which there is either a malfunction or deficiency of T lymphocytes and NK cells. This results in complex disorders of the cell-mediated immune defense.

Depending on the SCID variant, malfunctions and deficiencies of B lymphocytes are also detectable. Often, however, the term "SCID" is used as an umbrella term for immunodeficiencies of a general nature. See below Immunodeficiencies primary (classification).

Predominant are defects of the

• ADA gene (adenosine deaminase gene/ADA-SCID)
• Cytokine receptor genes
• Antigen receptor genes

A useful clinical classification can be made according to absence (-) and presence (+) of T/B cells and NK cells.

• Adenosine deaminase deficiency (D81.3): 15% of all SCID cases. autosomal recessive mutation of the ADA gene (ADA) with deficiency of the ubiqitary enzyme adenosine deaminase.
• Recombination activating gene 1/2 (RAG1/2) deficiency (D81.3): 3% of all SCID cases. Mutations in the genes of the recombinases RAG1 and RAG2 lead to a defect of the T- and B-cell receptor.
• X-linked SCID (D81.2): 40% of all SCID cases,X-linked inheritance with with mutation in the IL2RG gene, which encodes the gamma chain of the IL-2 receptor (interleukin-7 receptor alpha gene - IL-7R-α; CD127). This chain is a component of several interleukin receptors of interleukins IL-2, IL-4,IL-7, IL-9,IL-15, IL-21. The mutation causes a severe complex disorder of signal transduction.
• JAK3 deficiency (D81.2): about 20% of all SCID cases. Mutation of the cytoplasmic tyrosine kinase JAK 3.
• Omenn syndrome: different genetic defects are suggested for a phenotypically identical clinical picture: RAG1/RAG2 deficiency, Artemis defect, IL-7Ralpha deficiency. Clinical: IgE elevated, esosinophilic lymphadenopathy, erythroderma.
• MHC class I defect (D81.6) also Bare lymphocyte syndrome type I: mutation in theTAP I and TAP II genes. Complex disorder in antigen recognition
• MHC class II defect (D81.6) also Bare lymphocyte syndrome type II: Mutaions in the transcription factors CIITA, RFX5, RFXAP which transcribe the MHC II protein.
• Cartilage hair hyoplasia: short stature with dysostosis, fine brittle hair, granulomas of the skin, increased risk of tumors.
• DOCK8 deficiency: Mutation in DOCK8 gene (dedicator of cytogenesis 8) leads to hypereosinophilia, decreased B and cells, decreased IgM (normal IgA and IgG), recurrent bacterial and viral infections, severe atopic eczema, increased tumor rate.
• Missense mutation in the TFRC gene(transferritin receptor gene): The mutation results in increased surface expression of TFRC (up to 13-fold higher than controls) of lymphocytes and impaired internalization of TFRC in affected patients. Evidence suggests that inadequate iron uptake is the cause of impaired B- and T-cell activation in affected individuals. These results support the importance of TFRC for adaptive immunity (Radoshitzky SR et al. 2007).

S.a. under: immunodeficiencies primary / classification (Tangye SG et al. (2021).

Depending on the genetic defect, clinically very differently pronounced disease patterns whose commonality consists of severe viral, mycotic or bacterial infections. Extensive therapy-resistant HPV infections are also frequently observed. Since SCID usually occurs in infancy, diagnosis and sequelae will primarily concern pediatrics. The diseases are dermatologically relevant when repeated and severe infections with "unusual pathogens" and developmental disorders manifest in infancy and childhood.

If left untreated, SCID is usually fatal after only a few months or, in the best case, after years. Currently, the only curative treatment is allogeneic blood stem cell transplantation. Newer gene therapy methods, which aim to correct the different genetic defects by introducing a healthy gene, are still experimental in nature.

1. Booth C et al. (2016) Stem cell transplantation for the treatment of immunodeficiency in children: current status and hopes for the future. Expert Rev
2. Clin Immunol 12:713-723. Buelow BJ et al (2016) Newborn screening for SCID: lessons learned. Expert Rev Hematol 9:579-584.
3. Chinn IK et al (2015) Severe combined immunodeficiency disorders. Immunol Allergy Clin North Am 35:671-694.
4. Cirillo E et al (2015) Severe combined immunodeficiency--an update. Ann N Y Acad Sci 1356: 90-106.
5. Kobrynski L (2015) . Newborn screening for severe combined immune deficiency (technical and political aspects). Curr Opin Allergy Clin Immunol 15:539-546.
6. Radoshitzky SR et al (2007) Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses. Nature 446: 92-96
7. Tangye SG et al (2021) The Ever-Increasing Array of Novel Inborn Errors of Immunity: an Interim Update by the IUIS Committee. J Clin Immunol 41:666-679.
8. Williams KW et al (2015) Eosinophilia Associated with Disorders of Immune Deficiency or Immune Dysregulation. Immunol Allergy Clin North Am 35:523-544.