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Chapter: Biology of Disease: Disorders of the Immune System

Combined T and B deficiencies - Primary Immunodeficiency Disease

Deficiencies that affect both B and T lymphocyte numbers and/ or their functions are life threatening.

Combined T and B deficiencies


Deficiencies that affect both B and T lymphocyte numbers and/ or their functions are life threatening. Such deficiencies are termed severecombined immunodeficiency (SCID). The term SCID represents a groupof disorders associated with more than 20 different mutations and with a frequency of between one in 50 000 and one in 500 000 births. As some forms of SCID are inherited in an X-linked fashion , more boys than girls are affected, with the male : female ratio of approximately 3 : 1.

Depending on the mutation involved, T and B cells may both be decreased (TB SCID) or B cells numbers may be normal or increased (TB+SCID). In the latter, the absence of T cells renders B cells functionally inactive, owing to the need for the cytokines produced by TH cells for antibody production as described. In either case, the disorder becomes apparent in the first few weeks or months of life with the mean age at diagnosis being 6.5 months.

 

The disease is characterized by chronic viral and fungal infections. Chronic diarrhea and oral Candida infections are common and in the presence of other infections, the child fails to thrive. Affected infants may suffer generalized viral infections if given live viral vaccines, such as the MMR and polio vaccines. Laboratory tests show fewer than 3000 per mm3 circulating lymphocytes (where the reference range for an infant of six months is between 4000 and 13 500 per mm3). The lymphocytes present are functionally inactive and do not respond in vitro to knownmitogens. Chest X-rays show an abnormally smallor absent thymus.

Approximately 20% of TB SCID arises from mutations in the gene encoding adenosine deaminase (ADA). The absence of this enzyme results in the accumulation of metabolites, such as ADP, GTP and dATP, which are toxic to small lymphocytes. A similar syndrome arises from deficiency of the purine nucleoside phosphorylase (PNP) that results in an accumulation of dGTP. Approximately 40% of cases of TB+ SCID are X-linked and arise from mutations in a polypeptide that forms part of the receptor for several interleukins (ILs), so that affected lymphocytes are unable to respond to interleukin signals.

If not diagnosed early and treated appropriately, children with SCID usually die from infections in the first few years of life. Management of this condition includes administering antiviral, antibacterial and antifungal drugs and measures must be taken to avoid infection. Keeping such infants in totally aseptic conditions is neither feasible nor ethical, since this would preclude direct contact with other humans. Their immune system may be restored with a bone marrow transplant. This can lead to long-term survival but is not without danger, chiefly graft versus host disease. Gene therapy has been attempted with some ADA deficient patients and, in a few cases, has been reported to be successful.


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