Comprehensive immunogenetics / W.H. Hildemann, E.A. Clark, R.L. Raison.

  • Hildemann, W. H., 1927-
Date:
[1981], ©1981
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Comprehensive immunogenetics / W.H. Hildemann, E.A. Clark, R.L. Raison. Source: Wellcome Collection.

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    274 Immunodeficiency and Immunogenetic Diseases cell pathway, while another subpopulation migrates to the thymus where they proliferate and differentiate into thymocytes. In adult animals the bone mar¬ row is the major source of lymphoid stem cells. The most profound immuno¬ deficiency diseases, together termed severe combined immunodeficiency disease (SCID), affect these stem cell precursors, produce marked impairment of both T-cell and B-cell pathways, and thus are invariably fatal. The more common form of inheritance is autosomal recessive but X-linked SCID has also been reported. Patients with SCID have recurring infections very early in life in the skin, respiratory tract, and GI tract. They are lymphopenic, hy- pogammaglobulinemic, and display little or no response to mitogens, specific antigens, or alloantigens. SCID includes a broad spectrum of syndromes de¬ fined in terms of mode of inheritance and site of the cellular or enzymatic de¬ fect. The most severe form of SCID affects primitive hematopoietic stem cells. Patients with this disorder have virtually no T- and B-lymphocytes or granu¬ locytes. The Swiss type of SCID originally termed hereditary thymic aplasia derives from defective lymphocytic stem cell development; consequently, pa¬ tients with this disorder have much reduced numbers of T- and B-cells. For¬ tunately, the defect in these patients can sometimes be repaired with HLA- identical bone marrow or fetal liver transplants. About half of the autosomal recessively inherited SCID are associated with a deficiency in the enzyme adenosine-deaminase (ADA), which plays a key role in purine metabolism by degrading adenosine to inosine. Without ADA, adenosine and adenosine- monophosphate accumulate in cells at high concentrations and can be toxic. Lymphocytes and thymocytes are normally very rich in ADA and, therefore, may be particularly vulnerable to a lack of this enzyme. In man, ADA is con¬ trolled by a gene on chromosome 20. Another form of severe combined im¬ munodeficiency disease is associated with the absence of T-lymphocytes and abnormally low levels of the T-cell dependent immunoglobulins IgG and IgA. These patients may have a defect in the stem cells required for T-cell matu¬ ration or in the thymic environment. Fortunately, primary SCID are rare and compatible transplant or enzyme therapy is potentially available. A more common form of secondary SCID is associated with severe malnutrition, particularly protein deprivation. Severely malnourished children are frequently lymphopenic and have reduced numbers of T-cells. The metabolic basis of this immunodeficiency, a major problem in underdeveloped countries, invites further study. T-Cell Developmental Defects Upon migration to the thymus, T-cell precursors are induced to express a se¬ ries of T-cell markers by thymic epithelial cells and hormones. The thymocytes undergo further differentiation in the thymus and several distinct T-cell sub- populations then migrate to the peripheral lymphoid tissues. T-cell-associated immunodeficiency disorders can be divided into two broad groups: the defects that impair the development and function of the thymus and thereby prevent