Congenital (Primary) Immunodeficiencies
المؤلف:
Abbas, A. K., Lichtman, A. H., & Pillai, S
المصدر:
Basic Immunology : Function and disorders of immune system
الجزء والصفحة:
6th ed , page 236-237
2025-06-12
434
Congenital immunodeficiencies are caused by genetic defects that lead to impaired maturation or function of different components of the immune system. It is estimated that as many as 1 in 500 individuals in the United States and Europe suffer from congenital immune deficiencies of varying severity. These immunodeficiencies share several features, the most common being increased susceptibility to infections (Fig. 1). Congenital immunodeficiency diseases may, however, differ considerably in clinical and pathologic manifestations. Some of these disorders result in greatly increased incidence of infections that may manifest early after birth and may be fatal unless the immunologic defects are corrected. Other congenital immunodeficiencies lead to mild infections and may first be detected in adult life.
Fig1. Features of immunodeficiency diseases. The figure summarizes the important diagnostic features and clinical manifestations of immunodeficiencies affecting different components of the immune system. Within each group, different diseases, and even different patients with the same disease, may show considerable variation. Reduced numbers of circulating B or T cells are often detected in some of these diseases. DTH, Delayed-type hypersensitivity; EBV, Epstein-Barr virus; Ig, immunoglobulin.
Mutations in over 300 different genes have been identified as causes of primary immunodeficiencies. Predict ably, most of these genes are expressed in immune cells. Some interesting features of these mutations are worth noting. First, immune deficiency is more frequently caused by mutations in X-linked genes than in autosomal genes. Because boys have only one X chromosome, mutations in only one gene will cause the disease in boys (and girls with the mutation will be carriers but not affected because they have two X chromosomes). Autosomal recessive diseases are seen in populations in which cosanguinous marriages are common, and these are being detected more frequently now because of the widespread use of whole genome sequencing. Second, while a complete loss-of-function mutation in a gene might lead to one disease state, a hypomorphic mutation in the same gene, which only partially compromises the function of the encoded protein, may lead to a very different disease. As an example, complete loss of function mutations in RAG1 or RAG2, discussed below, lead to a disorder called severe combined immunodeficiency (SCID), whereas a hypomorphic mutation in one of these genes can lead to a very different disease (called Omenn syndrome) in which autoimmunity predominates. The third interesting feature is that mutations in certain sets of genes contribute to susceptibility to specific subsets of pathogens. For example, mutations affecting Toll-like receptor 3 (TLR3) and proteins in the TLR3 signaling pathway contribute to herpes simplex virus infection of the brain (encephalitis), while mutations in interleukin-12 (IL-12) and genes related to Th1 cell development or function result in atypical mycobacterial infections.
Mutations in complement genes encoding proteins that form the membrane attack complex contribute to Neis seria infections. These restricted clinical phenotypes suggest considerable redundancy in host defense mechanisms, so defects in one pathway can be compensated by other pathways, and patients are not susceptible to a wide variety of infections. Clearly the immune system has evolved numerous pathways that are often specialized for combating subsets of pathogens.
The following discussion summarizes the pathogenesis of select immunodeficiencies, several of which were mentioned in earlier chapters to illustrate the physio logic importance of various components of the immune system.
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