Multisystem Disorders with Immunodeficiency Ataxia Telangiectasia

Immunodeficiency is often one of a constellation of symptoms in a number of inherited disorders. Examples of such syndromes discussed before include Ch├ędiak-Higashi syndrome, Wiskott-Aldrich syndrome, and DiGeorge syndrome. Ataxia-telangiectasia is an autosomal recessive disorder characterized by abnormal gait (ataxia), vascular malformations (telangiectases), neurologic deficits, increased incidence of tumors, and immunodeficiency. The immunologic defects are of variable severity and may affect both B and T cells. The most common humoral immune defects are IgA and IgG2 deficiency, probably because of the crucial role the ATM protein plays in class switch recombination (discussed later). The T cell defects, which are usually less pronounced, are associated with thymic hypoplasia. Patients experience upper and lower respiratory tract bacterial infections, multiple autoimmune phenomena, and increasingly frequent cancers with advancing age. The gene responsible for this disorder is located on chromosome 11 and encodes a protein called ATM (ataxia-telangiectasia mutated) that is related structurally to phosphatidylinositol 3-kinase but is a protein kinase. The ATM protein can activate cell cycle checkpoints and apop-tosis in response to double-stranded DNA breaks and has also been shown to contribute to the stability of DNA double-stranded break complexes during V(D)J recombination. Because of these abnormalities in DNA repair, the generation of antigen receptors may also be abnormal.

DNA repair during class switch recombination not only involves the nonhomologous end-joining pathway but also requires the ATM protein, the MRE11 (meiotic recombination 11) protein, and the NBS1 (Nijmegen breakpoint syndrome 1) protein. Patients with mutations in the genes encoding these proteins or ATM often exhibit decreased levels of IgG, IgA, and IgE.

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