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Chapter: Essential Clinical Immunology: Immunological Aspects of Immunodeficiency Diseases

Complex Immunodeficiencies Due to Miscellaneous Defects

Wiskott-Aldrich Syndrome, DNA Repair Defects Associated with Immunodeficiency.


Wiskott-Aldrich Syndrome

Patients with Wiskott-Aldrich syndrome typically develop eczema; purpura due to thrombocytopenia with small-sized, defec-tive platelets; and a variable immunode-ficiency. Antibody production to bacte-rial capsular polysaccharides is deficient. Patients therefore commonly develop recurrent sinopulmonary infections. T-cell and NK-cell function is deficient and progressive T lymphopenia develops with time. Hence, patients can develop opportu-nistic infections. Risk of malignancy (espe-cially leukemias or EBV-induced lympho-mas) is increased in these patients.


The defective gene, which is on the X chromosome, encodes for the Wiskott-Aldrich syndrome protein, which regu-lates actin polymerization, and therefore cytoskeletal change is required for normal platelet and lymphocyte function.

DNA Repair Defects Associated with Immunodeficiency



Ataxia telangiectasia (AT) is a condition characterized by cerebellar ataxia, oculo-cutaneous telangiectasia, growth retarda-tion, and a variable immunodeficiency. AT patients show increased sensitivity to ionized radiation and radiomimetic drugs. Increased susceptibility to leukemias and lymphomas is also a feature of this

syndrome. Patients often fail to produce antibodies to bacterial capsular polysaccha-rides and therefore develop sinopulmonary infections. Chromosomal translocations, involving immunoglobulin heavy-chain and TCR loci, are often detected in the T cells of AT patients.


The function of the protein encoded by the affected gene (called ataxia telangiecta-sia mutated, or ATM) is to detect double-strand breaks in DNA, initiating their repair. Mutated ATM results in defective control of the cell cycle. This explains the radiation sen-sitivity, abnormal immune cell development and function, and the cytogenetic abnor-malities seen in AT.


Nijmegen breakage syndrome, which is phenotypically similar to AT, is due to a mutation of the NBS1 gene that encodes a protein that acts as a substrate for ATM. DNA-ligase I defect, which also results in defective DNA repair, manifests with growth retardation and immunodeficiency. The product of the MRE11A gene is another component of the DNA damage sensing machinery. Mutation of the MRE11A gene results in a condition similar to AT.

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Essential Clinical Immunology: Immunological Aspects of Immunodeficiency Diseases : Complex Immunodeficiencies Due to Miscellaneous Defects |

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