Ataxia Telangiectasia: From DNA repair defect to antibody repertoire deficiency

Published Online: April 8, 2013

Ataxia Telangiectasia (AT) is an inherited disorder caused by mutations in the ATM gene that leads to a defect in repair of DNA damage. AT is named after the characteristic neurological abnormality called ataxia (a debilitating movement disorder) and abnormalities of small blood vessels visible in the skin and eye, called telangiectasias. In addition, the DNA repair disorder results in a propensity for the development of hematological malignancies and immunodeficiency, predominantly a defect in the production of antibodies. The latter is affected because ATM is critically important for DNA repair processes involved in the production of a diverse antibody repertoire. Little is known about the actual effect on immune responses leading to the immunodeficiency in AT.

In a study recently published in The Journal of Allergy and Clinical Immunology (JACI), Driessen and IJspeert et al. examined the mechanisms responsible for antibody deficiency in patients with AT. Fifteen patients were divided into 3 groups: classical AT plus severe antibody deficiency (hypogammaglobulinemia), classical AT with mild antibody deficiency, or variant AT. In classical  AT patients the ATM protein is absent or not functional, whereas patients with variant AT show residual ATM activity. Several immunological parameters were studied including detailed immunophenotyping of B and T cells and molecular techniques. In addition, they used next generation sequencing to assess antibody (antigen receptor) repertoire diversity.

The combined results of the immunological and molecular studies demonstrated that in all three groups of AT patients the numbers of newly generated naive B and T cells were reduced, however, the decrease was more pronounced in classical AT than in variant AT. These naive B and T cells show extensive compensatory proliferation, but the total numbers remain low. As a consequence of the low cell numbers the antigen receptor repertoire diversity was reduced. The limited number and the limited repertoire of naive B and T cells hamper a successful response to antigen. This results in reduced formation of immunological memory, which is critical for subsequent encounters with the same pathogen, and a reduced production of antibodies.

This study shows for the first time that a defect in DNA repair can cause a decrease in antigen receptor repertoire diversity leading to an antibody deficiency. Comparable antigen receptor repertoire defects are most likely present in other DNA repair syndromes (including Nijmegen Breakage Syndrome). Furthermore, it is expected that a subgroup of patients with Common Variable Immunodeficiency showing extensive proliferation of naive B and T cells also has disturbances in antigen receptor repertoire diversity. In this respect, the AT study illustrates the crucial role of adequate DNA repair for creating a broadly diverse antigen receptor repertoire.


The Journal of Allergy and Clinical Immunology (JACI) is the official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.

AAAAI - American Academy of Allergy Asthma & Immunology