Immune deficiencies, infection, and systemic immune disorders
Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity

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Background

Ataxia telangiectasia (AT) is a multisystem DNA-repair disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene. Patients with AT have reduced B- and T-cell numbers and a highly variable immunodeficiency. ATM is important for V(D)J recombination and immunoglobulin class-switch recombination (CSR); however, little is known about the mechanisms resulting in antibody deficiency severity.

Objective

We sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT.

Methods

In this study we included patients with classical AT plus early-onset hypogammaglobulinemia (n = 3), classical AT (n = 8), and variant AT (late onset, n = 4). We studied peripheral B- and T-cell subsets, B-cell subset replication history, somatic hypermutation frequencies, CSR patterns, B-cell repertoire, and ATM kinase activity.

Results

Patients with classical AT lacked ATM kinase activity, whereas patients with variant AT showed residual function. Most patients had disturbed naive B-cell and T-cell homeostasis, as evidenced by low cell numbers, increased proliferation, a large proportion CD21lowCD38low anergic B cells, and decreased antigen receptor repertoire diversity. Impaired formation of T cell–dependent memory B cells was predominantly found in patients with AT plus hypogammaglobulinemia. These patients had extremely low naive CD4+ T-cell counts, which were more severely reduced compared with those seen in patients with classical AT without hypogammaglobulinemia. Finally, AT deficiency resulted in defective CSR to distal constant regions that might reflect an impaired ability of B cells to undergo multiple germinal center reactions.

Conclusion

The severity of the antibody deficiency in patients with AT correlates with disturbances in B- and T-cell homeostasis resulting in reduced immune repertoire diversity, which consequently affects the chance of successful antigen-dependent cognate B-T interaction.

Section snippets

Patients

Peripheral blood samples and clinical data were collected from 15 patients with AT and 45 healthy age-matched control subjects. These studies were approved by the Medical Ethics Committees of the Radboud University Nijmegen Medical Center and Erasmus MC Rotterdam.

Flow cytometric analysis and high-speed cell sorting of blood B-cell subsets

Six-color flow cytometric immunophenotyping of peripheral blood was performed on a FACS LSR II (BD Biosciences, San Jose, Calif), and data were analyzed with FACSDiva software (BD Biosciences), as described previously.16 Memory B-cell

Patients

Patients' characteristics are summarized in Table I. Genotype-phenotype correlations of the patients (among others) have been reported elsewhere.15 Patients with AT were divided into 3 groups: classical AT plus hypogammaglobulinemia (n = 3), classical AT (n = 8), and variant AT (n = 4; ie, patients with late onset). None of the patients with classical AT showed ATM kinase activity, whereas patients with variant AT showed residual activity.

Patients with classical AT plus hypogammaglobulinemia

Discussion

In this study we demonstrated that the antibody deficiency in patients with AT is caused by disturbed naive B- and T-cell homeostasis, leading to reduced immune repertoire formation and reduced memory B-cell formation. Although these defects are present in all patients, 3 clinical subgroups can be defined, of which the disease severity correlated with numbers of circulating memory B cells and naive T cells.

Reduction of transitional and naive mature B-cell counts is the hallmark of abnormal

References (33)

  • B.B. Zhou et al.

    The DNA damage response: putting checkpoints in perspective

    Nature

    (2000)
  • Y. Xu

    DNA damage: a trigger of innate immunity but a requirement for adaptive immune homeostasis

    Nat Rev Immunol

    (2006)
  • A.L. Bredemeyer et al.

    ATM stabilizes DNA double-strand-break complexes during V(D)J recombination

    Nature

    (2006)
  • B. Reina-San-Martin et al.

    ATM is required for efficient recombination between immunoglobulin switch regions

    J Exp Med

    (2004)
  • J.M. Lumsden et al.

    Immunoglobulin class switch recombination is impaired in Atm-deficient mice

    J Exp Med

    (2004)
  • Q. Pan-Hammarstrom et al.

    ATM is not required in somatic hypermutation of VH, but is involved in the introduction of mutations in the switch mu region

    J Immunol

    (2003)
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    Supported by grants from the foundation “Sophia Kinderziekenhuis Fonds” (grant 589 H.I.) and ZonMW (Vidi grant 91712323 to M.v.d.B.).

    Disclosure of potential conflict of interest: H. IJspeert has been supported by one or more grants from Sophia Kinderziekenhuis Fonds (grant 589). Á. Haraldsson has received one or more grants from or has one or more grants pending with GlaxoSmithKline, has received one or more payments for lecturing from or is on the speakers' bureau for GlaxoSmithKline and Pfizer, and has received one or more payments for travel/accommodations/meeting expenses from GlaxoSmithKline, AstraZeneca, and CSL Behring. A. Warris has consultancy arrangements with and has received one or more grants from or has one or more grants pending with Pfizer and Gilead and has received one or more payments for the development of educational presentations for Pfizer. M. A. Taylor has been supported by one or more grants from Cancer Research UK. M. van der Burg has been supported by a VIDI grant of the Dutch Scientific Organization. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors contributed equally to this work.

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