Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity

Gertjan J. Driessen, Hanna Ijspeert, Corry M. R. Weemaes, Ásgeir Haraldsson, Margreet Trip, Adilia Warris, Michiel van der Flier, Nico Wulffraat, Mijke M. M. Verhagen, Malcolm A. Taylor, Menno C. van Zelm, Jacques J. M. van Dongen, Marcel van Deuren, Mirjam van der Burg

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1367-1375.e9
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Volume131
Issue number5
Early online date18 Apr 2013
DOIs
Publication statusPublished - May 2013

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Ataxia Telangiectasia
Homeostasis
T-Lymphocytes
Antibodies
Agammaglobulinemia
B-Lymphocytes
Genetic Recombination
B-Lymphocyte Subsets
Phosphotransferases
Cell Count
V(D)J Recombination
Telangiectasis
B-Cell Antigen Receptors
Germinal Center
Immunoglobulin Isotypes
T-Lymphocyte Subsets
CD4 Lymphocyte Count
DNA Repair
History
Antigens

Keywords

  • adolescent
  • adult
  • agammaglobulinemia
  • ataxia telangiectasia
  • B-lymphocyte subsets
  • case-control studies
  • child
  • female
  • homeostasis
  • humans
  • immunologic deficiency syndromes
  • male
  • middle aged
  • T-lymphocyte subsets

Cite this

Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. / Driessen, Gertjan J.; Ijspeert, Hanna; Weemaes, Corry M. R.; Haraldsson, Ásgeir; Trip, Margreet; Warris, Adilia; van der Flier, Michiel; Wulffraat, Nico; Verhagen, Mijke M. M.; Taylor, Malcolm A.; van Zelm, Menno C.; van Dongen, Jacques J. M.; van Deuren, Marcel; van der Burg, Mirjam.

In: Journal of Allergy and Clinical Immunology, Vol. 131, No. 5, 05.2013, p. 1367-1375.e9.

Research output: Contribution to journalArticle

Driessen, GJ, Ijspeert, H, Weemaes, CMR, Haraldsson, Á, Trip, M, Warris, A, van der Flier, M, Wulffraat, N, Verhagen, MMM, Taylor, MA, van Zelm, MC, van Dongen, JJM, van Deuren, M & van der Burg, M 2013, 'Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity', Journal of Allergy and Clinical Immunology, vol. 131, no. 5, pp. 1367-1375.e9. https://doi.org/10.1016/j.jaci.2013.01.053
Driessen, Gertjan J. ; Ijspeert, Hanna ; Weemaes, Corry M. R. ; Haraldsson, Ásgeir ; Trip, Margreet ; Warris, Adilia ; van der Flier, Michiel ; Wulffraat, Nico ; Verhagen, Mijke M. M. ; Taylor, Malcolm A. ; van Zelm, Menno C. ; van Dongen, Jacques J. M. ; van Deuren, Marcel ; van der Burg, Mirjam. / Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. In: Journal of Allergy and Clinical Immunology. 2013 ; Vol. 131, No. 5. pp. 1367-1375.e9.
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abstract = "BackgroundAtaxia 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.ObjectiveWe sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT.MethodsIn 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.ResultsPatients 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.ConclusionThe 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.",
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TY - JOUR

T1 - Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity

AU - Driessen, Gertjan J.

AU - Ijspeert, Hanna

AU - Weemaes, Corry M. R.

AU - Haraldsson, Ásgeir

AU - Trip, Margreet

AU - Warris, Adilia

AU - van der Flier, Michiel

AU - Wulffraat, Nico

AU - Verhagen, Mijke M. M.

AU - Taylor, Malcolm A.

AU - van Zelm, Menno C.

AU - van Dongen, Jacques J. M.

AU - van Deuren, Marcel

AU - van der Burg, Mirjam

N1 - Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

PY - 2013/5

Y1 - 2013/5

N2 - BackgroundAtaxia 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.ObjectiveWe sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT.MethodsIn 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.ResultsPatients 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.ConclusionThe 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.

AB - BackgroundAtaxia 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.ObjectiveWe sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT.MethodsIn 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.ResultsPatients 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.ConclusionThe 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.

KW - adolescent

KW - adult

KW - agammaglobulinemia

KW - ataxia telangiectasia

KW - B-lymphocyte subsets

KW - case-control studies

KW - child

KW - female

KW - homeostasis

KW - humans

KW - immunologic deficiency syndromes

KW - male

KW - middle aged

KW - T-lymphocyte subsets

U2 - 10.1016/j.jaci.2013.01.053

DO - 10.1016/j.jaci.2013.01.053

M3 - Article

VL - 131

SP - 1367-1375.e9

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 5

ER -