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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.
We sought to examine the immunologic mechanisms responsible for antibody deficiency heterogeneity in patients with AT.
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.
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.
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.Le texte complet de cet article est disponible en PDF.
Key words : Ataxia telangiectasia, class switch recombination, somatic hypermutation, κ-deleting recombination excision circle, hypogammaglobulinemia, B-cell subsets, T-cell subsets
Abbreviations used : AT, ATM, DSB, GC, NBS, TREC
| 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.