Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia (original) (raw)
Abstract
Objective
Ataxia telangiectasia (AT) is a rare genetic, multi-system disorder characterized by neurodegeneration, chromosome instability, B and T cell immunodeficiency and a predisposition to cancer. We examined immunologic parameters reflecting cell development and proliferation and their relevancy to the clinical phenotype in affected individuals.
Patients and Methods
AT patients from the AT National Clinic in Israel underwent immunological investigation. Their T and B cell workup included lymphocyte subset counts, immunoglobulin levels, responses to mitogenic stimulations, TCR-Vβ families and BCR immunoglobulin heavy chain spectratyping, TCR rearrangement excision circles (TRECs) and Kappa-deleting recombination excision circles (KRECs).
Results
Thirty-seven AT patients (median age 12.7 years, range 4.2–25.1) were evaluated. CD20 B and CD3 T lymphocytes were decreased in 67 % and 64 % of the patients, respectively, while only 33 % of the patients had reduced lymphoproliferative responses. Almost all AT patients displayed extremely low TRECs and KRECs levels, irrespective of their age. Those levels were correlated to one another and to the amounts of CD3+ and CD20+ cells, respectively. Abnormal TCR-Vβ repertoires were found with different degrees of clonality or reduced expression in these AT patients. There was no clear clustering of expansions to specific TCR-Vβ genes. PCR spectratyping analysis of the FR2 IgH BCR gene rearrangements in peripheral blood was abnormal in 50 % of the patients.
Conclusion
The immunodeficiency associated with AT is combined, remains low over time and not progressive. It is characterized by low TREC and KREC copies suggestive of abnormal T and B cell neogenesis.
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Article Open access 02 November 2017
Abbreviations
AT:
Ataxia telangiectasia
ATM:
AT mutated
BCR:
B-cell receptor
CJ:
Coding joints
CPM:
Counts per minutes
IGH:
Immunoglobulin heavy chain
IVIG:
Intravenous immunoglobulin
KREC:
Kappa-deleting recombination excision circles
ND:
Not done
PMBC:
Peripheral blood mononuclear cell
RQ-PCR:
Real-time quantitative polymerase chain reaction
SJ:
Signal joints
TCR:
T-cell receptor
TREC:
T-cell receptor excision circle
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Acknowledgments
The Jeffrey Modell Foundation (JMF), the Legacy Heritage Biomedical Science Partnership Program of the Israel Science Foundation and the Chief Scientist Office of the Ministry of Health for their support of Dr. Somech. Esther Eshkol is thanked for editorial assistance. This work was performed in partial fulfillment of the M.D. thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University (M.K.).
The authors have no financial relationships relevant to this article to disclose.
The authors have no conflicts of interest relevant to this article to disclose.
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Authors and Affiliations
- Pediatric Immunology Unit, Jeffrey Modell Foundation (JMF) Center and Department of Pediatrics, Sheba Medical Center, Tel Hashomer, Israel
Matan Kraus, Atar Lev & Amos J. Simon - Pediatric Department, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
Inbal Levran - Pediatric Neurology Unit, Ataxia Telangiectasia National Clinic, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
Andrea Nissenkorn - Ataxia Telangiectasia National Clinic, Edmond and Lily Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
Yonit B. Levi - Ataxia Telangiectasia National Clinic, Hadassah-Hebrew University Medical Centerr, Mount Scopus Jerusalem, Israel
Yackov Berkun - Pediatric Pulmonary Unit, Ataxia Telangiectasia National Clinic, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
Ori Efrati - Cancer Research Center, Sheba Medical center, Tel Hashomer, Israel
Ninette Amariglio & Gideon Rechavi - Cancer Research Center, Pediatric Immunology Unit, Jeffrey Modell Foundation (JMF) Center, Department of Pediatrics, Ataxia Telangiectasia National Clinic, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, affiliated with the Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Raz Somech
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Matan Kraus and Atar Lev contributed equally
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Kraus, M., Lev, A., Simon, A.J. et al. Disturbed B and T cell homeostasis and neogenesis in patients with ataxia telangiectasia.J Clin Immunol 34, 561–572 (2014). https://doi.org/10.1007/s10875-014-0044-1
- Received: 01 September 2013
- Accepted: 09 April 2014
- Published: 01 May 2014
- Issue Date: July 2014
- DOI: https://doi.org/10.1007/s10875-014-0044-1