Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia
Zielen, Stefan; Duecker, Ruth Pia; Woelke, Sandra; Donath, Helena; Bakhtiar, Sharhzad; Buecker, Aileen; Kreyenberg, Hermann; Huenecke, Sabine; Bader, Peter; Mahlaoui, Nizar; Ehl, Stephan; El-Helou, Sabine M.; Pietrucha, Barbara; Plebani, Alessandro; van der Flier, Michiel; van Aerde, Koen; Kilic, Sara S.; Reda, Shereen M.; Kostyuchenko, Larysa; McDermott, Elizabeth; Galal, Nermeen; Pignata, Claudio; Pérez, Juan Luis Santos; Laws, Hans Juergen; Niehues, Tim; Kutukculer, Necil; Seidel, Markus G.; Marques, Laura; Ciznar, Peter; Edgar, John David M.; Soler-Palacín, Pere; von Bernuth, Horst; Krueger, Renate; Meyts, Isabelle; Baumann, Ulrich; Kanariou, Maria; Grimbacher, Bodo; Hauck, Fabian; Graf, Dagmar; Granado, Luis Ignacio Gonzalez; Prader, Seraina; Reisli, Ismail; Slatter, Mary; Rodríguez-Gallego, Carlos; Arkwright, Peter D.; Bethune, Claire; Deripapa, Elena; Sharapova, Svetlana O.; Lehmberg, Kai; Davies, E. Graham
(2021) Journal of Clinical Immunology, volume 41, issue 8, pp. 1878 - 1892
(Article)
Abstract
Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard
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to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978)
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Keywords: Ataxia-telangiectasia, IgA deficiency, Immunodeficiency, Immunoglobulins, Lymphopenia, Mortality, Immunology and Allergy, Immunology
ISSN: 0271-9142
Publisher: Springer New York
Note: Funding Information: The ESID Registry was in part used for collecting data for this study. It is based on contributions by the following national registries: CEREDIH (France), REDIP (Spain), PID-NET (Germany), UKPIN (UK), IPINET (Italy), AGPI (Austria), WID (the Netherlands), Greece, Russia, and Czech Republic. Additional contributions are received from the following countries: Turkey, Poland, Ireland, Iran, Lithuania, Portugal, Belgium, Switzerland, Slovakia, Slovenia, Sweden, Croatia, Serbia, Belarus, Hungary, Romania, Ukraine, Estonia, Egypt, and Israel. Funding Information: Dr. Kindle reports grants from ESID (European Society for Immunodeficiencies) and grants from BMBF (German Federal Ministry of Education and Research), during the conduct of the study. Funding Information: Dr. Schubert reports grants from A-T Children’s Project, DFG, SPARKS–Action for A-T, Starke Lunge Foundation, personal fees from Biotest Pharma GmbH and Vifor Pharma Deutschland GmbH, outside the submitted work. Funding Information: Dr. Grimbacher reports grants from DZIF, DFG, BMBF, Fritz Thyssen Stiftung, Shire/Baxalta, Merck, BMS, Novartis, CSL Behring, personal fees from Janssen Cilag, Novartis, during the conduct of the study, outside the submitted work. Funding Information: Open Access funding enabled and organized by Projekt DEAL. The ESID Registry was supported by the German Federal Ministry of Education and Research (BMBF 01GM0896, 01GM1111B, 01GM1517C, 01EO1303 and 01ZZ1801B) EU grant no. HEALTH-F2-2008–201549 (EURO-PADnet), the pharmaceutical companies Novartis, GlaxoSmithKline, LFB, and UCB UK, the Plasma Protein Therapeutics Association (PPTA), the Care-for-Rare Foundation, PROimmune e.V, LFB, and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2155 RESIST—Project ID 39087428. EGD is supported by the UK National Institute of Health Research and the Great Ormond Street Hospital Biomedical Research Centre. Funding Information: Dr. Sabine M. El-Helou was funded by the Federal Ministry of Education and Research (BMBF), by the European Society for Immunodeficiencies (ESID), by the Care-for-Rare Foundation, by PROimmun e.V., and by a restricted grant from LFB, CSL Behring, and Grifols. For GAIN and RESIST, she was funded by the BMBF. Funding Information: Dr. Meyts reports grants from CSL Behring, outside the submitted work. IM is a senior clinical investigator at FWO Vlaanderen (supported by CSL Behring Chair of Primary Immunodeficiencies, by a KU Leuven C1 Grant C16/18/007, by a VIB GC PID Grant, by a FWO Grants G0C8517N; and G0E8420N and by the Jeffrey Modell Foundation. IM is a recipient of a ERC-StG MORE2ADA2. This work is supported by ERN-RITA. Publisher Copyright: © 2021, The Author(s).
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