Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

Stefan Zielen; Ruth Pia Duecker; Sandra Woelke; Helena Donath; Sharhzad Bakhtiar; Aileen Buecker; Hermann Kreyenberg; Sabine Huenecke; Peter Bader; Nizar Mahlaoui; Stephan Ehl; Sabine M. El-Helou; Barbara Pietrucha; Alessandro Plebani; Michiel van der Flier; Koen van Aerde; Sara S. Kilic; Shereen M. Reda; Larysa Kostyuchenko; Elizabeth McDermott; Nermeen Galal; Claudio Pignata; Juan Luis Santos Pérez; Hans Juergen Laws; Tim Niehues; Necil Kutukculer; Markus G. Seidel; Laura Marques; Peter Ciznar; John David M. Edgar; Pere Soler-Palacín; Horst von Bernuth; Renate Krueger; Isabelle Meyts; Ulrich Baumann; Maria Kanariou; Bodo Grimbacher; Fabian Hauck; Dagmar Graf; Luis Ignacio Gonzalez Granado; Seraina Prader; Ismail Reisli; Mary Slatter; Carlos Rodríguez-Gallego; Peter D. Arkwright; Claire Bethune; Elena Deripapa; Svetlana O. Sharapova; Kai Lehmberg; E. Graham Davies

doi:10.1007/s10875-021-01090-8

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

Stefan Zielen, Ruth Pia Duecker^*, Sandra Woelke, Helena Donath, Sharhzad Bakhtiar, Aileen Buecker, Hermann Kreyenberg, Sabine Huenecke, Peter Bader, Nizar Mahlaoui, Stephan Ehl, Sabine M. El-Helou, Barbara Pietrucha, Alessandro Plebani, Michiel van der Flier, Koen van Aerde, Sara S. Kilic, Shereen M. Reda, Larysa Kostyuchenko, Elizabeth McDermottNermeen Galal, Claudio Pignata, Juan Luis Santos Pérez, Hans Juergen Laws, Tim Niehues, Necil Kutukculer, Markus G. Seidel, Laura Marques, Peter Ciznar, John David M. Edgar, Pere Soler-Palacín, Horst von Bernuth, Renate Krueger, Isabelle Meyts, Ulrich Baumann, Maria Kanariou, Bodo Grimbacher, Fabian Hauck, Dagmar Graf, Luis Ignacio Gonzalez Granado, Seraina Prader, Ismail Reisli, Mary Slatter, Carlos Rodríguez-Gallego, Peter D. Arkwright, Claire Bethune, Elena Deripapa, Svetlana O. Sharapova, Kai Lehmberg, E. Graham Davies

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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 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)

Original language	English
Pages (from-to)	1878-1892
Number of pages	15
Journal	Journal of Clinical Immunology
Volume	41
Issue number	8
DOIs	https://doi.org/10.1007/s10875-021-01090-8
Publication status	Published - Nov 2021

Keywords

Ataxia-telangiectasia
IgA deficiency
Immunodeficiency
Immunoglobulins
Lymphopenia
Mortality

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Zielen2021_Article_SimpleMeasurementOfIgAPredictsFinal published version, 3.05 MBLicence: CC BY

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Zielen, S., Duecker, R. P., Woelke, S., Donath, H., Bakhtiar, S., Buecker, A., Kreyenberg, H., Huenecke, S., Bader, P., Mahlaoui, N., Ehl, S., El-Helou, S. M., Pietrucha, B., Plebani, A., van der Flier, M., van Aerde, K., Kilic, S. S., Reda, S. M., Kostyuchenko, L., ... Davies, E. G. (2021). Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia. Journal of Clinical Immunology, 41(8), 1878-1892. https://doi.org/10.1007/s10875-021-01090-8

@article{ab172df3da6c45b289276ba78f9ec29a,

title = "Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia",

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 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 na{\"i}ve 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)",

keywords = "Ataxia-telangiectasia, IgA deficiency, Immunodeficiency, Immunoglobulins, Lymphopenia, Mortality",

author = "Stefan Zielen and Duecker, {Ruth Pia} and Sandra Woelke and Helena Donath and Sharhzad Bakhtiar and Aileen Buecker and Hermann Kreyenberg and Sabine Huenecke and Peter Bader and Nizar Mahlaoui and Stephan Ehl and El-Helou, {Sabine M.} and Barbara Pietrucha and Alessandro Plebani and {van der Flier}, Michiel and {van Aerde}, Koen and Kilic, {Sara S.} and Reda, {Shereen M.} and Larysa Kostyuchenko and Elizabeth McDermott and Nermeen Galal and Claudio Pignata and P{\'e}rez, {Juan Luis Santos} and Laws, {Hans Juergen} and Tim Niehues and Necil Kutukculer and Seidel, {Markus G.} and Laura Marques and Peter Ciznar and Edgar, {John David M.} and Pere Soler-Palac{\'i}n and {von Bernuth}, Horst and Renate Krueger and Isabelle Meyts and Ulrich Baumann and Maria Kanariou and Bodo Grimbacher and Fabian Hauck and Dagmar Graf and Granado, {Luis Ignacio Gonzalez} and Seraina Prader and Ismail Reisli and Mary Slatter and Carlos Rodr{\'i}guez-Gallego and Arkwright, {Peter D.} and Claire Bethune and Elena Deripapa and Sharapova, {Svetlana O.} and Kai Lehmberg and Davies, {E. Graham}",

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{\textquoteright}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{\textquoteright}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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = nov,

doi = "10.1007/s10875-021-01090-8",

language = "English",

volume = "41",

pages = "1878--1892",

journal = "Journal of Clinical Immunology",

issn = "0271-9142",

publisher = "Springer New York",

number = "8",

}

Zielen, S, Duecker, RP, Woelke, S, Donath, H, Bakhtiar, S, Buecker, A, Kreyenberg, H, Huenecke, S, Bader, P, Mahlaoui, N, Ehl, S, El-Helou, SM, Pietrucha, B, Plebani, A, van der Flier, M, van Aerde, K, Kilic, SS, Reda, SM, Kostyuchenko, L, McDermott, E, Galal, N, Pignata, C, Pérez, JLS, Laws, HJ, Niehues, T, Kutukculer, N, Seidel, MG, Marques, L, Ciznar, P, Edgar, JDM, Soler-Palacín, P, von Bernuth, H, Krueger, R, Meyts, I, Baumann, U, Kanariou, M, Grimbacher, B, Hauck, F, Graf, D, Granado, LIG, Prader, S, Reisli, I, Slatter, M, Rodríguez-Gallego, C, Arkwright, PD, Bethune, C, Deripapa, E, Sharapova, SO, Lehmberg, K & Davies, EG 2021, 'Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia', Journal of Clinical Immunology, vol. 41, no. 8, pp. 1878-1892. https://doi.org/10.1007/s10875-021-01090-8

TY - JOUR

T1 - Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

AU - Zielen, Stefan

AU - Duecker, Ruth Pia

AU - Woelke, Sandra

AU - Donath, Helena

AU - Bakhtiar, Sharhzad

AU - Buecker, Aileen

AU - Kreyenberg, Hermann

AU - Huenecke, Sabine

AU - Bader, Peter

AU - Mahlaoui, Nizar

AU - Ehl, Stephan

AU - El-Helou, Sabine M.

AU - Pietrucha, Barbara

AU - Plebani, Alessandro

AU - van der Flier, Michiel

AU - van Aerde, Koen

AU - Kilic, Sara S.

AU - Reda, Shereen M.

AU - Kostyuchenko, Larysa

AU - McDermott, Elizabeth

AU - Galal, Nermeen

AU - Pignata, Claudio

AU - Pérez, Juan Luis Santos

AU - Laws, Hans Juergen

AU - Niehues, Tim

AU - Kutukculer, Necil

AU - Seidel, Markus G.

AU - Marques, Laura

AU - Ciznar, Peter

AU - Edgar, John David M.

AU - Soler-Palacín, Pere

AU - von Bernuth, Horst

AU - Krueger, Renate

AU - Meyts, Isabelle

AU - Baumann, Ulrich

AU - Kanariou, Maria

AU - Grimbacher, Bodo

AU - Hauck, Fabian

AU - Graf, Dagmar

AU - Granado, Luis Ignacio Gonzalez

AU - Prader, Seraina

AU - Reisli, Ismail

AU - Slatter, Mary

AU - Rodríguez-Gallego, Carlos

AU - Arkwright, Peter D.

AU - Bethune, Claire

AU - Deripapa, Elena

AU - Sharapova, Svetlana O.

AU - Lehmberg, Kai

AU - Davies, E. Graham

N1 - 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).

PY - 2021/11

Y1 - 2021/11

N2 - 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 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)

AB - 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 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)

KW - Ataxia-telangiectasia

KW - IgA deficiency

KW - Immunodeficiency

KW - Immunoglobulins

KW - Lymphopenia

KW - Mortality

UR - http://www.scopus.com/inward/record.url?scp=85114133044&partnerID=8YFLogxK

U2 - 10.1007/s10875-021-01090-8

DO - 10.1007/s10875-021-01090-8

M3 - Article

C2 - 34477998

AN - SCOPUS:85114133044

SN - 0271-9142

VL - 41

SP - 1878

EP - 1892

JO - Journal of Clinical Immunology

JF - Journal of Clinical Immunology

IS - 8

ER -

Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia

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