Loss-of-function nuclear factor ?B subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans - 05/10/18

Doi : 10.1016/j.jaci.2018.01.039

Paul Tuijnenburg, MD ^a,^b,^{^{∗
These authors contributed equally to this work.}}, Hana Lango Allen, PhD ^c,^d,^{^{∗
These authors contributed equally to this work.}}, Siobhan O. Burns, MRCP, PhD ^e,^{^{∗
These authors contributed equally to this work.}}, Daniel Greene, MPhil ^c,^d, Machiel H. Jansen, BSc ^a,^b, Emily Staples, MRCP, FRCPath, PhD ^f, Jonathan Stephens, PhD ^c,^d, Keren J. Carss, PhD ^c,^d, Daniele Biasci, PhD ^f, Helen Baxendale, MRCP, PhD ^f, Moira Thomas, MRCP, FRCPath, BSc ^g, Anita Chandra, MRCP, FRCPath, PhD ^f, Sorena Kiani-Alikhan, FRCP, FRCPath, PhD ^h, Hilary J. Longhurst, MD, PhD ⁱ, Suranjith L. Seneviratne, MD ^e, Eric Oksenhendler, MD ^j, Ilenia Simeoni, PhD ^c, Godelieve J. de Bree, MD, PhD ^k, Anton T.J. Tool, PhD ^l, Ester M.M. van Leeuwen, PhD ^b, Eduard H.T.M. Ebberink, MSc ^m, Alexander B. Meijer, PhD ^m, Salih Tuna, PhD ^c,^d, Deborah Whitehorn, BSc ^c,^d, Matthew Brown, BSc ^c,^d, Ernest Turro, PhD ^c,^d, Adrian J. Thrasher, MD, PhD ⁿ, Kenneth G.C. Smith, PhD, FMedSci ^f, James E. Thaventhiran, MRCP, FRCPath, PhD ^f,^⁎,^{^{‡
These authors contributed equally to this work.}} , Taco W. Kuijpers, MD, PhD ^a,^b,^k,^⁎,^{^{‡
These authors contributed equally to this work.}}
on behalf of the
NIHR BioResource–Rare Diseases Consortium^o
Zoe Adhya, Hana Alachkar, Ariharan Anantharachagan, Richard Antrobus, Gururaj Arumugakani, Chiara Bacchelli, Helen Baxendale, Claire Bethune, Shahnaz Bibi, Barbara Boardman, Claire Booth, Michael Browning, Mary Brownlie, Siobhan Burns, Anita Chandra, Hayley Clifford, Nichola Cooper, Sophie Davies, John Dempster, Lisa Devlin, Rainer Doffinger, Elizabeth Drewe, David Edgar, William Egner, Tariq El-Shanawany, Bobby Gaspar, Rohit Ghurye, Kimberley Gilmour, Sarah Goddard, Pavel Gordins, Sofia Grigoriadou, Scott Hackett, Rosie Hague, Lorraine Harper, Grant Hayman, Archana Herwadkar, Stephen Hughes, Aarnoud Huissoon, Stephen Jolles, Julie Jones, Peter Kelleher, Nigel Klein, Taco Kuijpers, Dinakantha Kumararatne, James Laffan, Hana Lango Allen, Sara Lear, Hilary Longhurst, Lorena Lorenzo, Jesmeen Maimaris, Ania Manson, Elizabeth McDermott, Hazel Millar, Anoop Mistry, Valerie Morrisson, Sai Murng, Iman Nasir, Sergey Nejentsev, Sadia Noorani, Eric Oksenhendler, Mark Ponsford, Waseem Qasim, Ellen Quinn, Isabella Quinti, Alex Richter, Crina Samarghitean, Ravishankar Sargur, Sinisa Savic, Suranjith Seneviratne, Carrock Sewall, Fiona Shackley, Ilenia Simeoni, Kenneth G.C. Smith, Emily Staples, Hans Stauss, Cathal Steele, James Thaventhiran, Moira Thomas, Adrian Thrasher, Steve Welch, Lisa Willcocks, Sarita Workman, Austen Worth, Nigel Yeatman, Patrick Yong, Sofie Ashford, John Bradley, Debra Fletcher, Tracey Hammerton, Roger James, Nathalie Kingston, Willem Ouwehand, Christopher Penkett, F Lucy Raymond, Kathleen Stirrups, Marijke Veltman, Tim Young, Sofie Ashford, Matthew Brown, Naomi Clements-Brod, John Davis, Eleanor Dewhurst, Marie Erwood, Amy Frary, Rachel Linger, Jennifer Martin, Sofia Papadia, Karola Rehnstrom, William Astle, Antony Attwood, Marta Bleda, Keren Carss, Louise Daugherty, Sri Deevi, Stefan Graf, Daniel Greene, Csaba Halmagyi, Matthias Haimel, Fengyuan Hu, Roger James, Hana Lango Allen, Vera Matser, Stuart Meacham, Karyn Megy, Christopher Penkett, Olga Shamardina, Kathleen Stirrups, Catherine Titterton, Salih Tuna, Ernest Turro, Ping Yu, Julie von Ziegenweldt, Abigail Furnell, Rutendo Mapeta, Ilenia Simeoni, Simon Staines, Jonathan Stephens, Kathleen Stirrups, Deborah Whitehorn, Paula Rayner-Matthews, Christopher Watt

^a Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands
^b Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
^k Department of Internal Medicine, Academic Medical Center, Amsterdam, The Netherlands
^c Department of Haematology, University of Cambridge, Cambridge, United Kingdom
^f Department of Medicine, University of Cambridge, Cambridge, United Kingdom
^d NHS Blood and Transplant Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
^o NIHR BioResource–Rare Diseases, Cambridge Biomedical Campus, Cambridge, United Kingdom
^e Department of Immunology, Royal Free London NHS Foundation Trust, University College London Institute of Immunity and Transplantation, London, United Kingdom
^g Department of Immunology, Queen Elizabeth University Hospital, Glasgow, United Kingdom
^h Department of Immunology, Royal Surrey County Hospital, Guildford, United Kingdom
ⁱ Department of Immunology, Barts Health NHS Trust, London, United Kingdom
^j Department of Clinical Immunology, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris (APHP), Paris, France
^l Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands
^m Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands
ⁿ Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital NHS Trust London, London, United Kingdom

^∗Corresponding author: Taco W. Kuijpers, MD, PhD, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.Meibergdreef 9, 1105 AZAmsterdamThe Netherlands^∗∗James E. Thaventhiran, MRCP, FRCPath, PhD, Addenbrooke's Hospital (Box 157), Hills Rd, Cambridge CB2 0QQ, United Kingdom.Addenbrooke's Hospital (Box 157), Hills RdCambridgeCB2 0QQUnited Kingdom

Abstract

Background

The genetic cause of primary immunodeficiency disease (PID) carries prognostic information.

Objective

We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource–Rare Diseases cohort.

Methods

In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses.

Results

Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21^low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases.

Conclusion

We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

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Graphical abstract

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Key words : B cells, common variable immunodeficiency, nuclear factor κB1

Abbreviations used : CFSE, CVID, LOF, NF-κB, NFKB1, NIHRBR-RD, PID, PML, RHD, VEP

Plan

Methods

Cohort

Sequencing and variant filtering

Gene and variant pathogenicity estimation

Immunophenotyping and B- and T-cell functional assays

ELISA

SDS-PAGE and Western blot analysis

NF-κB1 protein structure

Statistical analysis of lymphocyte data

Results

Pathogenic variants in NFKB1 are the most common monogenic cause of CVID

NFKB1 LOF as the disease mechanism

Variable disease manifestations in NFKB1 LOF subjects

B-cell phenotype in subjects with NFKB1 LOF mutations and immune cell activation

T-cell phenotype in subjects NFKB1 LOF variants

Discussion

Supported by The National Institute for Health Research England (grant no. RG65966) and the Center of Immunodeficiencies Amsterdam (CIDA). J.E.T. is supported by an MRC Clinician Scientist Fellowship (MR/L006197/1). A.J.T. is supported by both the Wellcome Trust (104807/Z/14/Z) and the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.

Disclosure of potential conflict of interest: S. O. Burns has received grants from HEFCE, University College London, the National Institute of Health Research (NIHR), UCLH III BRC, and GOSH/ICH BRC and has received personal fees from CSL Behring, Immunodeficiency Canada/IAACI, CSL Behring, Baxalta, and Octagam. A. Chandra has received grants from the Wellcome Trust and GlaxoSmithKline. H. J. Longhurst has received personal fees from BioTest, CSL Behring, and Baxalta; has received grants from CSL Behring; has received nonfinancial support from BioTest and CSL Behring; and has research collaborations with CSL Behring and GlaxoSmithKline. E. Oksenhendler has received personal fees from CSL Behring and MSD. A. J. Thrasher has received personal fees from Orchard Therapeutics, Rocket Pharmaceuticals, and Torus Therapeutics. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 142 - N° 4

P. 1285-1296 - octobre 2018 Retour au numéro

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Loss-of-function nuclear factor ?B subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans - 05/10/18

Abstract

Background

Objective

Methods

Results

Conclusion

Graphical abstract

Plan

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