Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestationsTranslational Research Unit, National Institute for Infectious Diseases Lazzaro Spallanzani (IRCCS), Rome, Italy ; B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Sweden.
Institute of Pathophysiology and Allergy Research, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Sweden ; Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Centre for Primary Immune Deficiency, AUO Policlinico Umberto I, Rome, Italy.
Department of Molecular Medicine, Sapienza University of Rome, Italy.
Clinical and Research Department for Infectious Diseases, National Institute for Infectious Diseases L. Spallanzani (IRCCS), Rome, Italy.
Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Sweden.
Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Institute for Research in Biomedicine (IRB), Università della Svizzera Italiana (USI), Bellinzona, Switzerland.
Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy.
Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Department of Clinical Immunology and Transfusion Medicine, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russian Federation ; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russian Federation ; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russian Federation ; Central European Institute of Technology, Brno, Czech Republic.
B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy ; Unit of Diagnostic Immunology, Department of Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
Institute of Pathophysiology and Allergy Research, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Austria ; Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Sweden ; B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
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2023 (English)In: Cell Reports, E-ISSN 2211-1247, Vol. 42, no 5, article id 112446
Article in journal (Refereed) Published
Abstract [en]
Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity.
Place, publisher, year, edition, pages
Elsevier, 2023. Vol. 42, no 5, article id 112446
Keywords [en]
CD27
bright memory B cells, common variable immunodeficiency, CP: Immunology, immunoglobulin sequencing, naive B cells, peripheral B cell selection, receptor editing, transcriptomic analysis
National Category
Immunology in the medical area Immunology
Research subject
Infection Biology
Identifiers
URN: urn:nbn:se:his:diva-22484DOI: 10.1016/j.celrep.2023.112446ISI: 000996158800001PubMedID: 37119135Scopus ID: 2-s2.0-85153595326OAI: oai:DiVA.org:his-22484DiVA, id: diva2:1754826
Funder
EU, Horizon 2020, 754412Wilhelm och Martina Lundgrens Vetenskapsfond, 2018-2300, 2019-2986, 2020-3395Swedish Society of Medicine, SLS-593371Gunvor och Josef Anérs stiftelse, FB19-0054O.E. och Edla Johanssons vetenskapliga stiftelseStiftelsen Sigurd och Elsa Goljes minneStiftelsen Sigurd och Elsa Goljes minneStiftelsen Apotekare Hedbergs Fund for Medical ResearchRegion Västra Götaland
Note
CC BY 4.0
© 2023 The Author(s)
Correspondence ola.grimsholm@meduniwien.ac.at
This work has received funding from the European Union’s Horizon 2020 research and innovation program under Marie Skłodowska-Curie grant agreement 754412 (to O.G.). O.G. was also supported by a personal fellowship from EFIS as well as research grants from the Wilhelm and Martina Lundgren Foundation (grants 2018-2300, 2019-2986, and 2020-3395), the Axel Linder Foundation, the Swedish Medical Society (grant SLS-593371), the Gunvor and Josef Anér Foundation (grant FB19-0054), the O.E. and Edla Johansson Science Foundation, the Elsa and Sigurd Memorial Foundation, the Pharmacist Hedberg Foundation for Medical Research, The Royal Society of Arts and Sciences in Gothenburg (grants 2018-184, 2020-422, and 2021-548), the Tore Nilsson Foundation (grants 2015-00218, 2018-00648, and 2020-00789), and The Healthcare Committee, Region Västra Götaland. This work was also supported by The Health & Medical Care Committee of the Region Västra Götaland and by grants from the Swedish state under an agreement between the Swedish government and the country councils, the ALF agreement (73740) (to V.F.). The work of S.P.A. was supported by a grant from the Austrian Science Fund (FWF, project P32953). The work was also supported by the Italian Ministry of Health (grant RF2013-02358960) (to R.C.). A.N.D. was supported by the Ministry of Education, Youth and Sports of the Czech Republic (project CEITEC 2020 LQ1601). M.S. and D.M.C. were supported by the Ministry of Science and Higher Education of the Russian Federation (project 075-15-2019-1789). None of the funding sources had any involvement in the study design. We thank Dr. Mattias Svensson for critical input to the manuscript. We are also thankful to Dr. Vincent Collins for help with language editing of the manuscript.
2023-05-042023-05-042024-01-17Bibliographically approved