Cell Reports (May 2023)
Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations
- Vanda Friman,
- Isabella Quinti,
- Alexey N. Davydov,
- Mikhail Shugay,
- Chiara Farroni,
- Erik Engström,
- Shirin Pour Akaber,
- Sabina Barresi,
- Ahmed Mohamed,
- Federica Pulvirenti,
- Cinzia Milito,
- Guido Granata,
- Ezio Giorda,
- Sara Ahlström,
- Johanna Karlsson,
- Emiliano Marasco,
- Valentina Marcellini,
- Chiara Bocci,
- Simona Cascioli,
- Marco Scarsella,
- Ganesh Phad,
- Andreas Tilevik,
- Marco Tartaglia,
- Mats Bemark,
- Dmitriy M. Chudakov,
- Rita Carsetti,
- Ola Grimsholm
Affiliations
- Vanda Friman
- Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Isabella Quinti
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Alexey N. Davydov
- Central European Institute of Technology, Brno, Czech Republic
- Mikhail Shugay
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia
- Chiara Farroni
- Translational 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
- Erik Engström
- Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Shirin Pour Akaber
- Institute of Pathophysiology and Allergy Research, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria
- Sabina Barresi
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy
- Ahmed Mohamed
- Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Faculty of Health Sciences, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
- Federica Pulvirenti
- Centre for Primary Immune Deficiency, AUO Policlinico Umberto I, Rome, Italy
- Cinzia Milito
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Guido Granata
- Clinical and Research Department for Infectious Diseases, National Institute for Infectious Diseases L. Spallanzani (IRCCS), 00149 Rome, Italy
- Ezio Giorda
- Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
- Sara Ahlström
- Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Johanna Karlsson
- Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Emiliano Marasco
- Division of Rheumatology, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
- Valentina Marcellini
- Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
- Chiara Bocci
- B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy
- Simona Cascioli
- Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
- Marco Scarsella
- Research Laboratories, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
- Ganesh Phad
- Institute for Research in Biomedicine (IRB), Università della Svizzera Italiana (USI), Bellinzona, Switzerland
- Andreas Tilevik
- School of Bioscience, University of Skövde, Skövde, Sweden
- Marco Tartaglia
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy
- Mats Bemark
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Department of Clinical Immunology and Transfusion Medicine, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
- Dmitriy M. Chudakov
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia; Institute of Translational Medicine, Pirogov Russian National Research Medical University, Moscow, Russia; Central European Institute of Technology, Brno, Czech Republic
- Rita Carsetti
- 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
- Ola Grimsholm
- Institute of Pathophysiology and Allergy Research, Centre for Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna, Austria; Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; B Cell Pathophysiology Unit, Immunology Research Area, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy; Corresponding author
- Journal volume & issue
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Vol. 42,
no. 5
p. 112446
Abstract
Summary: 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.
