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.

B Cell Pathophysiology Unit Immunology Research Area Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy

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

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

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

Central European Institute of Technology Brno Czech Republic

Centre for Primary Immune Deficiency AUO Policlinico Umberto 1 Rome Italy

Clinical and Research Department for Infectious Diseases National Institute for Infectious Diseases L Spallanzani 00149 Rome Italy

Department of Infectious Diseases Institute of Biomedicine The Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

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

Department of Molecular Medicine Sapienza University of Rome Rome Italy

Department of Rheumatology and Inflammation Research The Sahlgrenska Academy University of Gothenburg Gothenburg Sweden

Department of Rheumatology and Inflammation Research The Sahlgrenska Academy University of Gothenburg Gothenburg Sweden; Faculty of Health Sciences A 1 Virtanen Institute for Molecular Sciences University of Eastern Finland Kuopio Finland

Division of Rheumatology Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy

Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy

Institute for Research in Biomedicine Bellinzona Switzerland

Institute of Pathophysiology and Allergy Research Centre for Pathophysiology Infectiology and Immunology Medical University of Vienna Vienna Austria

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

Research Laboratories Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy

School of Bioscience University of Skövde Skövde Sweden

Translational Research Unit National Institute for Infectious Diseases Lazzaro Spallanzani Rome Italy; B Cell Pathophysiology Unit Immunology Research Area Ospedale Pediatrico Bambino Gesù IRCCS Rome Italy

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