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 Wallin Ahlström, Johanna Karlsson, Emiliano Marasco, Valentina Marcellini, Chiara Bocci, Simona Cascioli, Marco Scarsella, Ganesh E. Phad, Andreas Tilevik, Marco Tartaglia, Mats Bemark, Dmitriy M. Chudakov, Rita Carsetti, Ola Grimsholm
Abstract
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 CD27 bright 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.