Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations

Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infec-tions, 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 k:l 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, function-ally, 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 develop-ment of autoimmunity.

Automated summary

CVID is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but the mechanisms of B cell central and peripheral selection in CVID are not fully understood. This study found that central tolerance is increased in transitional B cells from CVID patients with autoimmune manifestations, while the selection pressure in germinal center on CD27bright memory B cells is decreased. Naive B cells in CVID patients also showed poor activation and induction of mismatch repair genes. These findings suggest defective peripheral selection in CVID patients with autoimmune manifestations, which may contribute to the development of autoimmunity.