Generation of circulating autoreactive pre-plasma cells fueled by naive B cells in celiac disease

Autoantibodies against the enzyme transglutaminase 2 (TG2) are characteristic of celiac disease (CeD), and TG2-specific immunoglobulin (Ig) A plasma cells are abundant in gut biopsies of patients. Here, we describe the corresponding population of autoreactive B cells in blood. Circulating TG2-specific IgA cells are present in untreated patients on a gluten-containing diet but not in controls. They are clonally related to TG2-specific small intestinal plasma cells, and they express gut-homing molecules, indicating that they are plasma cell precursors. Unlike other IgA-switched cells, the TG2-specific cells are negative for CD27, placing them in the double-negative (IgD−CD27−) category. They have a plasmablast or activated memory B cell phenotype, and they harbor fewer variable region mutations than other IgA cells. Based on their similarity to naive B cells, we propose that autoreactive IgA cells in CeD are generated mainly through chronic recruitment of naive B cells via an extrafollicular response involving gluten-specific CD4+ T cells. [Display omitted] •TG2-specific IgA+ B cells are present in the blood of untreated celiac disease patients•The autoreactive B cells are gut homing and clonally related to duodenal plasma cells•Most of the circulating cells are activated pre-plasma cells that are CD27 negative•The phenotype of TG2-specific B cells is mirrored by in vitro stimulation of naive B cells Celiac disease is associated with IgA-class autoantibodies to transglutaminase 2 (TG2). Lindeman et al. identify TG2-specific IgA+ B cells in the blood of celiac disease patients. These cells are gut-homing pre-plasma cells with a phenotype suggesting that they arise from continuous recruitment of naive B cells during a chronic immune response.