Rituximab does not reset defective early B cell tolerance checkpoints

Type 1 diabetes (T1D) patients show abnormalities in early B celltolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cellsin their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve β cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti– B celltherapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cellsfrom 4 patients with T1D before and 52 weeks after treatment to determine whether rituximabresets early B celltolerance checkpoints. We found that anti– B celltherapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximabtreatment. Moreover, the limited proliferative history of autoreactive B cellsafter treatment revealed that these clones were newly generated B cellsand not self-reactive B cellsthat had escaped depletion and repopulatedthe periphery through homeostatic expansion. We conclude that anti– B celltherapy may provide a temporary dampening of autoimmune processes through B celldepletion. However, repletion with autoreactive B cellsmay explain the relapse that occurs in many autoimmune patients after anti– B celltherapy.