title: Rituximab does not reset defective early B cell tolerance checkpoints.
abstract: Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in 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 cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti-B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti-B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti-B cell therapy.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chamberlain
authors.forename: Christopher
authors.initials: C
authors.lastname: Massad
authors.forename: Tyler
authors.initials: T
authors.lastname: Oe
authors.forename: Tineke
authors.initials: T
authors.lastname: Cantaert
authors.forename: Kevan C
authors.initials: KC
authors.lastname: Herold
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D008212:Lymphocyte Depletion; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D000069283:Rituximab / Q000494:pharmacology*
chemical_list: D011947:Receptors, Antigen, B-Cell; D000069283:Rituximab