B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6–producing B cells

TLDR

B cells can be both pathogenic and protective in autoimmunity, and disease can improve with B cell depletion even without affecting autoantibodies, yet the underlying mechanisms remain unclear. The study investigates whether removing IL‑6–secreting B cells by B cell depletion therapy can alleviate central nervous system autoimmunity. The authors demonstrate that B cell depletion reduces disease by ablating IL‑6–producing B cells. Elevated IL‑6 from B cells drives disease in EAE and MS, and B cell depletion improves outcomes only when IL‑6–producing B cells are present, indicating IL‑6 secretion is a key pathogenic mechanism.

Abstract

B cells have paradoxical roles in autoimmunity, exerting both pathogenic and protective effects. Pathogenesis may be antibody independent, as B cell depletion therapy (BCDT) leads to amelioration of disease irrespective of autoantibody ablation. However, the mechanisms of pathogenesis are poorly understood. We demonstrate that BCDT alleviates central nervous system autoimmunity through ablation of IL-6–secreting pathogenic B cells. B cells from mice with experimental autoimmune encephalomyelitis (EAE) secreted elevated levels of IL-6 compared with B cells from naive controls, and mice with a B cell–specific IL-6 deficiency showed less severe disease than mice with wild-type B cells. Moreover, BCDT ameliorated EAE only in mice with IL-6–sufficient B cells. This mechanism of pathogenesis may also operate in multiple sclerosis (MS) because B cells from MS patients produced more IL-6 than B cells from healthy controls, and this abnormality was normalized with B cell reconstitution after Rituximab treatment. This suggests that BCDT improved disease progression, at least partly, by eliminating IL-6–producing B cells in MS patients. Taking these data together, we conclude that IL-6 secretion is a major mechanism of B cell–driven pathogenesis in T cell–mediated autoimmune disease such as EAE and MS.