B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells.
B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells.
复制标题
DOI：
10.1084/jem.20111675
复制
发表时间：
2012-05-07
期刊：
影响因子：
--
通讯作者：
Gray D
中科院分区：
文献类型：
--
作者：
Barr TA;Shen P;Brown S;Lampropoulou V;Roch T;Lawrie S;Fan B;O'Connor RA;Anderton SM;Bar-Or A;Fillatreau S;Gray D
产生IL-6的B细胞有助于EAE病理学和可能的人MS，而B细胞IL-6的消除与Th 17应答降低相关。B细胞在自身免疫中具有自相矛盾的作用，发挥致病和保护作用。发病机制可能是抗体无关的，因为B细胞耗竭疗法（BCDT）导致疾病的改善，而与自身抗体消融无关。然而，发病机制知之甚少。我们证明BCDT通过消除分泌IL-6的致病性B细胞来增强中枢神经系统自身免疫。实验性自身免疫性脑脊髓炎（EAE）小鼠的B细胞分泌的IL-6水平高于未处理对照组的B细胞，而B细胞特异性IL-6缺乏小鼠的疾病严重程度低于野生型B细胞小鼠。此外，BCDT仅在IL-6充足的B细胞的小鼠中改善EAE。这种发病机制也可能在多发性硬化症（MS）中起作用，因为MS患者的B细胞比健康对照的B细胞产生更多的IL-6，并且这种异常在利妥昔单抗治疗后通过B细胞重建而正常化。这表明BCDT至少部分通过消除MS患者中产生IL-6的B细胞来改善疾病进展。综合这些数据，我们得出结论，IL-6分泌是T细胞介导的自身免疫性疾病（如EAE和MS）中B细胞驱动的发病机制的主要机制。
IL-6–producing B cells contribute to EAE pathology and possibly human MS, whereas ablation of B cell IL-6 is associated with a reduced Th17 response. 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.
登录
查看更多内容
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
15.9
作者：
Haak, Stefan;Croxford, Andrew L.;Waisman, Ari
通讯作者：
Waisman, Ari
影响因子：
4.4
作者：
Lampropoulou, Vicky;Hoehlig, Kai;Fillatreau, Simon
通讯作者：
Fillatreau, Simon
影响因子：
4.4
作者：
Good, Kim L.;Bryant, Vanessa L.;Tangye, Stuart G.
通讯作者：
Tangye, Stuart G.
影响因子：
5.4
作者：
Barr, Tom A;Brown, Sheila;Ryan, Gemma;Zhao, Jiexin;Gray, David
通讯作者：
Gray, David