B cell depletion therapy exacerbates murine primary biliary cirrhosis.
B cell depletion therapy exacerbates murine primary biliary cirrhosis.
复制标题
DOI：
10.1002/hep.24044
复制
发表时间：
2011-02
期刊：
影响因子：
13.5
通讯作者：
Gershwin, M. Eric
中科院分区：
文献类型：
--
作者：
Dhirapong, Amy;Lleo, Ana;Yang, Guo-Xiang;Tsuneyama, Koichi;Dunn, Robert;Kehry, Marilyn;Packard, Thomas A.;Cambier, John C.;Liu, Fu-Tong;Lindor, Keith;Coppel, Ross L.;Ansari, Aftab A.;Gershwin, M. Eric
原发性胆汁性肝硬化（PBC）被认为是一种典型的自身免疫性疾病，由于患者的临床同质性和抗线粒体抗体（AMAS）的经典标志。事实上，AMAS的存在是自身免疫性疾病中最高度定向和特异性的自身抗体。然而，B细胞在PBC发病机制中的作用尚不清楚。因此，尽管AMA似乎与胆道细胞亲和力相互作用并导致胆道病理学，但疾病严重程度与AMA滴度无关。最近开发了对B细胞群体特异性的充分表征的mAb，抗-CD 20和抗-CD 79，以及开发了明确的异生物素诱导的自身免疫性胆管炎模型，促使我们利用这些试剂和模型来解决B细胞在小鼠PBC发病机制中的作用。在诱导自身免疫性胆管炎之前，用抗CD 20、抗CD 79或同种型匹配的对照mAb处理小鼠，并跟踪B细胞发育、AMA的出现、肝脏病理学和细胞因子产生。本文报道的研究结果表明，使用抗-CD 20或抗-CD 79体内耗竭B细胞导致比对照小鼠更严重形式的胆管炎的发展，这与许多其他自身免疫模型的结果相反，这些模型已经证明了B细胞特异性耗竭的重要治疗作用。抗CD 20/CD 79处理的小鼠具有增加的肝脏T细胞浸润和更高水平的促炎细胞因子。总之，我们的研究结果反映了B细胞在PBC中的一种新的疾病保护作用，并表明在PBC患者中进行B细胞耗竭治疗应谨慎。
Primary biliary cirrhosis (PBC) is considered a model autoimmune disease due to the clinical homogeneity of patients and the classic hallmark of anti-mitochondrial antibodies (AMAS). Indeed, the presence of AMAS is the most highly directed and specific autoantibody in autoimmune diseases. However, the contribution of B cells to the pathogenesis of PBC is unclear. Thus, although AMAs appear to interact with the biliary cell apotope and contribute to biliary pathology, there is no correlation of disease severity and titer of AMA. The recent development of well characterized mAbs specific for the B cell populations, anti-CD20 and anti-CD79, and the development of a well defined xenobiotic induced model of autoimmune cholangitis, prompted us to utilize these reagents and the model to address the contribution of B cells in the pathogenesis of murine PBC. Prior to the induction of autoimmune cholangitis, mice were treated with either anti-CD20, anti-CD79, or isotype matched control mAb and followed for B cell development, the appearance of AMAs, liver pathology and cytokine production. Results of the studies reported herein show that the in vivo depletion of B cells using either anti-CD20 or anti-CD79 led to the development of a more severe form of cholangitis than control mice which is in contrast with results from a number of other autoimmune models which have documented an important therapeutic role of B cell specific depletion. The anti-CD20/CD79 treated mice have increased liver T cell infiltrates and higher levels of pro-inflammatory cytokines. In conclusion, our results reflect a novel disease protective role of B cells in PBC and suggest that B cell depletion therapy in humans with PBC should be approached with caution.
登录
查看更多内容
影响因子：
15.9
作者：
Matsushita, Takashi;Yanaba, Koichi;Tedder, Thomas F.
通讯作者：
Tedder, Thomas F.
影响因子：
6
作者：
Hasegawa, Minoru;Hamaguchi, Yasuhito;Tedder, Thomas F.
通讯作者：
Tedder, Thomas F.
影响因子：
12.8
作者：
Chuang, Ya-Hui;Lian, Zhe-Xiong;Gershwin, M. Eric
通讯作者：
Gershwin, M. Eric
影响因子：
12.8
作者：
Chen J;Crispín JC;Tedder TF;Dalle Lucca J;Tsokos GC
通讯作者：
Tsokos GC
影响因子：
4.4
作者：
Leung, Patrick S. C.;Park, Ogyi;Gershwin, M. Eric
通讯作者：
Gershwin, M. Eric