Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA 95616, USA.
Hepatology. 2011 Feb;53(2):527-35. doi: 10.1002/hep.24044. Epub 2010 Dec 28.
Primary biliary cirrhosis (PBC) is considered a model autoimmune disease due to the clinical homogeneity of patients and the classic hallmark of antimitochondrial antibodies (AMAs). Indeed, the presence of AMAs represents the most highly directed and specific autoantibody in autoimmune diseases. However, the contribution of B cells to the pathogenesis of PBC is unclear. Therefore, 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 AMAs. The recent development of well-characterized monoclonal antibodies 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 use 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 monoclonal antibody 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 observed in control mice, which is in contrast with results from several other autoimmune models that have documented an important therapeutic role of B cell-specific depletion. Anti-CD20/CD79-treated mice had increased liver T cell infiltrates and higher levels of proinflammatory cytokines.
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.
原发性胆汁性肝硬化（PBC）被认为是一种自身免疫性疾病模型，这是由于患者的临床表现均一，以及经典的抗线粒体抗体（AMA）标志物。事实上，AMA 的存在代表了自身免疫性疾病中最具针对性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 似乎与胆管细胞自身抗原相互作用并导致胆管病理，但疾病严重程度与 AMA 滴度并无相关性。最近，针对 B 细胞群体的特征明确的单克隆抗体，如抗 CD20 和抗 CD79 的发展，以及明确定义的异种诱导自身免疫性胆管炎模型的发展，促使我们使用这些试剂和模型来探讨 B 细胞在 PBC 发病机制中的作用。在诱导自身免疫性胆管炎之前，用抗 CD20、抗 CD79 或同种型匹配的对照单克隆抗体处理小鼠，然后检测 B 细胞发育、AMA 出现、肝脏病理和细胞因子产生情况。本文报道的研究结果表明，体内用抗 CD20 或抗 CD79 耗竭 B 细胞会导致比对照小鼠更严重的胆管炎，这与其他几种已证明 B 细胞特异性耗竭具有重要治疗作用的自身免疫模型的结果相反。抗 CD20/CD79 处理的小鼠肝内 T 细胞浸润增加，促炎细胞因子水平升高。
我们的结果反映了 B 细胞在 PBC 中的一种新型疾病保护作用，并提示 PBC 患者的 B 细胞耗竭疗法应谨慎应用。
