当前位置: X-MOL 学术Hepatology › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics
Hepatology ( IF 12.9 ) Pub Date : 2017-07-20 , DOI: 10.1002/hep.29245
Toshihiro Tanaka 1 , Weici Zhang 1 , Ying Sun 2 , Zongwen Shuai 3 , Asiya Seema Chida 4 , Thomas P. Kenny 1 , Guo-Xiang Yang 1 , Ignacio Sanz 4 , Aftab Ansari 5 , Christopher L. Bowlus 6 , Gregory C. Ippolito 7 , Ross L. Coppel 8 , Kazuichi Okazaki 9 , Xiao-Song He 1 , Patrick S.C. Leung 1 , M. Eric Gershwin 1
Affiliation  

A major problem in autoimmunity has been identification of the earliest events that lead to breach of tolerance. Although there have been major advances in dissecting effector pathways and the multilineage immune responses to mitochondrial self‐antigens in primary biliary cholangitis, the critical links between environmental factors and tolerance remain elusive. We hypothesized that environmental xenobiotic modification of the E2 subunit of the pyruvate dehydrogenase (PDC‐E2) inner lipoyl domain can lead to loss of tolerance to genetically susceptible hosts. Previously we demonstrated that serum anti‐PDC‐E2 autoantibodies cross‐react with the chemical xenobiotics 2‐octynoic acid and 6,8‐bis (acetylthio) octanoic acid and further that there is a high frequency of PDC‐E2‐specific peripheral plasmablasts. Herein we generated 104 recombinant monoclonal antibodies (mAbs) based on paired heavy‐chain and light‐chain variable regions of individual plasmablasts derived from primary biliary cholangitis patients. We identified 32 mAbs reactive with native PDC‐E2, including 20 specific for PDC‐E2 and 12 cross‐reactive with both PDC‐E2 and 2‐octynoic acid and 6,8‐bis (acetylthio) octanoic acid. A lower frequency of replacement somatic hypermutations, indicating a lower level of affinity maturation, was observed in the complementarity‐determining regions of the cross‐reactive mAbs in comparison to mAbs exclusively recognizing PDC‐E2 or those for irrelevant antigens. In particular, when the highly mutated heavy‐chain gene of a cross‐reactive mAb was reverted to the germline sequence, the PDC‐E2 reactivity was reduced dramatically, whereas the xenobiotic reactivity was retained. Importantly, cross‐reactive mAbs also recognized lipoic acid, a mitochondrial fatty acid that is covalently bound to PDC‐E2. Conclusion: Our data reflect that chemically modified lipoic acid or lipoic acid itself, through molecular mimicry, is the initial target that leads to the development of primary biliary cholangitis. (Hepatology 2017;66:885–895)

中文翻译:

原发性胆汁性胆管炎患者的自身反应性单克隆抗体可识别环境异生素

自身免疫的一个主要问题是识别导致耐受性破坏的最早事件。尽管在解析效应通路和对原发性胆汁性胆管炎中线粒体自身抗原的多向免疫反应方面取得了重大进展,但环境因素与耐受性之间的关键联系仍然难以捉摸。我们假设丙酮酸脱氢酶 (PDC-E2) 内脂酰域的 E2 亚基的环境异生物质修饰会导致对遗传易感宿主的耐受性丧失。之前我们证明血清抗 PDC-E2 自身抗体与化学异生物质 2-辛酸和 6,8-双(乙酰硫基)辛酸发生交叉反应,而且 PDC-E2 特异性外周浆母细胞的频率很高。在此,我们基于源自原发性胆汁性胆管炎患者的单个浆母细胞的成对重链和轻链可变区生成了 104 种重组单克隆抗体 (mAb)。我们鉴定了 32 种与天然 PDC-E2 反应的 mAb,包括 20 种对 PDC-E2 特异,12 种与 PDC-E2 和 2-辛酸以及 6,8-双(乙酰硫基)辛酸有交叉反应。与仅识别 PDC-E2 或不相关抗原的 mAb 相比,在交叉反应性 mAb 的互补决定区中观察到的置换体细胞超突变频率较低,表明亲和力成熟水平较低。特别是,当交叉反应性 mAb 的高度突变的重链基因恢复为种系序列时,PDC-E2 反应性显着降低,而保留了异生物质的反应性。重要的是,交叉反应性 mAb 还识别硫辛酸,这是一种与 PDC-E2 共价结合的线粒体脂肪酸。结论:我们的数据反映了化学修饰的硫辛酸或硫辛酸本身,通过分子模拟,是导致原发性胆汁性胆管炎发展的最初目标。(肝病学 2017;66:885–895)
更新日期:2017-07-20
down
wechat
bug