Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics.
Autoreactive monoclonal antibodies from patients with primary biliary cholangitis recognize environmental xenobiotics.
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来自原发性胆管炎患者的自身反应性单克隆抗体识别环境异种生物。
DOI：
10.1002/hep.29245
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发表时间：
2017-09
期刊：
影响因子：
--
通讯作者：
Gershwin ME
中科院分区：
文献类型：
--
作者：
Tanaka T;Zhang W;Sun Y;Shuai Z;Chida AS;Kenny TP;Yang GX;Sanz I;Ansari A;Bowlus CL;Ippolito GC;Coppel RL;Okazaki K;He XS;Leung PSC;Gershwin ME
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。虽然在解剖效应通路和对原发性胆管炎（PBC）中线粒体自身抗原的多谱系免疫应答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，环境异生素修饰的E2亚基的丙酮酸脱氢酶（PDC-E2）内硫辛酰结构域可以导致遗传易感宿主的耐受性丧失。先前我们证明血清抗PDC-E2自身抗体与化学异生物质2-辛炔酸（2-OA）和6，8-双（乙酰硫基）辛酸（SAc）交叉反应，并且进一步证明存在高频率的PDC-E2特异性外周浆母细胞。在此，我们产生了104个重组单克隆抗体的基础上配对的重链和轻链可变区的单个浆母细胞来源于PBC患者。我们鉴定了32种与天然PDC-E2反应的mAb，包括20种对PDC-E2特异的mAb和12种与PDC-E2和2-OA和SAc交叉反应的mAb。与专门识别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（CDR）中观察到较低频率的置换体细胞超突变，表明较低水平的亲和力成熟。特别是，当交叉反应性mAb的高度突变的重链基因回复到种系序列时，PDC-E2反应性显著降低，而外源性反应性保留。重要的是，交叉反应性mAb还识别硫辛酸（LA），一种与PDC-E2共价结合的线粒体脂肪酸。我们的数据反映了化学修饰的LA或LA本身，通过分子模拟，是导致PBC发展的初始目标。
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 multi-lineage immune responses to mitochondrial self-antigens in primary biliary cholangitis (PBC), 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 (2-OA) and 6,8-bis (acetylthio) octanoic acid (SAc) and further that there is a high frequency of PDC-E2 specific peripheral plasmablasts. Herein we generated 104 recombinant mAbs based on paired heavy- and light-chain variable regions of individual plasmablasts derived from PBC 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-OA and SAc. A lower frequency of replacement somatic hypermutations, indicating lower level of affinity maturation, was observed in the complementarity-determining regions (CDR) 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 xenobiotics reactivity was retained. Importantly, cross-reactive mAbs also recognized lipoic acid (LA), a mitochondrial fatty acid that is covalently bound to PDC-E2. Our data reflect that chemically modified LA or LA itself, via molecular mimicry, is the initial target that leads to the development of PBC.
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影响因子：
24.5
作者：
Kuja-Halkola, Ralf;Lebwohl, Benjamin;Ludvigsson, Jonas F.
通讯作者：
Ludvigsson, Jonas F.
影响因子：
7.3
作者：
Kaminski DA;Wei C;Qian Y;Rosenberg AF;Sanz I
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Sanz I
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16.6
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Bohannon, Caitlin;Powers, Ryan;Jacob, Joshy
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Jacob, Joshy
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12.8
作者：
Rieger, Roman;Leung, Patrick S. C.;Gershwin, M. Eric
通讯作者：
Gershwin, M. Eric