1 Department of Medicine, School of Medicine, Teikyo University, Tokyo 1738606, Japan.
2 Division of Rheumatology Allergy and Clinical Immunology, University of California School of Medicine, Davis, CA 95616, USA.
Exp Biol Med (Maywood). 2018 Jan;243(2):184-189. doi: 10.1177/1535370217748893. Epub 2018 Jan 7.
Autoimmunity is a consequence of both genetic and environmental factors, occurring in genetically susceptible hosts with environmental triggers. While genome-wide association studies have revealed a number of susceptible genes contributing to etiology, the environmental triggers remain poorly understood. Primary biliary cholangitis, formally known as primary biliary cirrhosis, is considered a model autoimmune disease for which our group has extensively evaluated environmental factors involved in its etiology. Bacterial infection and xenobiotics have been proposed as candidate environmental factors that may explain tolerance breakdown and production of primary biliary cholangitis-specific antimitochondrial autoantibodies. Large-scale case-control studies have consistently detected an association of primary biliary cholangitis with urinary tract infections caused by Escherichia coli, as E. coli PDC-E2 is molecularly similar to human PDC-E2, the immunodominant target of AMAs. Another bacterium of interest is Novosphingobium aromaticivorans, a ubiquitous xenobiotic-metabolizing bacterium that produces lipoylated proteins, which are highly reactive with sera from primary biliary cholangitis patients. Regarding xenobiotics, case-control studies have suggested that frequent use of nail polish is associated with an increased susceptibility to primary biliary cholangitis. We found that 2-octynamide, the conjugate derived from 2-octynoic acid present in cosmetics, lipsticks, and some chewing gums, was unique in both its quantitative structure-activity relationship analysis and reactivity with primary biliary cholangitis sera. 2-nonyamide is another xenobiotic that also has the optimal chemical structure for xenobiotic modification of the PDC-E2 epitope, as demonstrated by the enhanced epitope recognition with AMA-positive PBC sera. Moreover, we found that C57BL/6 mice immunized with 2-octynoic acid-BSA possess many of the features characteristic to primary biliary cholangitis. Impact statement Autoimmunity is believed to develop in genetically susceptible hosts with triggers from the environment. Researchers have recently demonstrated that bacteria and xenobiotics commonly present in our environment are potential triggers of tolerance breakdown against autoantigens and autoimmunity, particularly in primary biliary cholangitis (PBC). The link between xenobiotics and PBC has been further confirmed with the establishment of PBC model mice by immunizing mice with xenobiotics.
自身免疫是遗传和环境因素共同作用的结果，发生在具有环境触发因素的遗传易感宿主中。虽然全基因组关联研究已经揭示了许多导致发病机制的易感基因，但环境触发因素仍知之甚少。原发性胆汁性胆管炎，以前称为原发性胆汁性肝硬化，被认为是一种自身免疫性疾病模型，我们的研究小组已经广泛评估了其发病机制中涉及的环境因素。细菌感染和外源性化学物质已被提出作为可能的环境因素，这些因素可能导致耐受失败和产生原发性胆汁性胆管炎特异性抗线粒体自身抗体。大规模病例对照研究一致发现，原发性胆汁性胆管炎与大肠杆菌引起的尿路感染有关，因为大肠杆菌 PDCE2 在分子上与人类 PDCE2 相似，而人类 PDCE2 是 AMAs 的免疫优势靶标。另一种感兴趣的细菌是新鞘氨醇单胞菌，这是一种普遍存在的外源性化学物质代谢细菌，它产生脂酰化蛋白，这些蛋白与原发性胆汁性胆管炎患者的血清高度反应。关于外源性化学物质，病例对照研究表明，经常使用指甲油会增加患原发性胆汁性胆管炎的易感性。我们发现，2-辛酰胺，来源于化妆品、口红和一些口香糖中存在的 2-辛酸的共轭物，在定量构效关系分析和与原发性胆汁性胆管炎血清的反应性方面都是独特的。2-壬酰胺是另一种外源性化学物质，也具有修饰 PDCE2 表位的最佳化学结构，因为它与 AMA 阳性 PBC 血清的增强表位识别能力证明了这一点。此外，我们发现，用 2-辛酸-BSA 免疫 C57BL/6 小鼠具有许多原发性胆汁性胆管炎的特征。 影响说明 自身免疫被认为是在具有环境触发因素的遗传易感宿主中发展的。研究人员最近表明，我们环境中常见的细菌和外源性化学物质可能是针对自身抗原和自身免疫的耐受失败的潜在触发因素，特别是在原发性胆汁性胆管炎（PBC）中。通过用外源性化学物质免疫小鼠建立 PBC 模型小鼠，进一步证实了外源性化学物质与 PBC 之间的联系。
