E. coli and the etiology of human PBC: Antimitochondrial antibodies and spreading determinants
E. coli and the etiology of human PBC: Antimitochondrial antibodies and spreading determinants
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DOI：
10.1002/hep.32172
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发表时间：
2021-12-12
期刊：
影响因子：
13.5
通讯作者：
Gershwin，M. Eric
中科院分区：
文献类型：
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作者：
Yang，Yao;Choi，Jinjung;Gershwin，M. Eric
背景与目的原发性胆管炎(PBC)患者尿路感染发生率的增加以及人丙酮酸脱氢酶复合体(hPDC-E_2)硫辛基结构域(LD)与大肠杆菌IPDC-E_2(ePDC-E_2)的交叉反应早已提示大肠埃希菌在PBC发病机制中的作用。然而，这个问题仍然是投机性的。我们假设，通过生成人类安德的特定结构。ColiPDC-E2，我们将能够评估自身抗体反应的特异性，并确定是否暴露于E。方法与结果重要的是，hPDC-E2LD(hPDC-E2LD)亲和纯化的抗hPDC-E2LD抗体的反应性只能被hPDC-E2LD预先吸收而不能被ePDC-E2消除，这表明存在独特的人PDC-E2表位。ColiPDC-E2。为了确定hPDC-E2LD中存在的自身表位(S)，使用各种pDC-E2构建物进行了更详细的研究，包括硫辛酸(LA)对ePDC-E2构象和AMA识别的影响。单独的重组ePDCE2 LD结构域LD1、LD2和LD3既不与AMA反应，也不与LA抗体(抗LA)反应，相反，抗LA很容易与串联表达的纯化重组LD1、LD2和LD3反应；当LP与LA预培养时，这种反应性增加。此外，当三个LD(LD1，LD2，LD3)结构域在pET28a中串联表达或当LD1在另一质粒pGEX中表达时，它们被脂基化并与PBC血清反应。结论我们的数据与TOE的暴露情况一致。引起ePDC-E2特异性抗体的大肠埃希菌，导致决定簇扩散和经典的hPDC-E2LD自身抗体。我们认为这是人类PBC发展的第一步。
Background and AimsThe increased frequency of urinary tract infections in patients with primary biliary cholangitis (PBC) and the cross‐reactivity between the lipoyl domains (LD) of human pyruvate dehydrogenase complex (hPDC‐E2) andEscherichia coliPDC‐E2 (ePDC‐E2) have long suggested a role ofE.coliin causality of PBC. This issue, however, has remained speculative. We hypothesized that by generating specific constructs of human andE. coliPDC‐E2, we would be able to assess the specificity of autoantibody responses and define whether exposure toE. coliin susceptible hosts is the basis for the antimitochondrial antibody (AMA) response.Approach and ResultsImportantly, the reactivity of hPDC‐E2 LD (hPDC‐E2LD) affinity‐purified antibodies against hPDC‐E2LD could only be removed by prior absorption with hPDC‐E2LD and not ePDC‐E2, suggesting the presence of unique human PDC‐E2 epitopes distinct fromE. coliPDC‐E2. To identify the autoepitope(s) present in hPDC‐E2LD, a more detailed study using a variety of PDC‐E2 constructs was tested, including the effect of lipoic acid (LA) on ePDC‐E2 conformation and AMA recognition. Individual recombinant ePDCE2 LD domains LD1, LD2 and LD3 did not react with either AMA or antibodies to LA (anti‐LA), but in contrast, anti‐LA was readily reactive against purified recombinant LD1, LD2, and LD3 expressed in tandem (LP); such reactivity increased when LP was precultured with LA. Moreover, when the three LD (LD1, LD2, LD3) domains were expressed in tandem in pET28a or when LD1 was expressed in another plasmid pGEX, they were lipoylated and reactive to PBC sera.ConclusionsIn conclusion, our data are consistent with an exposure toE. colithat elicits specific antibody to ePDC‐E2 resulting in determinant spreading and the classic autoantibody to hPDC‐E2LD. We argue this is the first step to development of human PBC.