Extensive homology between the major immunodominant mitochondrial antigen in primary biliary cirrhosis and Helicobacter pylori does not lead to immunological cross-reactivity
Extensive homology between the major immunodominant mitochondrial antigen in primary biliary cirrhosis and Helicobacter pylori does not lead to immunological cross-reactivity
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DOI：
10.1080/00365520410003236
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发表时间：
2004-10-01
影响因子：
1.9
通讯作者：
Vergani, D
中科院分区：
文献类型：
--
作者：
Bogdanos, DP;Baum, H;Vergani, D
背景：原发性胆汁性肝硬化（PBC）是一种免疫介导的慢性胆汁淤积性疾病，其特征是存在主要针对丙酮酸脱氢酶复合物（PDC-E2）的E2亚基的抗体。尽管有证据表明微生物可能通过分子拟态机制诱导抗线粒体抗体（AMA），但导致 PBC 耐受性破坏的原因仍有待确定。方法：发现幽门螺杆菌 (HELPY) 的脲酶 β (UREB)(22-36) 抗原与主要线粒体自身表位 PDC-E2(212-226) 具有广泛 (87%) 的相似性，推测这也会导致交叉反应。由此构建了 UREB/PDC-E2 模拟物，并通过 ELISA 在 112 名 PBC 患者和 114 名对照者中进行了测试。结果：104名患者发现对PDC-E2(212-226)有反应性，但只有2名患者对UREB22-36有反应性。在这两名患者中，双重反应性不存在交叉反应性。通过三维模型预测分析证明，UREB22-36 缺乏表面抗体可及性，这可能解释了这一意外发现。有人猜测 HELPY UREB22-36 是否可能充当交叉反应性 CD4 T 细胞表位。所有七名 PBC 患者在针对 PDC-E2(212-226) 的标准增殖测定中进行测试，均给出了阳性反应。所有七人对 HELPY URB22-36 均无反应。免疫印迹显示，抗 PDC-E2 阳性和阴性 PBC 病例之间以及 PBC 患者和对照之间对 HELPY 抗原的反应模式相似。结论：与普遍看法相反，自身和微生物之间广泛的序列同源性（分子模拟）并不一定会导致交叉反应。因此，当存在时，自身与微生物之间的交叉反应很可能具有生物学重要性。
Background: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic disease characterized by the presence of antibodies directed predominantly against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). What provokes tolerance breakdown in PBC remains to be established, though there is evidence to indicate that microbes may induce anti-mitochondrial antibodies (AMA) through a mechanism of molecular mimicry. Methods: Having found that urease beta (UREB)(22-36) antigen of Helicobacter pylori (HELPY) shares extensive (87%) similarity with PDC-E2(212-226), the major mitochondrial autoepitope, it was hypothesized that this would also lead to cross-reactivity. The UREB/PDC-E2 mimics were thus constructed and tested by ELISA in 112 PBC patients and 114 controls. Results: Reactivity to PDC-E2(212-226) was found in 104 patients but to UREB22-36 in only 2. In these two patients, the double reactivity was not cross-reactive. The lack of surface antibody accessibility to UREB22-36, as demonstrated through three-dimensional model prediction analysis, may explain this unexpected finding. There was some speculation on whether HELPY UREB22-36 might act as a cross-reactive CD4 T-cell epitope. All seven PBC patients, tested in a standard proliferation assay against PDC-E2(212-226), gave a positive response. All seven were unresponsive to HELPY UREB22-36. The pattern of reactivity to HELPY antigens by immunoblot was similar between anti-PDC-E2-positive and negative PBC cases, as well as between PBC patients and controls. Conclusion: Contrary to common belief, extensive sequence homology ( molecular mimicry) between self and microbe does not necessarily result in cross-reactivity. It is therefore likely that, when present, cross-reactivity between self and microbes is of biological importance.