HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases.
HLA DRB4 0101-restricted immunodominant T cell autoepitope of pyruvate dehydrogenase complex in primary biliary cirrhosis: evidence of molecular mimicry in human autoimmune diseases.
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HLA DRB4 0101丙酮酸丙酮酸脱氢酶复合物的限制性免疫主导T细胞自动tip虫中胆汁肝硬化：人体自身免疫性疾病中分子模仿的证据。
DOI：
10.1084/jem.181.5.1835
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发表时间：
1995-05-01
期刊：
影响因子：
--
通讯作者：
Niho Y
中科院分区：
文献类型：
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作者：
Shimoda S;Nakamura M;Ishibashi H;Hayashida K;Niho Y
我们利用与人PDC-E2对应的17-20个氨基酸残基的33种不同肽作为刺激抗原，建立了4例原发性胆汁性肝硬化患者的6个特异性丙酮酸脱氢酶复合物（PDC -E2）肽的T细胞克隆。这6个T细胞克隆的最小T细胞表位都被定位到PDC-E2肽163-176 （GDLLAEIETDKATI）的同一区域，该区域与PDC-E2的内脂酰结构域相对应。该表位的HLA限制性分子均鉴定为HLA drb40101。这些T细胞克隆的共同必需氨基酸分别是位于170、172和173位的E、D和K；这个表位的其他关键氨基酸在每个T细胞克隆中都是不同的。此外，位于170和173位的丙氨酸取代肽抑制了由人PDC-E2 163-176原肽诱导的所有T细胞克隆的增殖，而不是172位，这表明172位的氨基酸D是所有T细胞克隆的关键mhc结合位点。有趣的是，所有T细胞克隆都对PDC-E2肽36-49 （GDLIAEVETDKATV）产生反应，该肽36-49与人PDC-E2的外脂酰结构域相对应。此外，一个T细胞克隆与外源抗原如大肠杆菌PDC-E2肽31- 44/134-147/235-248 （EQSLITVEGDKASM）发生交叉反应，该抗原具有EXDK序列。这是T细胞克隆水平在人类自身免疫性疾病中存在分子拟态的明确证明。根据原发性胆汁性肝硬化中T细胞自身表位的发现，设计肽特异性免疫疗法也被认为是可能的。
We established six T cell clones specific for pyruvate dehydrogenase complex (PDC)-E2 peptides from four different patients with primary biliary cirrhosis using 33 different peptides of 17-20 amino acid residues corresponding to human PDC-E2 as stimulating antigens. The minimal T cell epitopes of these six T cell clones were all mapped to the same region of the PDC-E2 peptide 163-176 (GDLLAEIETDKATI), which corresponds to the inner lipoyl domain of PDC-E2. The HLA restriction molecules for this epitope were all identified as HLA DRB4 0101. The common essential amino acids of this epitope for these T cell clones were E, D, and K at positions 170, 172, and 173, respectively; other crucial amino acids for this epitope differed in each T cell clone. In addition, the alanine-substituted peptides at positions 170 and 173, but not 172, inhibited the proliferation of all T cell clones induced by the original peptide of human PDC-E2 163-176, indicating that amino acid D at position 172 is a critical MHC-binding site for all T cell clones tested. Interestingly, all T cell clones reacted to PDC-E2 peptide 36-49 (GDLIAEVETDKATV), which corresponds to the outer lipoyl domain of human PDC-E2. Furthermore, one T cell clone cross-reacted with exogenous antigens such as Escherichia coli PDC-E2 peptide 31- 44/134-147/235-248 (EQSLITVEGDKASM), which has an EXDK sequence. This is a definite demonstration of the presence of molecular mimicry at the T cell clonal level in human autoimmune diseases. It is also considered possible to design peptide-specific immunotherapy based on the findings of T cell autoepitopes in primary biliary cirrhosis.