T-cell molecular mimicry in Chagas disease:: identification and partial structural analysis of multiple cross-reactive epitopes between Trypanosoma cruzi B13 and cardiac myosin heavy chain
T-cell molecular mimicry in Chagas disease:: identification and partial structural analysis of multiple cross-reactive epitopes between Trypanosoma cruzi B13 and cardiac myosin heavy chain
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DOI：
10.1016/j.jaut.2005.01.006
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发表时间：
2005-03-01
影响因子：
12.8
通讯作者：
Cunha-Neto, E
中科院分区：
文献类型：
--
作者：
Iwai, LK;Juliano, MA;Cunha-Neto, E
查加斯病心脏病（CCC）是感染后自身免疫的少数例子之一，其中已建立的病原体，原生动物寄生虫克氏锥虫的感染发作，明确触发分子模拟相关的靶器官免疫损伤。浸润CCC患者心脏的CD 4（+）T细胞克隆交叉反应性识别人心肌肌球蛋白（主要心脏蛋白）和T细胞免疫优势蛋白B 13蛋白。克鲁兹此外，在体外引发与B 13导致心肌肌球蛋白交叉反应性T细胞克隆的恢复。为了鉴定B 13蛋白和人心肌肌球蛋白之间的交叉反应性表位，我们使用CCC患者优先识别的B13肽S15.4来建立来自HLA-DQ 7个体的T细胞克隆。在增殖试验中针对15种Lys/His取代的S15.4衍生肽测试B13 S15.4肽特异性CD 4（+）T细胞克隆3E 5，用于TCR/HLA接触分析。结合先前的HLA结合数据和HLA-DQ 7-肽S15.4复合物的分子建模，Lys/His扫描分析显示了8个TCR/HLA接触位置。克隆3E 5还针对来自携带中心HLA-DQ 7结合基序的人β-心肌肌球蛋白重链的45个15-mer肽进行了测试。克隆3135识别心肌肌球蛋白的13个肽段。心脏肌球蛋白中交叉反应性肽的比对显示在比对位置具有相似化学/结构特征的残基或侧链的共享非常有限，表明非常简并的TCR识别模式。简并分子内识别的存在，与多个低同源性，交叉反应性表位在一个单一的自身抗原蛋白可能有影响，在CCC和其他自身免疫性疾病的自身免疫反应的幅度增加。(c)2005爱思唯尔有限公司保留所有权利。
Chagas disease cardiornyopathy (CCC) is one of the few examples of post-infectious autoimmunity, where infectious episodes with an established pathogen, the protozoan parasite Trypanosoma cruzi, clearly triggers molecular mimicry-related target organ immune damage. CD4(+) T-cell clones infiltrating hearts from CCC patients cross-reactively recognize human cardiac myosin, the major heart protein, and the immunodominam B 13 protein from T. cruzi. Moreover, in vitro priming with B 13 leads to the recovery of cardiac myosin cross-reactive T-cell clones. In order to identify cross-reactive epitopes between B 13 protein and human cardiac myosin, we used B13 peptide S15.4, preferentially recognized by CCC patients, to establish a T-cell clone from an HLA-DQ7 individual. The B13 S15.4 peptide- specific CD4(+) T-cell clone 3E5 was tested in proliferation assays against 15 Lys/His-substituted S15.4-derived peptides for TCR/HLA contact analysis. Together with previous HLA-binding data and molecular modeling of the HLA-DQ7-peptide S15.4 complex, Lys/His scanning analysis showed eight TCR/HLA contact positions. Clone 3E5 was also tested against 45 15-mer peptides from human beta-cardiac myosin heavy chain bearing the central HLA-DQ7 binding motif. Clone 3135 recognized 13 peptides from cardiac myosin. The alignment of cross-reactive peptides in cardiac myosin showed very limited sharing of residues or side chains with similar chemical/structural features at aligned positions, indicative of a very degenerate TCR recognition pattern. The existence of degenerate intramolecular recognition, with multiple low-homology, cross-reactive epitopes in a single autoantigenic protein may have implications in increasing the magnitude of the autoimmune response in CCC and other autoimmune diseases. (c) 2005 Elsevier Ltd. All rights reserved.