Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS lyme disease
Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS lyme disease
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DOI：
10.1006/jaut.2000.0501
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发表时间：
2001-05-01
影响因子：
12.8
通讯作者：
Pinilla, C
中科院分区：
文献类型：
--
作者：
Martin, R;Gran, B;Pinilla, C
分子模拟的概念为外来病原体的抗原与自身蛋白质之间的交叉反应如何引发自身免疫性疾病提供了一个精妙的框架。虽然以前认为外来蛋白质和自身蛋白质之间的序列和结构同源性，或者T细胞受体（TCR）和主要组织相容性复合体（MHC）结合基序的共享是发生分子模拟所必需的，但我们已经表明，即使完全不相关的肽序列也可能导致T细胞的交叉识别。使用位置扫描格式的合成组合肽库（PS - SCL）以及新的生物特征预测方法，使我们能够以前所未有的准确性描述单个自身反应性T细胞克隆（TCC）的识别特征。通过对髓鞘特异性TCC以及慢性中枢神经系统（CNS）莱姆病患者神经系统中的克隆的研究，已经清楚地表明，至少一些T细胞比以前预期的更具简并性。这些数据不仅将帮助我们重新定义什么构成特异性T细胞识别，还将使我们能够更详细地研究分子模拟的生物学作用。最近一项针对多发性硬化症（MS）中一种候选髓鞘碱性蛋白（MBP）表位（氨基酸83 - 99）的改变肽配体（APL）的临床试验表明，这种修饰的MBP肽不仅可能具有治疗功效，还可能具有加重疾病的潜力。因此，我们提供了确凿的证据，表明交叉识别的基本原理及其致病意义与MS相关。（C）2001学术出版社
The concept of molecular mimicry provides and elegant framework as to how cross-reactivity between antigens from a foreign agent with self proteins may trigger autoimmune diseases. While it was previously thought that sequence and structural homology between foreign and self proteins or the sharing of T cell receptor (TCR) and MHC-binding motifs are required for molecular mimicry to occur, we have shown that even completely unrelated peptide sequences may lead to cross-recognition by T cells. The use of synthetic combinatorial peptide libraries in the positional scanning format (PS-SCL) together with novel biometric prediction approaches has allowed us to describe the recognition profiles of individual autoreactive T cell clones (TCC) with unprecedented accuracy. Through studies of myelin-specific TCC as well as clones from the nervous system of patients suffering from chronic central nervous (CNS) Lyme disease it has become clear that at least some T cells are more degenerate than previously anticipated. These data will not only help us to redefine what constitutes specific T cell recognition, but also allow us to study in more detail the biological role of molecular mimicry. A recent clinical trial with an altered peptide ligand (APL) of one of the candidate myelin basic protein (MBP) epitopes in MS (amino acids 83-99) has shown that such a modified MBP peptide may not only have therapeutic efficacy, but also bears the potential to exacerbate disease. Thus, we provide firm evidence that the basic principles of cross-recognition and their pathogenetic significance are relevant in MS. (C) 2001 Academic Press.