Roep B O, Hiemstra H S, Schloot N C, De Vries R R P, Chaudhuri A, Behan P O, Drijfhout J W
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
Ann N Y Acad Sci. 2002 Apr;958:163-5.
Type 1 diabetes is caused by a T cell-mediated autoimmune destruction of the pancreatic beta cells. Molecular mimicry between viral pathogens and beta cell protein has been a popular theory to explain loss of tolerance in type 1 diabetes. However, functional data in support of this hypothesis have been lacking, presumably because the homologies were defined on the basis of linear similarities in peptide sequences, which ignores the criteria of HLA versus T cell receptor contact residues in peptide epitopes required for T cell recognition. We applied a HLA-binding dedicated peptide microarray analysis using autoreactive T cell clones specific for the autoantigen GAD65 to determine the algorithm of T cell recognition by this given T cell clone. The subsequent database search identified a 100% fit with cytomegalovirus peptide, which was subsequently shown to be recognized by these clonal T cells. However, T cell clones reactive with linear homologies previously described as putative candidates for T cell cross-reactivity between GAD65 and Coxsackie virus peptide were unable to recognize the homologous counterparts.
1型糖尿病是由T细胞介导的胰腺β细胞自身免疫性破坏引起的。病毒病原体与β细胞蛋白之间的分子模拟一直是解释1型糖尿病耐受性丧失的流行理论。然而，支持这一假设的功能数据一直缺乏，大概是因为同源性是基于肽序列的线性相似性定义的，这忽略了T细胞识别所需的肽表位中HLA与T细胞受体接触残基的标准。我们使用针对自身抗原GAD65的自身反应性T细胞克隆进行了HLA结合专用肽微阵列分析，以确定该特定T细胞克隆的T细胞识别算法。随后的数据库搜索发现与巨细胞病毒肽100%匹配，随后证明这些克隆T细胞能够识别该肽。然而，与先前描述为GAD65和柯萨奇病毒肽之间T细胞交叉反应性推定候选物的线性同源物反应的T细胞克隆无法识别同源对应物。
