In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope
In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope
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DOI：
10.1038/73200
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发表时间：
2000-03-01
期刊：
影响因子：
82.9
通讯作者：
Hill, AVS
中科院分区：
文献类型：
--
作者：
Anderson, RP;Degano, P;Hill, AVS
乳糜泻（CD）是一种越来越多诊断的肠病（患病率，1：200-1：300）（1），由饮食暴露于小麦醇溶蛋白（2）（以及黑麦和大麦中的相关蛋白）诱导，与HLA-DQ 2（α 1*0501，β 1*0201）密切相关，超过90%的CD患者中存在HLA-DQ 2（3）。由于多种麦胶蛋白肽已被鉴定为麦胶蛋白特异性T细胞克隆的表位（4-6），并在喂养研究和离体CD肠活检激发中被鉴定为生物活性序列（7-9），因此尚不清楚“显性”T细胞表位是否与CD相关。在这里，我们使用新鲜的外周血淋巴细胞，从个别受试者进行短期抗原的挑战和组织转氨酶处理，重叠合成肽跨越A-麦胶蛋白，以证明一个短暂的，疾病特异性，DQ 2限制，CD 4 T细胞反应的一个单一的优势表位。ELISPOT测定中最佳γ干扰素释放由对应于A-麦醇溶蛋白氨基酸57-73（Q65 E）的部分脱酰胺肽的17-氨基酸肽引起。与先前的报道一致，表明麦醇溶蛋白的宿主组织转氨酶修饰增强麦醇溶蛋白特异性CD T细胞应答（10），组织转氨酶特异性脱酰胺A-麦醇溶蛋白氨基酸56-75的肽中的Q65。这种优势表位的发现可能允许开发CD的抗原特异性免疫疗法。
Celiac disease (CD) is an increasingly diagnosed enteropathy (prevalence, 1:200-1:300)(1) that is induced by dietary exposure to wheat gliadins(2) (as well as related proteins in rye and barley) and is strongly associated with HLA-DQ2 (alpha 1*0501, beta 1*0201), which is present in over 90% of CD patients(3). Because a variety of gliadin peptides have been identified as epitopes for gliadin-specific T-cell clones(4-6) and as bioactive sequences in feeding studies and in ex vivo CD intestinal biopsy challenge(7-9), it has been unclear whether a 'dominant' T-cell epitope is associated with CD. Here, we used fresh peripheral blood lymphocytes from individual subjects undergoing shortterm antigen challenge and tissue transglutaminase-treated, overlapping synthetic peptides spanning A-gliadin to demonstrate a transient, disease-specific, DQ2-restricted, CD4 T-cell response to a single dominant epitope. Optimal gamma interferon release in an ELISPOT assay was elicited by a 17-amino-acid peptide corresponding to the partially deamidated peptide of A-gliadin amino acids 57-73 (Q65E). Consistent with earlier reports indicating that host tissue transglutaminase modification of gliadin enhances gliadin-specific CD T-cell responses(10), tissue transglutaminase specifically deamidated Q65 in the peptide of A-gliadin amino acids 56-75. Discovery of this dominant epitope may allow development of antigen-specific immunotherapy for CD.