Comprehensive, Quantitative Mapping of T Cell Epitopes in Gluten in Celiac Disease
Comprehensive, Quantitative Mapping of T Cell Epitopes in Gluten in Celiac Disease
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DOI：
10.1126/scitranslmed.3001012
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发表时间：
2010-07-21
影响因子：
17.1
通讯作者：
Anderson, Robert P.
中科院分区：
文献类型：
--
作者：
Tye-Din, Jason A.;Stewart, Jessica A.;Anderson, Robert P.
乳糜泻是一种遗传性疾病，导致肠道对谷物中的抗原产生衰弱性免疫反应。引起这种疾病的T细胞识别的抗原肽尚未完全确定。我们对致病性CD 4（+）T细胞表位的理解主要基于肠道T细胞对致病抗原谷蛋白的水解产物或多肽的体外反应。来自小麦α-麦醇溶蛋白的蛋白酶抗性33-氨基酸肽是免疫显性抗原，但对黑麦和大麦中T细胞表位的谱或体内T细胞表位识别的免疫显性和一致性的层次结构知之甚少。我们诱导多克隆谷蛋白特异性T细胞在乳糜泻患者的外周血中喂养他们的谷物，并进行了全面的，公正的分析，所有腹腔毒性醇溶蛋白，一类植物储存蛋白的反应。刺激T细胞的肽在吃相同谷物的患者中是相同的，但在小麦，大麦和黑麦摄入后是不同的。出乎意料的是，来自ω-麦醇溶蛋白（小麦）和C-大麦醇溶蛋白（大麦）而不是α-麦醇溶蛋白的序列是免疫显性的，无论所消耗的谷物如何。此外，仅对三种肽特异的T细胞占大多数谷蛋白特异性T细胞，并且它们对谷蛋白肽的识别是高度冗余的。我们的研究结果表明，乳糜泻中的致病性T细胞显示出有限的多样性，因此表明，这种疾病和潜在的其他强烈的人类白细胞抗原限制性免疫疾病的肽为基础的治疗应该是可能的。
Celiac disease is a genetic condition that results in a debilitating immune reaction in the gut to antigens in grain. The antigenic peptides recognized by the T cells that cause this disease are incompletely defined. Our understanding of the epitopes of pathogenic CD4(+) T cells is based primarily on responses shown by intestinal T cells in vitro to hydrolysates or polypeptides of gluten, the causative antigen. A protease-resistant 33-amino acid peptide from wheat alpha-gliadin is the immunodominant antigen, but little is known about the spectrum of T cell epitopes in rye and barley or the hierarchy of immunodominance and consistency of recognition of T cell epitopes in vivo. We induced polyclonal gluten-specific T cells in the peripheral blood of celiac patients by feeding them cereal and performed a comprehensive, unbiased analysis of responses to all celiac toxic prolamins, a class of plant storage protein. The peptides that stimulated T cells were the same among patients who ate the same cereal, but were different after wheat, barley, and rye ingestion. Unexpectedly, a sequence from omega-gliadin (wheat) and C-hordein (barley) but not alpha-gliadin was immunodominant regardless of the grain consumed. Furthermore, T cells specific for just three peptides accounted for most gluten-specific T cells, and their recognition of gluten peptides was highly redundant. Our findings show that pathogenic T cells in celiac disease show limited diversity and therefore suggest that peptide-based therapeutics for this disease and potentially other strongly human leukocyte antigen-restricted immune diseases should be possible.