The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease.
The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease.
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DOI：
10.1038/nature07524
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发表时间：
2008-11-27
期刊：
影响因子：
64.8
通讯作者：
Jabri B
中科院分区：
文献类型：
--
作者：
Hovhannisyan Z;Weiss A;Martin A;Wiesner M;Tollefsen S;Yoshida K;Ciszewski C;Curran SA;Murray JA;David CS;Sollid LM;Koning F;Teyton L;Jabri B
主要组织相容性复合体（MHC）II类等位基因HLA-DQ 8和在β57位缺乏典型天冬氨酸残基的小鼠同源物I-Ag 7与乳糜泻和I型糖尿病相关。然而，这种单一的多态性在疾病的发生和发展中的作用仍然知之甚少。Asp 57的缺乏产生带正电荷的P9口袋，其赋予对带负电荷的肽的偏好。谷蛋白缺乏这样的肽，但组织转氨酶（TG 2）通过基于其与脯氨酸残基的间隔将特定谷氨酰胺残基脱酰胺而在限定位置处将带负电荷的残基引入谷蛋白T细胞表位。普遍接受的模型，提出HLA-DQ 8只是有利于带负电荷的肽的结合，没有考虑到TG 2需要炎症来激活的事实，并且发现了针对天然谷蛋白肽的T细胞应答，特别是在儿童中。在这里，我们发现β57多态性促进了T细胞受体的募集，这些T细胞受体在腹腔疾病中对HLA-DQ 8呈递的天然谷蛋白肽的应答期间在互补决定区3β（CDR 3 β）中携带负特征电荷。这些T细胞表现出对脱酰胺谷蛋白肽的交叉反应性和异型性（更强）反应。此外，谷蛋白肽脱酰胺通过减轻对CDR 3 β中带电残基的需求来扩展T细胞受体库。因此，在MHC II类中β57位缺乏负电荷是通过T细胞受体或肽中的带负电荷残基来满足的，这两者的组合可以解释HLA-DQ 8在放大针对膳食麸质的T细胞应答中的作用。
Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-Ag7 lacking a canonical aspartic acid residue at position β57 are associated with coeliac disease and type I diabetes. However, the role of this single polymorphism in disease initiation and progression remains poorly understood. The lack of Asp 57 creates a positively charged P9 pocket, which confers a preference for negatively charged peptides. Gluten lacks such peptides, but tissue transglutaminase (TG2) introduces negatively charged residues at defined positions into gluten T-cell epitopes by deamidating specific glutamine residues on the basis of their spacing to proline residues. The commonly accepted model, proposing that HLA-DQ8 simply favours binding of negatively charged peptides, does not take into account the fact that TG2 requires inflammation for activation and that T-cell responses against native gluten peptides are found, particularly in children. Here we show that β57 polymorphism promotes the recruitment of T-cell receptors bearing a negative signature charge in the complementary determining region 3β (CDR3β) during the response against native gluten peptides presented by HLA-DQ8 in coeliac disease. These T cells showed a crossreactive and heteroclitic (stronger) response to deamidated gluten peptides. Furthermore, gluten peptide deamidation extended the T-cell-receptor repertoire by relieving the requirement for a charged residue in CDR3β. Thus, the lack of a negative charge at position β57 in MHC class II was met by negatively charged residues in the T-cell receptor or in the peptide, the combination of which might explain the role of HLA-DQ8 in amplifying the T-cell response against dietary gluten.
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DOI：
10.1084/jem.169.1.345
发表时间：
1989-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sollid LM;Markussen G;Ek J;Gjerde H;Vartdal F;Thorsby E
通讯作者：
Thorsby E
DOI：
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发表时间：
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期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
15.3
作者：
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影响因子：
56.9
作者：
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EISENBARTH, GS
DOI：
10.1038/ncpgasthep0582
发表时间：
2006-09-01
期刊：
NATURE CLINICAL PRACTICE GASTROENTEROLOGY & HEPATOLOGY
影响因子：
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作者：
Jabri, Bana;Sollid, Ludvig M.
通讯作者：
Sollid, Ludvig M.