“主要组织相容性复合体”（MHC）蛋白的某些遗传变体与自身免疫疾病的易感性增强有关。Hovhannisyan等人提出了一个机制，它能部分解释这样一种联系，即腹腔病的发病，该疾病与人HLA-DQ8等位基因及小鼠的对应基因IAg7的表达密切相关。这项新的研究工作表明，与在所有其他MHC等位基因中存在的一种Asp57的缺失相关的结构性质，会改变HLA-DQ8 和 IAg7的特异性。这会导致食用谷蛋白肽中的谷酰胺残留物在转氨酶调控下发生去氨基反应，使它们更紧密地结合到与疾病相关的MHC等位基因上，产生一个放大的抗谷蛋白反应。HLA-DQ8 和 IAg7还与I-型糖尿病有密切联系，虽然尚不清楚其中是否涉及一个类似的机制。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature 456, 534-538 (27 November 2008) | doi:10.1038/nature07524
The role of HLA-DQ8 57 polymorphism in the anti-gluten T-cell response in coeliac disease
Zaruhi Hovhannisyan1, Angela Weiss2, Alexandra Martin1, Martina Wiesner3, Stig Tollefsen4, Kenji Yoshida5, Cezary Ciszewski1, Shane A. Curran1, Joseph A. Murray6, Chella S. David6, Ludvig M. Sollid4,7, Frits Koning3, Luc Teyton5 & Bana Jabri1
1 Department of Medicine, Pathology, Pediatrics and Committee of Immunology, University of Chicago, Chicago, Illinois 60637, USA
2 Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA
3 Department of Immunohematology and Blood Transfusion, Leiden University, 2300 RC, Leiden, The Netherlands
4 Centre for Immune Regulation, Institute of Immunology, Rikshospitalet University Hospital, 0027 Oslo, Norway
5 The Scripps Research Institute, La Jolla, California 92037, USA
6 Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
7 Centre for Immune Regulation, Institute of Immunology, University of Oslo, 0027 Oslo, Norway
Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-Ag7 lacking a canonical aspartic acid residue at position 57 are associated with coeliac disease1, 2 and type I diabetes3, 4. 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 residues5, 6 on the basis of their spacing to proline residues7. 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 activation8 and that T-cell responses against native gluten peptides are found9, 10, particularly in children11. Here we show that 57 polymorphism promotes the recruitment of T-cell receptors bearing a negative signature charge in the complementary determining region 3(CDR3) 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 CDR3. Thus, the lack of a negative charge at position 57 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.
