“主要組織相容性復(fù)合體”（MHC）蛋白的某些遺傳變體與自身免疫疾病的易感性增強(qiáng)有關(guān),。Hovhannisyan等人提出了一個機(jī)制,，它能部分解釋這樣一種聯(lián)系，即腹腔病的發(fā)病,，該疾病與人HLA-DQ8等位基因及小鼠的對應(yīng)基因IAg7的表達(dá)密切相關(guān),。這項新的研究工作表明，與在所有其他MHC等位基因中存在的一種Asp57的缺失相關(guān)的結(jié)構(gòu)性質(zhì),，會改變HLA-DQ8 和 IAg7的特異性,。這會導(dǎo)致食用谷蛋白肽中的谷酰胺殘留物在轉(zhuǎn)氨酶調(diào)控下發(fā)生去氨基反應(yīng)，使它們更緊密地結(jié)合到與疾病相關(guān)的MHC等位基因上,，產(chǎn)生一個放大的抗谷蛋白反應(yīng),。HLA-DQ8 和 IAg7還與I-型糖尿病有密切聯(lián)系，雖然尚不清楚其中是否涉及一個類似的機(jī)制,。（生物谷Bioon.com）
生物谷推薦原始出處：
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.
