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      HLA‐A*33‐DR3 and A*33‐DR9 haplotypes enhance the risk of type 1 diabetes in Han Chinese

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          Abstract

          Aims/Introduction

          To investigate the typing for human leukocyte antigen ( HLA ) class I in Chinese patients with type 1 diabetes as a complement screening for HLA class II.

          Materials and Methods

          A total of 212 type 1 diabetic patients and 200 healthy controls were enrolled. The genetic polymorphisms of HLA class I and II were examined with a high‐resolution polymerase chain reaction sequence‐based typing method.

          Results

          The haplotype, A*33:03‐B*58:01‐C*03:02(A33), was associated with type 1 diabetes ( P = 1.0 × 10 −4, odds ratio 3.2 [1.738–5.843]). The A33‐ DR3 and A33‐ DR9 haplotypes significantly enhanced the risk of type 1 diabetes (A33‐ DR3 , odds ratio 5.1 [2.40–10.78], P = 4.0 × 10 −6; A33‐ DR9 , odds ratio 13.0 [1.69–100.32], P = 0.004). In type 1 diabetic patients, compared with A33‐ DR3 ‐negative carriers, A33‐ DR3 ‐positive carriers had significantly lower percentages of CD3 + CD4 + T cells (42.5 ± 7.72 vs 37.0 ± 8.35%, P = 0.023), higher percentages of CD3 + CD8 + T cells (27.4 ± 7.09 vs 32.8 ± 5.98%, P = 0.005) and T‐cell receptor α/β T cells (70.0 ± 7.00 vs 73.6 ± 6.25%, P = 0.031), and lower CD4/ CD8 ratios (1.71 ± 0.75 vs 1.16 ± 0.35, P = 0.003).

          Conclusions

          It is the first time that the haplotypes A33‐ DR3 and A33‐ DR9 were found with an enhanced predisposition to type 1 diabetes in Han Chinese. A33‐ DR3 was associated with a reduction in the helper‐to‐cytotoxic cell ratio and preferential increase of T‐cell receptor α/β T cell. The typing for HLA class I and its immunogenetic effects are important for more accurate HLA class II haplotype risk prediction and etiology research in type 1 diabetic patients.

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          Most cited references27

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          Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus

          (2002)
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            The mechanism and regulation of chromosomal V(D)J recombination.

            V(D)J recombination is of fundamental importance to the generation of diverse antigen receptor repertoires. We review our current understanding of the V(D)J recombination reaction and how it is regulated during lymphocyte development. We also discuss how defects in the mechanism or regulation of V(D)J recombination can lead to human disease.
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              Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes.

              Type 1 diabetes develops over many years and is characterized ultimately by the destruction of insulin-producing pancreatic beta cells by autoreactive T cells. Nonetheless, the role of innate cells in the initiation of this disease remains poorly understood. Here, we show that in young female nonobese diabetic mice, physiological beta cell death induces the recruitment and activation of B-1a cells, neutrophils and plasmacytoid dendritic cells (pDCs) to the pancreas. Activated B-1a cells secrete IgGs specific for double-stranded DNA. IgGs activate neutrophils to release DNA-binding cathelicidin-related antimicrobial peptide (CRAMP), which binds self DNA. Then, self DNA, DNA-specific IgG and CRAMP peptide activate pDCs through the Toll-like receptor 9-myeloid differentiation factor 88 pathway, leading to interferon-α production in pancreatic islets. We further demonstrate through the use of depleting treatments that B-1a cells, neutrophils and IFN-α-producing pDCs are required for the initiation of the diabetogenic T cell response and type 1 diabetes development. These findings reveal that an innate immune cell crosstalk takes place in the pancreas of young NOD mice and leads to the initiation of T1D.
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                Author and article information

                Journal
                J Diabetes Investig
                J Diabetes Investig
                10.1111/(ISSN)2040-1124
                JDI
                Journal of Diabetes Investigation
                John Wiley and Sons Inc. (Hoboken )
                2040-1116
                2040-1124
                03 May 2016
                July 2016
                : 7
                : 4 ( doiID: 10.1111/jdi.2016.7.issue-4 )
                : 514-521
                Affiliations
                [ 1 ] Department of Endocrine and Metabolic diseases Ruijin Hospital Shanghai Jiao‐Tong University School of Medicine Shanghai Key Laboratory for Endocrine Tumors Shanghai Clinical Center for Endocrine and Metabolic DiseasesShanghai Institute of Endocrine and Metabolic Diseases and Shanghai E‐institute for Endocrinology ShanghaiChina
                [ 2 ] Center for Transplant and Renal Research Westmead Millennium InstituteUniversity of Sydney Sydney New South WalesAustralia
                [ 3 ] Laboratory for Endocrine & Metabolic Diseases Institute of Health Science Shanghai JiaoTong University School of Medicine and Shanghai Institutes for Biological SciencesChinese Academy of Sciences ShanghaiChina
                Author notes
                [*] [* ] Correspondence

                Weiqiong Gu

                Tel.: +86‐21‐64370045 Ext. 665340

                Fax: +86‐21‐64373514

                E‐mail address: weiqionggu@ 123456163.com

                [†]

                These authors contributed equally to this study.

                Article
                JDI12462
                10.1111/jdi.12462
                4931201
                27181214
                01933dd4-4eb0-4714-8426-0704f5f615a1
                © 2015 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 07 June 2015
                : 13 December 2015
                : 16 December 2015
                Page count
                Pages: 8
                Funding
                Funded by: Chinese National Natural Science Foundation
                Award ID: 81370934
                Funded by: Ministry of Health
                Award ID: 201202008
                Funded by: International Program Development Fund of University of Sydney
                Award ID: CON156446
                Categories
                Original Article
                Articles
                Epidemiology
                Custom metadata
                2.0
                jdi12462
                July 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:04.07.2016

                genetics,hla‐a*33,type 1 diabetes
                genetics, hla‐a*33, type 1 diabetes

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