Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility
Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility Xinhui Ge 1 2 , Jon D. Piganelli 2 , Hubert M. Tse 2 , Suzanne Bertera 2 , Clayton E. Mathews 2 , Massimo Trucco 2 , Li Wen 3 and William A. Rudert 2 1 Department of Human Genetics, Graduate School of P...
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| creator | XINHUI GE PIGANELLI, Jon D TSE, Hubert M BERTERA, Suzanne MATHEWS, Clayton E TRUCCO, Massimo LI WEN RUDERT, William A |
| description | Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility
Xinhui Ge 1 2 ,
Jon D. Piganelli 2 ,
Hubert M. Tse 2 ,
Suzanne Bertera 2 ,
Clayton E. Mathews 2 ,
Massimo Trucco 2 ,
Li Wen 3 and
William A. Rudert 2
1 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
2 Division of Immunogenetics, Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
3 Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to William A. Rudert, MD, PhD, Rangos Research Center, Children’s Hospital of
Pittsburgh, 3460 5th Ave., Pittsburgh, PA 15213. E-mail: war1{at}pitt.edu
Abstract
This study addressed an important biological question, namely how certain HLA molecules modulate the disease risk conferred
by other HLA molecules. The HLA molecules under investigation were HLA-DQ8 and -DR4, the two most prevalent HLA class II alleles
found in Caucasian type 1 diabetic patients. A panel of human GAD (hGAD65)-specific CD4 T-cell lines and hybridomas was generated
to serve as detection reagents for evaluating the peptide occupancy of DQ8 and DR4. Results indicated that DQ8 and DR4 (0401)
were able to bind the same hGAD65 peptides. The coexpression of DR4 (0401) diminished DQ8-restricted T-cell responses. In
addition, we also demonstrated that the diminished T-cell response varied according to the specific DRB1*04 alleles. Taken
together, this study provides evidence that DR4 is able to modulate DQ8-restricted T-cell responses, possibly by competing
for peptides. Given that DQ8 is a primary genetic determinant of type 1 diabetes, the decreased DQ8-restricted CD4 T-cell
activity due to peptide competition may be the mechanism explaining the modulation effect of DR4 to type 1 diabetes susceptibility.
APC, antigen-presenting cell
B-LCL, B-lymphoblastoid cell line
ELISA, enzyme-linked immunosorbent assay
FITC, fluorescein isothiocyanate
hGAD65, human GAD
IFN-γ, γ-interferon
IL, interleukin
MHC, major histocompatibility complex
TCR, T-cell receptor
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 6, 2006.
Received May 16, 2006.
DIABETES |
| doi_str_mv | 10.2337/db06-0680 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_pasca</sourceid><recordid>TN_cdi_gale_incontextcollege_GICCO_A155665447</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A155665447</galeid><sourcerecordid>A155665447</sourcerecordid><originalsourceid>FETCH-LOGICAL-c592t-6d1c7922387de57d5297d3ec84a32cd0662b4ea1d4bb1da851ea4647cf1ed52b3</originalsourceid><addsrcrecordid>eNqF0l2LEzEUBuBBFLeuXvgHJAgKgrPmeyaXS6ursLJYK3gXMsmZbpZ0UpMZtP_elC2UlYLkIiE8OUkOb1W9JPiCMtZ8cB2WNZYtflTNiGKqZrT5-biaYUxoTRrVnFXPcr7DGMsynlZnpCEMc0Vnlfka3RTMGNMOLWMAFHu0WPIajREtvrV1gjwmb0dwaL7gaFXPIQS0hLyNQ4aMzODQarcFRNDCmw7Gsvd9yha2o-988OPuefWkNyHDi8N8Xv349HE1_1xf31x9mV9e11YoOtbSEdsoSlnbOBCNE1Q1joFtuWHUOiwl7TgY4njXEWdaQcBwyRvbEyi4Y-fV2_u62xR_TeXZeuPLO0IwA8Qpa9mSlklF_wuJ4qr0sinw9T_wLk5pKJ_QlJSrlaSqoPoerU0A7Yc-jsnYNQyQTIgD9L5sXxIhpBSc74tenPBlONh4e_LAuwcHihnhz7g2U866vbp-aOtT1sYQYA269Ht-c7K2TTHnBL3eJr8xaacJ1vto6X209D5axb46dGPqNuCO8pClAt4cgMnWhD6Zwfp8dC3jmAhS3Pt7d-vXt799Au0OyTkuhNCEasaFYH8B-Jbfog</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>216479629</pqid></control><display><type>article</type><title>Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility</title><source>MEDLINE</source><source>PubMed Central (PMC)</source><source>EZB Electronic Journals Library</source><creator>XINHUI GE ; PIGANELLI, Jon D ; TSE, Hubert M ; BERTERA, Suzanne ; MATHEWS, Clayton E ; TRUCCO, Massimo ; LI WEN ; RUDERT, William A</creator><creatorcontrib>XINHUI GE ; PIGANELLI, Jon D ; TSE, Hubert M ; BERTERA, Suzanne ; MATHEWS, Clayton E ; TRUCCO, Massimo ; LI WEN ; RUDERT, William A</creatorcontrib><description>Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility
Xinhui Ge 1 2 ,
Jon D. Piganelli 2 ,
Hubert M. Tse 2 ,
Suzanne Bertera 2 ,
Clayton E. Mathews 2 ,
Massimo Trucco 2 ,
Li Wen 3 and
William A. Rudert 2
1 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
2 Division of Immunogenetics, Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
3 Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to William A. Rudert, MD, PhD, Rangos Research Center, Children’s Hospital of
Pittsburgh, 3460 5th Ave., Pittsburgh, PA 15213. E-mail: war1{at}pitt.edu
Abstract
This study addressed an important biological question, namely how certain HLA molecules modulate the disease risk conferred
by other HLA molecules. The HLA molecules under investigation were HLA-DQ8 and -DR4, the two most prevalent HLA class II alleles
found in Caucasian type 1 diabetic patients. A panel of human GAD (hGAD65)-specific CD4 T-cell lines and hybridomas was generated
to serve as detection reagents for evaluating the peptide occupancy of DQ8 and DR4. Results indicated that DQ8 and DR4 (0401)
were able to bind the same hGAD65 peptides. The coexpression of DR4 (0401) diminished DQ8-restricted T-cell responses. In
addition, we also demonstrated that the diminished T-cell response varied according to the specific DRB1*04 alleles. Taken
together, this study provides evidence that DR4 is able to modulate DQ8-restricted T-cell responses, possibly by competing
for peptides. Given that DQ8 is a primary genetic determinant of type 1 diabetes, the decreased DQ8-restricted CD4 T-cell
activity due to peptide competition may be the mechanism explaining the modulation effect of DR4 to type 1 diabetes susceptibility.
APC, antigen-presenting cell
B-LCL, B-lymphoblastoid cell line
ELISA, enzyme-linked immunosorbent assay
FITC, fluorescein isothiocyanate
hGAD65, human GAD
IFN-γ, γ-interferon
IL, interleukin
MHC, major histocompatibility complex
TCR, T-cell receptor
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 6, 2006.
Received May 16, 2006.
DIABETES</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db06-0680</identifier><identifier>PMID: 17130492</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Amino Acid Sequence ; Analysis ; Antigen-Presenting Cells - immunology ; Antigens ; Biological and medical sciences ; CD4-Positive T-Lymphocytes - immunology ; Cells ; Competition ; Diabetes ; Diabetes Mellitus, Type 1 - genetics ; Diabetes Mellitus, Type 1 - immunology ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Gene expression ; Genetic aspects ; Genetic Predisposition to Disease ; Genetic susceptibility ; Glutamate Decarboxylase - immunology ; Haplotypes ; HLA-DQ Antigens - immunology ; HLA-DR4 Antigen - immunology ; Humans ; Isoenzymes - immunology ; Medical sciences ; Molecular Sequence Data ; Peptide Fragments - chemistry ; Peptides ; Transgenic animals ; Type 1 diabetes ; White people</subject><ispartof>Diabetes (New York, N.Y.), 2006-12, Vol.55 (12), p.3455-3462</ispartof><rights>2007 INIST-CNRS</rights><rights>COPYRIGHT 2006 American Diabetes Association</rights><rights>COPYRIGHT 2006 American Diabetes Association</rights><rights>Copyright American Diabetes Association Dec 2006</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c592t-6d1c7922387de57d5297d3ec84a32cd0662b4ea1d4bb1da851ea4647cf1ed52b3</citedby><cites>FETCH-LOGICAL-c592t-6d1c7922387de57d5297d3ec84a32cd0662b4ea1d4bb1da851ea4647cf1ed52b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18340151$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17130492$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>XINHUI GE</creatorcontrib><creatorcontrib>PIGANELLI, Jon D</creatorcontrib><creatorcontrib>TSE, Hubert M</creatorcontrib><creatorcontrib>BERTERA, Suzanne</creatorcontrib><creatorcontrib>MATHEWS, Clayton E</creatorcontrib><creatorcontrib>TRUCCO, Massimo</creatorcontrib><creatorcontrib>LI WEN</creatorcontrib><creatorcontrib>RUDERT, William A</creatorcontrib><title>Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility
Xinhui Ge 1 2 ,
Jon D. Piganelli 2 ,
Hubert M. Tse 2 ,
Suzanne Bertera 2 ,
Clayton E. Mathews 2 ,
Massimo Trucco 2 ,
Li Wen 3 and
William A. Rudert 2
1 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
2 Division of Immunogenetics, Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
3 Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to William A. Rudert, MD, PhD, Rangos Research Center, Children’s Hospital of
Pittsburgh, 3460 5th Ave., Pittsburgh, PA 15213. E-mail: war1{at}pitt.edu
Abstract
This study addressed an important biological question, namely how certain HLA molecules modulate the disease risk conferred
by other HLA molecules. The HLA molecules under investigation were HLA-DQ8 and -DR4, the two most prevalent HLA class II alleles
found in Caucasian type 1 diabetic patients. A panel of human GAD (hGAD65)-specific CD4 T-cell lines and hybridomas was generated
to serve as detection reagents for evaluating the peptide occupancy of DQ8 and DR4. Results indicated that DQ8 and DR4 (0401)
were able to bind the same hGAD65 peptides. The coexpression of DR4 (0401) diminished DQ8-restricted T-cell responses. In
addition, we also demonstrated that the diminished T-cell response varied according to the specific DRB1*04 alleles. Taken
together, this study provides evidence that DR4 is able to modulate DQ8-restricted T-cell responses, possibly by competing
for peptides. Given that DQ8 is a primary genetic determinant of type 1 diabetes, the decreased DQ8-restricted CD4 T-cell
activity due to peptide competition may be the mechanism explaining the modulation effect of DR4 to type 1 diabetes susceptibility.
APC, antigen-presenting cell
B-LCL, B-lymphoblastoid cell line
ELISA, enzyme-linked immunosorbent assay
FITC, fluorescein isothiocyanate
hGAD65, human GAD
IFN-γ, γ-interferon
IL, interleukin
MHC, major histocompatibility complex
TCR, T-cell receptor
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 6, 2006.
Received May 16, 2006.
DIABETES</description><subject>Amino Acid Sequence</subject><subject>Analysis</subject><subject>Antigen-Presenting Cells - immunology</subject><subject>Antigens</subject><subject>Biological and medical sciences</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>Cells</subject><subject>Competition</subject><subject>Diabetes</subject><subject>Diabetes Mellitus, Type 1 - genetics</subject><subject>Diabetes Mellitus, Type 1 - immunology</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Genetic Predisposition to Disease</subject><subject>Genetic susceptibility</subject><subject>Glutamate Decarboxylase - immunology</subject><subject>Haplotypes</subject><subject>HLA-DQ Antigens - immunology</subject><subject>HLA-DR4 Antigen - immunology</subject><subject>Humans</subject><subject>Isoenzymes - immunology</subject><subject>Medical sciences</subject><subject>Molecular Sequence Data</subject><subject>Peptide Fragments - chemistry</subject><subject>Peptides</subject><subject>Transgenic animals</subject><subject>Type 1 diabetes</subject><subject>White people</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqF0l2LEzEUBuBBFLeuXvgHJAgKgrPmeyaXS6ursLJYK3gXMsmZbpZ0UpMZtP_elC2UlYLkIiE8OUkOb1W9JPiCMtZ8cB2WNZYtflTNiGKqZrT5-biaYUxoTRrVnFXPcr7DGMsynlZnpCEMc0Vnlfka3RTMGNMOLWMAFHu0WPIajREtvrV1gjwmb0dwaL7gaFXPIQS0hLyNQ4aMzODQarcFRNDCmw7Gsvd9yha2o-988OPuefWkNyHDi8N8Xv349HE1_1xf31x9mV9e11YoOtbSEdsoSlnbOBCNE1Q1joFtuWHUOiwl7TgY4njXEWdaQcBwyRvbEyi4Y-fV2_u62xR_TeXZeuPLO0IwA8Qpa9mSlklF_wuJ4qr0sinw9T_wLk5pKJ_QlJSrlaSqoPoerU0A7Yc-jsnYNQyQTIgD9L5sXxIhpBSc74tenPBlONh4e_LAuwcHihnhz7g2U866vbp-aOtT1sYQYA269Ht-c7K2TTHnBL3eJr8xaacJ1vto6X209D5axb46dGPqNuCO8pClAt4cgMnWhD6Zwfp8dC3jmAhS3Pt7d-vXt799Au0OyTkuhNCEasaFYH8B-Jbfog</recordid><startdate>20061201</startdate><enddate>20061201</enddate><creator>XINHUI GE</creator><creator>PIGANELLI, Jon D</creator><creator>TSE, Hubert M</creator><creator>BERTERA, Suzanne</creator><creator>MATHEWS, Clayton E</creator><creator>TRUCCO, Massimo</creator><creator>LI WEN</creator><creator>RUDERT, William A</creator><general>American Diabetes Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8GL</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>HCIFZ</scope><scope>K9-</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0R</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20061201</creationdate><title>Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility</title><author>XINHUI GE ; PIGANELLI, Jon D ; TSE, Hubert M ; BERTERA, Suzanne ; MATHEWS, Clayton E ; TRUCCO, Massimo ; LI WEN ; RUDERT, William A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c592t-6d1c7922387de57d5297d3ec84a32cd0662b4ea1d4bb1da851ea4647cf1ed52b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Amino Acid Sequence</topic><topic>Analysis</topic><topic>Antigen-Presenting Cells - immunology</topic><topic>Antigens</topic><topic>Biological and medical sciences</topic><topic>CD4-Positive T-Lymphocytes - immunology</topic><topic>Cells</topic><topic>Competition</topic><topic>Diabetes</topic><topic>Diabetes Mellitus, Type 1 - genetics</topic><topic>Diabetes Mellitus, Type 1 - immunology</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Genetic Predisposition to Disease</topic><topic>Genetic susceptibility</topic><topic>Glutamate Decarboxylase - immunology</topic><topic>Haplotypes</topic><topic>HLA-DQ Antigens - immunology</topic><topic>HLA-DR4 Antigen - immunology</topic><topic>Humans</topic><topic>Isoenzymes - immunology</topic><topic>Medical sciences</topic><topic>Molecular Sequence Data</topic><topic>Peptide Fragments - chemistry</topic><topic>Peptides</topic><topic>Transgenic animals</topic><topic>Type 1 diabetes</topic><topic>White people</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>XINHUI GE</creatorcontrib><creatorcontrib>PIGANELLI, Jon D</creatorcontrib><creatorcontrib>TSE, Hubert M</creatorcontrib><creatorcontrib>BERTERA, Suzanne</creatorcontrib><creatorcontrib>MATHEWS, Clayton E</creatorcontrib><creatorcontrib>TRUCCO, Massimo</creatorcontrib><creatorcontrib>LI WEN</creatorcontrib><creatorcontrib>RUDERT, William A</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: High School</collection><collection>ProQuest Central (Corporate)</collection><collection>Nursing & Allied Health Database</collection><collection>Health Medical collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>eLibrary</collection><collection>ProQuest Central</collection><collection>ProQuest Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>SciTech Premium Collection</collection><collection>Consumer Health Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Biological Sciences</collection><collection>Consumer Health Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest research library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>XINHUI GE</au><au>PIGANELLI, Jon D</au><au>TSE, Hubert M</au><au>BERTERA, Suzanne</au><au>MATHEWS, Clayton E</au><au>TRUCCO, Massimo</au><au>LI WEN</au><au>RUDERT, William A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2006-12-01</date><risdate>2006</risdate><volume>55</volume><issue>12</issue><spage>3455</spage><epage>3462</epage><pages>3455-3462</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility
Xinhui Ge 1 2 ,
Jon D. Piganelli 2 ,
Hubert M. Tse 2 ,
Suzanne Bertera 2 ,
Clayton E. Mathews 2 ,
Massimo Trucco 2 ,
Li Wen 3 and
William A. Rudert 2
1 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
2 Division of Immunogenetics, Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
3 Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Address correspondence and reprint requests to William A. Rudert, MD, PhD, Rangos Research Center, Children’s Hospital of
Pittsburgh, 3460 5th Ave., Pittsburgh, PA 15213. E-mail: war1{at}pitt.edu
Abstract
This study addressed an important biological question, namely how certain HLA molecules modulate the disease risk conferred
by other HLA molecules. The HLA molecules under investigation were HLA-DQ8 and -DR4, the two most prevalent HLA class II alleles
found in Caucasian type 1 diabetic patients. A panel of human GAD (hGAD65)-specific CD4 T-cell lines and hybridomas was generated
to serve as detection reagents for evaluating the peptide occupancy of DQ8 and DR4. Results indicated that DQ8 and DR4 (0401)
were able to bind the same hGAD65 peptides. The coexpression of DR4 (0401) diminished DQ8-restricted T-cell responses. In
addition, we also demonstrated that the diminished T-cell response varied according to the specific DRB1*04 alleles. Taken
together, this study provides evidence that DR4 is able to modulate DQ8-restricted T-cell responses, possibly by competing
for peptides. Given that DQ8 is a primary genetic determinant of type 1 diabetes, the decreased DQ8-restricted CD4 T-cell
activity due to peptide competition may be the mechanism explaining the modulation effect of DR4 to type 1 diabetes susceptibility.
APC, antigen-presenting cell
B-LCL, B-lymphoblastoid cell line
ELISA, enzyme-linked immunosorbent assay
FITC, fluorescein isothiocyanate
hGAD65, human GAD
IFN-γ, γ-interferon
IL, interleukin
MHC, major histocompatibility complex
TCR, T-cell receptor
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted September 6, 2006.
Received May 16, 2006.
DIABETES</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>17130492</pmid><doi>10.2337/db06-0680</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0012-1797 |
| ispartof | Diabetes (New York, N.Y.), 2006-12, Vol.55 (12), p.3455-3462 |
| issn | 0012-1797 1939-327X |
| language | eng |
| recordid | cdi_gale_incontextcollege_GICCO_A155665447 |
| source | MEDLINE; PubMed Central (PMC); EZB Electronic Journals Library |
| subjects | Amino Acid Sequence Analysis Antigen-Presenting Cells - immunology Antigens Biological and medical sciences CD4-Positive T-Lymphocytes - immunology Cells Competition Diabetes Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Etiopathogenesis. Screening. Investigations. Target tissue resistance Gene expression Genetic aspects Genetic Predisposition to Disease Genetic susceptibility Glutamate Decarboxylase - immunology Haplotypes HLA-DQ Antigens - immunology HLA-DR4 Antigen - immunology Humans Isoenzymes - immunology Medical sciences Molecular Sequence Data Peptide Fragments - chemistry Peptides Transgenic animals Type 1 diabetes White people |
| title | Modulatory Role of DR4- to DQ8-restricted CD4 T-Cell Responses and Type 1 Diabetes Susceptibility |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-07T14%3A53%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pasca&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Modulatory%20Role%20of%20DR4-%20to%20DQ8-restricted%20CD4%20T-Cell%20Responses%20and%20Type%201%20Diabetes%20Susceptibility&rft.jtitle=Diabetes%20(New%20York,%20N.Y.)&rft.au=XINHUI%20GE&rft.date=2006-12-01&rft.volume=55&rft.issue=12&rft.spage=3455&rft.epage=3462&rft.pages=3455-3462&rft.issn=0012-1797&rft.eissn=1939-327X&rft.coden=DIAEAZ&rft_id=info:doi/10.2337/db06-0680&rft_dat=%3Cgale_pasca%3EA155665447%3C/gale_pasca%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=216479629&rft_id=info:pmid/17130492&rft_galeid=A155665447&rfr_iscdi=true |