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High Affinity Presentation of an Autoantigenic Peptide in Type I Diabetes by an HLA Class II Protein Encoded in a Haplotype Protecting From Disease
Polymorphism of the genes coding for the human histocompatibility leukocyte antigen class II DR and DQ molecules makes the single largest genetic contribution to the risk of developing insulin-dependent diabetes mellitus (IDDM) and can be associated with highly elevated as well as decreased disease...
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Published in: | Journal of autoimmunity 1997-08, Vol.10 (4), p.375-386 |
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container_title | Journal of autoimmunity |
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creator | Bach, Jean-Marie Otto, Heike Nepom, Gerald T. Jung, Günther Cohen, Hélène Timsit, José Boitard, Christian van Endert, Peter M. |
description | Polymorphism of the genes coding for the human histocompatibility leukocyte antigen class II DR and DQ molecules makes the single largest genetic contribution to the risk of developing insulin-dependent diabetes mellitus (IDDM) and can be associated with highly elevated as well as decreased disease frequency. The mechanism of IDDM risk modification by HLA polymorphism is likely to involve differential presentation of autoantigenic peptides by HLA class II proteins. We have generated T cell lines (TCL) with specificity for the IDDM autoantigen 65kDa glutamic acid decarboxylase (GAD65) from lymphocytes of two patients carrying HLA class II alleles associated with distinct risk of IDDM (DRB1*0101/0401 and 1302/1501). For both patients, TCL generated at various time points all recognized single epitopes mapped as GAD 88–99 and 248–257, respectively. These epitopes are presented by the DRB1*0101 and DRB5*0101, HLA class II molecules associated with a moderately elevated risk of IDDM, or carried in a strongly protective haplotype, respectively. In an HLA/peptide binding assay, epitope GAD 248–257 was shown to possess high affinity for DRB5*0101. This epitope overlaps with a central GAD peptide binding to the high risk allele DQB1*0302 and containing a Coxsackie P2C-identical mimicry sequence, raising the possibility of competition of DRB5*0101 and DQB1*0302 for binding of a central GAD65 fragment. |
doi_str_mv | 10.1006/jaut.1997.0143 |
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The mechanism of IDDM risk modification by HLA polymorphism is likely to involve differential presentation of autoantigenic peptides by HLA class II proteins. We have generated T cell lines (TCL) with specificity for the IDDM autoantigen 65kDa glutamic acid decarboxylase (GAD65) from lymphocytes of two patients carrying HLA class II alleles associated with distinct risk of IDDM (DRB1*0101/0401 and 1302/1501). For both patients, TCL generated at various time points all recognized single epitopes mapped as GAD 88–99 and 248–257, respectively. These epitopes are presented by the DRB1*0101 and DRB5*0101, HLA class II molecules associated with a moderately elevated risk of IDDM, or carried in a strongly protective haplotype, respectively. In an HLA/peptide binding assay, epitope GAD 248–257 was shown to possess high affinity for DRB5*0101. This epitope overlaps with a central GAD peptide binding to the high risk allele DQB1*0302 and containing a Coxsackie P2C-identical mimicry sequence, raising the possibility of competition of DRB5*0101 and DQB1*0302 for binding of a central GAD65 fragment.</description><identifier>ISSN: 0896-8411</identifier><identifier>EISSN: 1095-9157</identifier><identifier>DOI: 10.1006/jaut.1997.0143</identifier><identifier>PMID: 9237801</identifier><language>eng</language><publisher>London: Elsevier Ltd</publisher><subject>Adult ; Amino Acid Sequence ; Antigen Presentation ; Autoantigens - genetics ; Autoantigens - metabolism ; Biological and medical sciences ; Cell Line ; Diabetes Mellitus, Type 1 - enzymology ; Diabetes Mellitus, Type 1 - genetics ; Diabetes Mellitus, Type 1 - immunology ; Diabetes. Impaired glucose tolerance ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Epitope Mapping ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Glutamate Decarboxylase - genetics ; Glutamate Decarboxylase - immunology ; glutamic acid decarboxylase ; Haplotypes ; Histocompatibility Antigens Class II - genetics ; Histocompatibility Antigens Class II - metabolism ; HLA class II presentation ; HLA-DR Antigens - genetics ; HLA-DR Antigens - metabolism ; Humans ; insulin-dependent diabetes mellitus ; Male ; Medical sciences ; Middle Aged ; Molecular Sequence Data ; Peptides - immunology ; Polymorphism, Genetic ; Protein Binding ; T cell epitopes ; T-Lymphocytes, Cytotoxic - immunology</subject><ispartof>Journal of autoimmunity, 1997-08, Vol.10 (4), p.375-386</ispartof><rights>1997 Academic Press</rights><rights>1997 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c399t-1fa4ab5266b732ff67ed3cc3c5e1db30170e245ad5f37b0345d3d79407433eb3</citedby><cites>FETCH-LOGICAL-c399t-1fa4ab5266b732ff67ed3cc3c5e1db30170e245ad5f37b0345d3d79407433eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2773080$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9237801$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bach, Jean-Marie</creatorcontrib><creatorcontrib>Otto, Heike</creatorcontrib><creatorcontrib>Nepom, Gerald T.</creatorcontrib><creatorcontrib>Jung, Günther</creatorcontrib><creatorcontrib>Cohen, Hélène</creatorcontrib><creatorcontrib>Timsit, José</creatorcontrib><creatorcontrib>Boitard, Christian</creatorcontrib><creatorcontrib>van Endert, Peter M.</creatorcontrib><title>High Affinity Presentation of an Autoantigenic Peptide in Type I Diabetes by an HLA Class II Protein Encoded in a Haplotype Protecting From Disease</title><title>Journal of autoimmunity</title><addtitle>J Autoimmun</addtitle><description>Polymorphism of the genes coding for the human histocompatibility leukocyte antigen class II DR and DQ molecules makes the single largest genetic contribution to the risk of developing insulin-dependent diabetes mellitus (IDDM) and can be associated with highly elevated as well as decreased disease frequency. The mechanism of IDDM risk modification by HLA polymorphism is likely to involve differential presentation of autoantigenic peptides by HLA class II proteins. We have generated T cell lines (TCL) with specificity for the IDDM autoantigen 65kDa glutamic acid decarboxylase (GAD65) from lymphocytes of two patients carrying HLA class II alleles associated with distinct risk of IDDM (DRB1*0101/0401 and 1302/1501). For both patients, TCL generated at various time points all recognized single epitopes mapped as GAD 88–99 and 248–257, respectively. These epitopes are presented by the DRB1*0101 and DRB5*0101, HLA class II molecules associated with a moderately elevated risk of IDDM, or carried in a strongly protective haplotype, respectively. In an HLA/peptide binding assay, epitope GAD 248–257 was shown to possess high affinity for DRB5*0101. This epitope overlaps with a central GAD peptide binding to the high risk allele DQB1*0302 and containing a Coxsackie P2C-identical mimicry sequence, raising the possibility of competition of DRB5*0101 and DQB1*0302 for binding of a central GAD65 fragment.</description><subject>Adult</subject><subject>Amino Acid Sequence</subject><subject>Antigen Presentation</subject><subject>Autoantigens - genetics</subject><subject>Autoantigens - metabolism</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Diabetes Mellitus, Type 1 - enzymology</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>Epitope Mapping</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Glutamate Decarboxylase - genetics</subject><subject>Glutamate Decarboxylase - immunology</subject><subject>glutamic acid decarboxylase</subject><subject>Haplotypes</subject><subject>Histocompatibility Antigens Class II - genetics</subject><subject>Histocompatibility Antigens Class II - metabolism</subject><subject>HLA class II presentation</subject><subject>HLA-DR Antigens - genetics</subject><subject>HLA-DR Antigens - metabolism</subject><subject>Humans</subject><subject>insulin-dependent diabetes mellitus</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Molecular Sequence Data</subject><subject>Peptides - immunology</subject><subject>Polymorphism, Genetic</subject><subject>Protein Binding</subject><subject>T cell epitopes</subject><subject>T-Lymphocytes, Cytotoxic - immunology</subject><issn>0896-8411</issn><issn>1095-9157</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1997</creationdate><recordtype>article</recordtype><recordid>eNqFkTFv2zAUhIWiReqkXbsV4FB0k0uKpGiNhpvEBgw0g3eCIh9dBjKpklQB_4784VK1ka3o9Ib77vBwV1WfCF4SjNtvz2rKS9J1YokJo2-qBcEdrzvCxdtqgVddW68YIe-r25SeMSaEc35T3XQNFStMFtXL1h1_orW1zrt8Rk8REvissgseBYuUR-spB-WzO4J3Gj3BmJ0B5Dw6nEdAO_TdqR4yJNSfZ3y7X6PNoFJCu12JCxkKeu91MGBml0JbNQ4hz-a_ss7OH9FDDKcSlUAl-FC9s2pI8PF676rDw_1hs633Px53m_W-1rTrck2sYqrnTdv2gjbWtgIM1ZpqDsT0FBOBoWFcGW6p6DFl3FAjOoYFoxR6eld9vcSOMfyaIGV5cknDMCgPYUpSlBJZaey_IGkJaRkTBVxeQB1DShGsHKM7qXiWBMt5LTmvJee15LxWMXy-Jk_9Ccwrfp2n6F-uukpaDTYqr116xRohKF7hgq0uGJS2fjuIMmkHXoNxsfQrTXD_-uAPL16wcw</recordid><startdate>19970801</startdate><enddate>19970801</enddate><creator>Bach, Jean-Marie</creator><creator>Otto, Heike</creator><creator>Nepom, Gerald T.</creator><creator>Jung, Günther</creator><creator>Cohen, Hélène</creator><creator>Timsit, José</creator><creator>Boitard, Christian</creator><creator>van Endert, Peter M.</creator><general>Elsevier Ltd</general><general>Elsevier</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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>19970801</creationdate><title>High Affinity Presentation of an Autoantigenic Peptide in Type I Diabetes by an HLA Class II Protein Encoded in a Haplotype Protecting From Disease</title><author>Bach, Jean-Marie ; Otto, Heike ; Nepom, Gerald T. ; Jung, Günther ; Cohen, Hélène ; Timsit, José ; Boitard, Christian ; van Endert, Peter M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c399t-1fa4ab5266b732ff67ed3cc3c5e1db30170e245ad5f37b0345d3d79407433eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1997</creationdate><topic>Adult</topic><topic>Amino Acid Sequence</topic><topic>Antigen Presentation</topic><topic>Autoantigens - genetics</topic><topic>Autoantigens - metabolism</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Diabetes Mellitus, Type 1 - enzymology</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>Epitope Mapping</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Glutamate Decarboxylase - genetics</topic><topic>Glutamate Decarboxylase - immunology</topic><topic>glutamic acid decarboxylase</topic><topic>Haplotypes</topic><topic>Histocompatibility Antigens Class II - genetics</topic><topic>Histocompatibility Antigens Class II - metabolism</topic><topic>HLA class II presentation</topic><topic>HLA-DR Antigens - genetics</topic><topic>HLA-DR Antigens - metabolism</topic><topic>Humans</topic><topic>insulin-dependent diabetes mellitus</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Molecular Sequence Data</topic><topic>Peptides - immunology</topic><topic>Polymorphism, Genetic</topic><topic>Protein Binding</topic><topic>T cell epitopes</topic><topic>T-Lymphocytes, Cytotoxic - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bach, Jean-Marie</creatorcontrib><creatorcontrib>Otto, Heike</creatorcontrib><creatorcontrib>Nepom, Gerald T.</creatorcontrib><creatorcontrib>Jung, Günther</creatorcontrib><creatorcontrib>Cohen, Hélène</creatorcontrib><creatorcontrib>Timsit, José</creatorcontrib><creatorcontrib>Boitard, Christian</creatorcontrib><creatorcontrib>van Endert, Peter M.</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>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of autoimmunity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bach, Jean-Marie</au><au>Otto, Heike</au><au>Nepom, Gerald T.</au><au>Jung, Günther</au><au>Cohen, Hélène</au><au>Timsit, José</au><au>Boitard, Christian</au><au>van Endert, Peter M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>High Affinity Presentation of an Autoantigenic Peptide in Type I Diabetes by an HLA Class II Protein Encoded in a Haplotype Protecting From Disease</atitle><jtitle>Journal of autoimmunity</jtitle><addtitle>J Autoimmun</addtitle><date>1997-08-01</date><risdate>1997</risdate><volume>10</volume><issue>4</issue><spage>375</spage><epage>386</epage><pages>375-386</pages><issn>0896-8411</issn><eissn>1095-9157</eissn><abstract>Polymorphism of the genes coding for the human histocompatibility leukocyte antigen class II DR and DQ molecules makes the single largest genetic contribution to the risk of developing insulin-dependent diabetes mellitus (IDDM) and can be associated with highly elevated as well as decreased disease frequency. The mechanism of IDDM risk modification by HLA polymorphism is likely to involve differential presentation of autoantigenic peptides by HLA class II proteins. We have generated T cell lines (TCL) with specificity for the IDDM autoantigen 65kDa glutamic acid decarboxylase (GAD65) from lymphocytes of two patients carrying HLA class II alleles associated with distinct risk of IDDM (DRB1*0101/0401 and 1302/1501). For both patients, TCL generated at various time points all recognized single epitopes mapped as GAD 88–99 and 248–257, respectively. These epitopes are presented by the DRB1*0101 and DRB5*0101, HLA class II molecules associated with a moderately elevated risk of IDDM, or carried in a strongly protective haplotype, respectively. In an HLA/peptide binding assay, epitope GAD 248–257 was shown to possess high affinity for DRB5*0101. This epitope overlaps with a central GAD peptide binding to the high risk allele DQB1*0302 and containing a Coxsackie P2C-identical mimicry sequence, raising the possibility of competition of DRB5*0101 and DQB1*0302 for binding of a central GAD65 fragment.</abstract><cop>London</cop><pub>Elsevier Ltd</pub><pmid>9237801</pmid><doi>10.1006/jaut.1997.0143</doi><tpages>12</tpages></addata></record> |
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subjects | Adult Amino Acid Sequence Antigen Presentation Autoantigens - genetics Autoantigens - metabolism Biological and medical sciences Cell Line Diabetes Mellitus, Type 1 - enzymology Diabetes Mellitus, Type 1 - genetics Diabetes Mellitus, Type 1 - immunology Diabetes. Impaired glucose tolerance Endocrine pancreas. Apud cells (diseases) Endocrinopathies Epitope Mapping Etiopathogenesis. Screening. Investigations. Target tissue resistance Glutamate Decarboxylase - genetics Glutamate Decarboxylase - immunology glutamic acid decarboxylase Haplotypes Histocompatibility Antigens Class II - genetics Histocompatibility Antigens Class II - metabolism HLA class II presentation HLA-DR Antigens - genetics HLA-DR Antigens - metabolism Humans insulin-dependent diabetes mellitus Male Medical sciences Middle Aged Molecular Sequence Data Peptides - immunology Polymorphism, Genetic Protein Binding T cell epitopes T-Lymphocytes, Cytotoxic - immunology |
title | High Affinity Presentation of an Autoantigenic Peptide in Type I Diabetes by an HLA Class II Protein Encoded in a Haplotype Protecting From Disease |
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