Use of Soluble Peptide-DR4 Tetramers to Detect Synovial T Cells Specific for Cartilage Antigens in Patients with Rheumatoid Arthritis
Considerable evidence indicates that CD4+T cells are important in the pathogenesis of rheumatoid arthritis (RA), but the antigens recognized by these T cells in the joints of patients remain unclear. Previous studies have suggested that type II collagen (CII) and human cartilage gp39 (HCgp39) are am...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2000-01, Vol.97 (1), p.291-296 |
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| creator | Kotzin, Brian L. Falta, Michael T. Crawford, Frances Rosloniec, Edward F. Bill, Jerry Marrack, Philippa Kappler, John |
| description | Considerable evidence indicates that CD4+T cells are important in the pathogenesis of rheumatoid arthritis (RA), but the antigens recognized by these T cells in the joints of patients remain unclear. Previous studies have suggested that type II collagen (CII) and human cartilage gp39 (HCgp39) are among the most likely synovial antigens to be involved in T cell stimulation in RA. Furthermore, experiments have defined dominant peptide determinants of these antigens when presented by HLA-DR4, the most important RA-associated HLA type. We used fluorescent, soluble peptide-DR4 complexes (tetramers) to detect synovial CD4+T cells reactive with CII and HCgp39 in DR4+patients. The CII-DR4 complex bound in a specific manner to CII peptide-reactive T cell hybridomas, but did not stain a detectable fraction of synovial CD4+cells. A background percentage of positive cells ( |
| doi_str_mv | 10.1073/pnas.97.1.291 |
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Previous studies have suggested that type II collagen (CII) and human cartilage gp39 (HCgp39) are among the most likely synovial antigens to be involved in T cell stimulation in RA. Furthermore, experiments have defined dominant peptide determinants of these antigens when presented by HLA-DR4, the most important RA-associated HLA type. We used fluorescent, soluble peptide-DR4 complexes (tetramers) to detect synovial CD4+T cells reactive with CII and HCgp39 in DR4+patients. The CII-DR4 complex bound in a specific manner to CII peptide-reactive T cell hybridomas, but did not stain a detectable fraction of synovial CD4+cells. A background percentage of positive cells (<0.2%) was not greater in DR4 (DRB1*0401) patients compared with those without this disease-associated allele. Similar results were obtained with the gp39-DR4 complex for nearly all RA patients. In a small subset of DR4+patients, however, the percentage of synovial CD4+cells binding this complex was above background and could not be attributed to nonspecific binding. These studies demonstrate the potential for peptide-MHC class II tetramers to be used to track antigen-specific T cells in human autoimmune diseases. Together, the results also suggest that the major oligoclonal CD4+T cell expansions present in RA joints are not specific for the dominant CII and HCgp39 determinants.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.97.1.291</identifier><identifier>PMID: 10618411</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Adult ; Aged ; Alleles ; Animals ; Antigens ; Antigens, CD - immunology ; Arthritis ; Arthritis, Rheumatoid - immunology ; Biological Sciences ; Cartilage ; Cartilage - immunology ; CD4-Positive T-Lymphocytes - immunology ; Collagen - immunology ; Epitopes ; Female ; Flow Cytometry ; Fluorescent Antibody Technique ; Fluorescent Dyes ; histocompatibility antigen HLA ; HLA-DR4 Antigen - immunology ; Humans ; Hybridomas ; Hybridomas - immunology ; Immunology ; Joint diseases ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Molecules ; Peptide Fragments - immunology ; Peptides ; Synovial fluid ; Synovial Fluid - cytology ; Synovial Fluid - immunology ; T cell antigen receptors ; T lymphocytes ; T-Lymphocytes - immunology</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2000-01, Vol.97 (1), p.291-296</ispartof><rights>Copyright 1993-2000 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Jan 4, 2000</rights><rights>Copyright © 2000, The National Academy of Sciences 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c510t-b99b599603285498159bf27dbdf4f1ca98844c78f02f51be2243740f9e9854e43</citedby><cites>FETCH-LOGICAL-c510t-b99b599603285498159bf27dbdf4f1ca98844c78f02f51be2243740f9e9854e43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/97/1.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/121783$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/121783$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10618411$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kotzin, Brian L.</creatorcontrib><creatorcontrib>Falta, Michael T.</creatorcontrib><creatorcontrib>Crawford, Frances</creatorcontrib><creatorcontrib>Rosloniec, Edward F.</creatorcontrib><creatorcontrib>Bill, Jerry</creatorcontrib><creatorcontrib>Marrack, Philippa</creatorcontrib><creatorcontrib>Kappler, John</creatorcontrib><title>Use of Soluble Peptide-DR4 Tetramers to Detect Synovial T Cells Specific for Cartilage Antigens in Patients with Rheumatoid Arthritis</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Considerable evidence indicates that CD4+T cells are important in the pathogenesis of rheumatoid arthritis (RA), but the antigens recognized by these T cells in the joints of patients remain unclear. Previous studies have suggested that type II collagen (CII) and human cartilage gp39 (HCgp39) are among the most likely synovial antigens to be involved in T cell stimulation in RA. Furthermore, experiments have defined dominant peptide determinants of these antigens when presented by HLA-DR4, the most important RA-associated HLA type. We used fluorescent, soluble peptide-DR4 complexes (tetramers) to detect synovial CD4+T cells reactive with CII and HCgp39 in DR4+patients. The CII-DR4 complex bound in a specific manner to CII peptide-reactive T cell hybridomas, but did not stain a detectable fraction of synovial CD4+cells. A background percentage of positive cells (<0.2%) was not greater in DR4 (DRB1*0401) patients compared with those without this disease-associated allele. Similar results were obtained with the gp39-DR4 complex for nearly all RA patients. In a small subset of DR4+patients, however, the percentage of synovial CD4+cells binding this complex was above background and could not be attributed to nonspecific binding. These studies demonstrate the potential for peptide-MHC class II tetramers to be used to track antigen-specific T cells in human autoimmune diseases. Together, the results also suggest that the major oligoclonal CD4+T cell expansions present in RA joints are not specific for the dominant CII and HCgp39 determinants.</description><subject>Adult</subject><subject>Aged</subject><subject>Alleles</subject><subject>Animals</subject><subject>Antigens</subject><subject>Antigens, CD - immunology</subject><subject>Arthritis</subject><subject>Arthritis, Rheumatoid - immunology</subject><subject>Biological Sciences</subject><subject>Cartilage</subject><subject>Cartilage - immunology</subject><subject>CD4-Positive T-Lymphocytes - immunology</subject><subject>Collagen - immunology</subject><subject>Epitopes</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Fluorescent Antibody Technique</subject><subject>Fluorescent Dyes</subject><subject>histocompatibility antigen HLA</subject><subject>HLA-DR4 Antigen - immunology</subject><subject>Humans</subject><subject>Hybridomas</subject><subject>Hybridomas - immunology</subject><subject>Immunology</subject><subject>Joint diseases</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Middle Aged</subject><subject>Molecules</subject><subject>Peptide Fragments - immunology</subject><subject>Peptides</subject><subject>Synovial fluid</subject><subject>Synovial Fluid - cytology</subject><subject>Synovial Fluid - immunology</subject><subject>T cell antigen receptors</subject><subject>T lymphocytes</subject><subject>T-Lymphocytes - immunology</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks2O0zAUhSMEYsrAkhUIWUiwS7EdJ7YlNlWHP2kkRtPO2nKS69aVEwfbGZgH4L1J1QKFBay8ON-xz70-WfaU4DnBvHgz9DrOJZ-TOZXkXjYjWJK8YhLfz2YYU54LRtlZ9ijGHcZYlgI_zM4IrohghMyy7zcRkDdo5d1YO0BXMCTbQn5xzdAaUtAdhIiSRxeQoEloddf7W6sdWqMlOBfRaoDGGtsg4wNa6pCs0xtAiz7ZDfQR2R5d6WShTxF9tWmLrrcwdjp526JFSNtgk42PswdGuwhPjud5dvP-3Xr5Mb_8_OHTcnGZNyXBKa-lrEspK1xQUTIpSClrQ3lbt4YZ0mgpBGMNFwZTU5IaKGUFZ9hIkBMPrDjP3h7uHca6g7aZUgXt1BBsp8Od8tqqP5XebtXG3ypaVWU12V8f7cF_GSEm1dnYTGvQPfgxKo4FphWn_wUJZ4UQch_o5V_gzo-hn3agKCaFYLgQE5QfoCb4GAOYX4EJVvsSqH0JlOSKqKkEE__idMoT-vDrE_D8COx9P-UT_6t_yMqMziX4libu2YHbxeTD72co4aIofgCdf86T</recordid><startdate>20000104</startdate><enddate>20000104</enddate><creator>Kotzin, Brian L.</creator><creator>Falta, Michael T.</creator><creator>Crawford, Frances</creator><creator>Rosloniec, Edward F.</creator><creator>Bill, Jerry</creator><creator>Marrack, Philippa</creator><creator>Kappler, John</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><general>The National Academy of Sciences</general><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20000104</creationdate><title>Use of Soluble Peptide-DR4 Tetramers to Detect Synovial T Cells Specific for Cartilage Antigens in Patients with Rheumatoid Arthritis</title><author>Kotzin, Brian L. ; 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Previous studies have suggested that type II collagen (CII) and human cartilage gp39 (HCgp39) are among the most likely synovial antigens to be involved in T cell stimulation in RA. Furthermore, experiments have defined dominant peptide determinants of these antigens when presented by HLA-DR4, the most important RA-associated HLA type. We used fluorescent, soluble peptide-DR4 complexes (tetramers) to detect synovial CD4+T cells reactive with CII and HCgp39 in DR4+patients. The CII-DR4 complex bound in a specific manner to CII peptide-reactive T cell hybridomas, but did not stain a detectable fraction of synovial CD4+cells. A background percentage of positive cells (<0.2%) was not greater in DR4 (DRB1*0401) patients compared with those without this disease-associated allele. Similar results were obtained with the gp39-DR4 complex for nearly all RA patients. In a small subset of DR4+patients, however, the percentage of synovial CD4+cells binding this complex was above background and could not be attributed to nonspecific binding. These studies demonstrate the potential for peptide-MHC class II tetramers to be used to track antigen-specific T cells in human autoimmune diseases. Together, the results also suggest that the major oligoclonal CD4+T cell expansions present in RA joints are not specific for the dominant CII and HCgp39 determinants.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>10618411</pmid><doi>10.1073/pnas.97.1.291</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adult Aged Alleles Animals Antigens Antigens, CD - immunology Arthritis Arthritis, Rheumatoid - immunology Biological Sciences Cartilage Cartilage - immunology CD4-Positive T-Lymphocytes - immunology Collagen - immunology Epitopes Female Flow Cytometry Fluorescent Antibody Technique Fluorescent Dyes histocompatibility antigen HLA HLA-DR4 Antigen - immunology Humans Hybridomas Hybridomas - immunology Immunology Joint diseases Male Mice Mice, Transgenic Middle Aged Molecules Peptide Fragments - immunology Peptides Synovial fluid Synovial Fluid - cytology Synovial Fluid - immunology T cell antigen receptors T lymphocytes T-Lymphocytes - immunology |
| title | Use of Soluble Peptide-DR4 Tetramers to Detect Synovial T Cells Specific for Cartilage Antigens in Patients with Rheumatoid Arthritis |
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