Maintenance of Tolerance by Regulation of Anti-myeloperoxidase B Cells

Anti-neutrophil cytoplasmic autoantibodies directed toward myeloperoxidase or proteinase 3 are detected in sera of patients with small vessel vasculitis and participate in the pathogenesis of this disease. Autoantibodies develop when self-reactive B cells escape the regulation that ensures self-tole...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Journal of the American Society of Nephrology 2008-09, Vol.19 (9), p.1763-1773
Hauptverfasser: BUNCH, Donna O, SILVER, Jonathan S, NACHMAN, Patrick H, MAJURE, Melanie C, SULLIVAN, Pamela, ALCORTA, David A, CHIN, Hyunsook, HOGAN, Susan L, LINDSTROM, Yoshi I, CLARKE, Stephen H, FALK, Ronald J
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 1773
container_issue 9
container_start_page 1763
container_title Journal of the American Society of Nephrology
container_volume 19
creator BUNCH, Donna O
SILVER, Jonathan S
NACHMAN, Patrick H
MAJURE, Melanie C
SULLIVAN, Pamela
ALCORTA, David A
CHIN, Hyunsook
HOGAN, Susan L
LINDSTROM, Yoshi I
CLARKE, Stephen H
FALK, Ronald J
description Anti-neutrophil cytoplasmic autoantibodies directed toward myeloperoxidase or proteinase 3 are detected in sera of patients with small vessel vasculitis and participate in the pathogenesis of this disease. Autoantibodies develop when self-reactive B cells escape the regulation that ensures self-tolerance. In this study, regulation of anti-myeloperoxidase B cells was examined in mice that express an anti-myeloperoxidase Vkappa1C-Jkappa5 light-chain transgene, which confers anti-myeloperoxidase specificity when combined with a variety of heavy chains. Vkappa1C-Jkappa5 transgenic mice have splenic anti-myeloperoxidase B cells but do not produce circulating anti-myeloperoxidase antibodies. Two groups of transgenic mice that differed by their relative dosage of the transgene were compared; high-copy mice had a mean relative transgene dosage of 1.92 compared with 1.02 in the low-copy mice. These mice exhibited a 90 and 60% decrease in mature follicular B cells, respectively. High-copy mice were characterized by a large population of anti-myeloperoxidase B cells, a preponderance of B-1 cells, and an increased percentage of apoptotic myeloperoxidase-binding B cells. Low-copy mice had similar changes in B cell phenotype with the exception of an expanded marginal zone population. B cells from low-copy mice but not high-copy mice produced anti-myeloperoxidase antibodies after stimulation with lipopolysaccharide. These results indicate that tolerance to myeloperoxidase is maintained by central and peripheral deletion and that some myeloperoxidase-binding B cells are positively selected into the marginal zone and B-1 B cell subsets. A defect in these regulatory pathways could result in autoimmune disease.
doi_str_mv 10.1681/ASN.2007030382
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2518447</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>69476597</sourcerecordid><originalsourceid>FETCH-LOGICAL-c418t-52f27153f76916365db45e59c298d6793448cedd4b1af97506a1eb83a75130c83</originalsourceid><addsrcrecordid>eNpVkD1PwzAQhi0E4qOwMqIssKX4286CVCoKSAUkKLPlOJdilMYlThH996S0KjDZ1j1-7-5B6JTgPpGaXA5eHvsUY4UZZpruoEMiGEsZF3i3u2MuUykVO0BHMb5jTARVah8dEC0F5lodotGD9XULta0dJKFMJqGC5ueRL5NnmC4q2_pQr0qDuvXpbAlVmEMTvnxhIyTXyRCqKh6jvdJWEU42Zw-9jm4mw7t0_HR7PxyMU8eJblNBS6q6CUslMyKZFEXOBYjM0UwXUmWMc-2gKHhObJkpgaUlkGtmlSAMO8166GqdO1_kMygc1G1jKzNv_Mw2SxOsN_8rtX8z0_BpqCCac9UFXGwCmvCxgNiamY-uW8HWEBbRyIwrKbIV2F-DrgkxNlBumxBsVupNp978qu8-nP0d7RffuO6A8w1go7NVudLs45ajWBJKGWffOZeLdA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>69476597</pqid></control><display><type>article</type><title>Maintenance of Tolerance by Regulation of Anti-myeloperoxidase B Cells</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>BUNCH, Donna O ; SILVER, Jonathan S ; NACHMAN, Patrick H ; MAJURE, Melanie C ; SULLIVAN, Pamela ; ALCORTA, David A ; CHIN, Hyunsook ; HOGAN, Susan L ; LINDSTROM, Yoshi I ; CLARKE, Stephen H ; FALK, Ronald J</creator><creatorcontrib>BUNCH, Donna O ; SILVER, Jonathan S ; NACHMAN, Patrick H ; MAJURE, Melanie C ; SULLIVAN, Pamela ; ALCORTA, David A ; CHIN, Hyunsook ; HOGAN, Susan L ; LINDSTROM, Yoshi I ; CLARKE, Stephen H ; FALK, Ronald J</creatorcontrib><description>Anti-neutrophil cytoplasmic autoantibodies directed toward myeloperoxidase or proteinase 3 are detected in sera of patients with small vessel vasculitis and participate in the pathogenesis of this disease. Autoantibodies develop when self-reactive B cells escape the regulation that ensures self-tolerance. In this study, regulation of anti-myeloperoxidase B cells was examined in mice that express an anti-myeloperoxidase Vkappa1C-Jkappa5 light-chain transgene, which confers anti-myeloperoxidase specificity when combined with a variety of heavy chains. Vkappa1C-Jkappa5 transgenic mice have splenic anti-myeloperoxidase B cells but do not produce circulating anti-myeloperoxidase antibodies. Two groups of transgenic mice that differed by their relative dosage of the transgene were compared; high-copy mice had a mean relative transgene dosage of 1.92 compared with 1.02 in the low-copy mice. These mice exhibited a 90 and 60% decrease in mature follicular B cells, respectively. High-copy mice were characterized by a large population of anti-myeloperoxidase B cells, a preponderance of B-1 cells, and an increased percentage of apoptotic myeloperoxidase-binding B cells. Low-copy mice had similar changes in B cell phenotype with the exception of an expanded marginal zone population. B cells from low-copy mice but not high-copy mice produced anti-myeloperoxidase antibodies after stimulation with lipopolysaccharide. These results indicate that tolerance to myeloperoxidase is maintained by central and peripheral deletion and that some myeloperoxidase-binding B cells are positively selected into the marginal zone and B-1 B cell subsets. A defect in these regulatory pathways could result in autoimmune disease.</description><identifier>ISSN: 1046-6673</identifier><identifier>EISSN: 1533-3450</identifier><identifier>DOI: 10.1681/ASN.2007030382</identifier><identifier>PMID: 18650487</identifier><identifier>CODEN: JASNEU</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams &amp; Wilkins</publisher><subject>Animals ; Antibodies - metabolism ; Apoptosis ; Autoimmune Diseases - metabolism ; B-Lymphocytes - immunology ; B-Lymphocytes - metabolism ; Basic Research ; Biological and medical sciences ; Bone Marrow Cells - cytology ; Cell Count ; Fundamental and applied biological sciences. Psychology ; Fundamental immunology ; Immune Tolerance ; Immunobiology ; Immunoglobulin kappa-Chains - genetics ; Immunoglobulin kappa-Chains - metabolism ; Immunological tolerance ; Medical sciences ; Mice ; Mice, Transgenic ; Nephrology. Urinary tract diseases ; Peroxidase - immunology ; Spleen - cytology</subject><ispartof>Journal of the American Society of Nephrology, 2008-09, Vol.19 (9), p.1763-1773</ispartof><rights>2008 INIST-CNRS</rights><rights>Copyright © 2008 by the American Society of Nephrology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c418t-52f27153f76916365db45e59c298d6793448cedd4b1af97506a1eb83a75130c83</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518447/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518447/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&amp;idt=20612234$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18650487$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>BUNCH, Donna O</creatorcontrib><creatorcontrib>SILVER, Jonathan S</creatorcontrib><creatorcontrib>NACHMAN, Patrick H</creatorcontrib><creatorcontrib>MAJURE, Melanie C</creatorcontrib><creatorcontrib>SULLIVAN, Pamela</creatorcontrib><creatorcontrib>ALCORTA, David A</creatorcontrib><creatorcontrib>CHIN, Hyunsook</creatorcontrib><creatorcontrib>HOGAN, Susan L</creatorcontrib><creatorcontrib>LINDSTROM, Yoshi I</creatorcontrib><creatorcontrib>CLARKE, Stephen H</creatorcontrib><creatorcontrib>FALK, Ronald J</creatorcontrib><title>Maintenance of Tolerance by Regulation of Anti-myeloperoxidase B Cells</title><title>Journal of the American Society of Nephrology</title><addtitle>J Am Soc Nephrol</addtitle><description>Anti-neutrophil cytoplasmic autoantibodies directed toward myeloperoxidase or proteinase 3 are detected in sera of patients with small vessel vasculitis and participate in the pathogenesis of this disease. Autoantibodies develop when self-reactive B cells escape the regulation that ensures self-tolerance. In this study, regulation of anti-myeloperoxidase B cells was examined in mice that express an anti-myeloperoxidase Vkappa1C-Jkappa5 light-chain transgene, which confers anti-myeloperoxidase specificity when combined with a variety of heavy chains. Vkappa1C-Jkappa5 transgenic mice have splenic anti-myeloperoxidase B cells but do not produce circulating anti-myeloperoxidase antibodies. Two groups of transgenic mice that differed by their relative dosage of the transgene were compared; high-copy mice had a mean relative transgene dosage of 1.92 compared with 1.02 in the low-copy mice. These mice exhibited a 90 and 60% decrease in mature follicular B cells, respectively. High-copy mice were characterized by a large population of anti-myeloperoxidase B cells, a preponderance of B-1 cells, and an increased percentage of apoptotic myeloperoxidase-binding B cells. Low-copy mice had similar changes in B cell phenotype with the exception of an expanded marginal zone population. B cells from low-copy mice but not high-copy mice produced anti-myeloperoxidase antibodies after stimulation with lipopolysaccharide. These results indicate that tolerance to myeloperoxidase is maintained by central and peripheral deletion and that some myeloperoxidase-binding B cells are positively selected into the marginal zone and B-1 B cell subsets. A defect in these regulatory pathways could result in autoimmune disease.</description><subject>Animals</subject><subject>Antibodies - metabolism</subject><subject>Apoptosis</subject><subject>Autoimmune Diseases - metabolism</subject><subject>B-Lymphocytes - immunology</subject><subject>B-Lymphocytes - metabolism</subject><subject>Basic Research</subject><subject>Biological and medical sciences</subject><subject>Bone Marrow Cells - cytology</subject><subject>Cell Count</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Fundamental immunology</subject><subject>Immune Tolerance</subject><subject>Immunobiology</subject><subject>Immunoglobulin kappa-Chains - genetics</subject><subject>Immunoglobulin kappa-Chains - metabolism</subject><subject>Immunological tolerance</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Peroxidase - immunology</subject><subject>Spleen - cytology</subject><issn>1046-6673</issn><issn>1533-3450</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkD1PwzAQhi0E4qOwMqIssKX4286CVCoKSAUkKLPlOJdilMYlThH996S0KjDZ1j1-7-5B6JTgPpGaXA5eHvsUY4UZZpruoEMiGEsZF3i3u2MuUykVO0BHMb5jTARVah8dEC0F5lodotGD9XULta0dJKFMJqGC5ueRL5NnmC4q2_pQr0qDuvXpbAlVmEMTvnxhIyTXyRCqKh6jvdJWEU42Zw-9jm4mw7t0_HR7PxyMU8eJblNBS6q6CUslMyKZFEXOBYjM0UwXUmWMc-2gKHhObJkpgaUlkGtmlSAMO8166GqdO1_kMygc1G1jKzNv_Mw2SxOsN_8rtX8z0_BpqCCac9UFXGwCmvCxgNiamY-uW8HWEBbRyIwrKbIV2F-DrgkxNlBumxBsVupNp978qu8-nP0d7RffuO6A8w1go7NVudLs45ajWBJKGWffOZeLdA</recordid><startdate>20080901</startdate><enddate>20080901</enddate><creator>BUNCH, Donna O</creator><creator>SILVER, Jonathan S</creator><creator>NACHMAN, Patrick H</creator><creator>MAJURE, Melanie C</creator><creator>SULLIVAN, Pamela</creator><creator>ALCORTA, David A</creator><creator>CHIN, Hyunsook</creator><creator>HOGAN, Susan L</creator><creator>LINDSTROM, Yoshi I</creator><creator>CLARKE, Stephen H</creator><creator>FALK, Ronald J</creator><general>Lippincott Williams &amp; Wilkins</general><general>American Society of Nephrology</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20080901</creationdate><title>Maintenance of Tolerance by Regulation of Anti-myeloperoxidase B Cells</title><author>BUNCH, Donna O ; SILVER, Jonathan S ; NACHMAN, Patrick H ; MAJURE, Melanie C ; SULLIVAN, Pamela ; ALCORTA, David A ; CHIN, Hyunsook ; HOGAN, Susan L ; LINDSTROM, Yoshi I ; CLARKE, Stephen H ; FALK, Ronald J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c418t-52f27153f76916365db45e59c298d6793448cedd4b1af97506a1eb83a75130c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Antibodies - metabolism</topic><topic>Apoptosis</topic><topic>Autoimmune Diseases - metabolism</topic><topic>B-Lymphocytes - immunology</topic><topic>B-Lymphocytes - metabolism</topic><topic>Basic Research</topic><topic>Biological and medical sciences</topic><topic>Bone Marrow Cells - cytology</topic><topic>Cell Count</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Fundamental immunology</topic><topic>Immune Tolerance</topic><topic>Immunobiology</topic><topic>Immunoglobulin kappa-Chains - genetics</topic><topic>Immunoglobulin kappa-Chains - metabolism</topic><topic>Immunological tolerance</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Peroxidase - immunology</topic><topic>Spleen - cytology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>BUNCH, Donna O</creatorcontrib><creatorcontrib>SILVER, Jonathan S</creatorcontrib><creatorcontrib>NACHMAN, Patrick H</creatorcontrib><creatorcontrib>MAJURE, Melanie C</creatorcontrib><creatorcontrib>SULLIVAN, Pamela</creatorcontrib><creatorcontrib>ALCORTA, David A</creatorcontrib><creatorcontrib>CHIN, Hyunsook</creatorcontrib><creatorcontrib>HOGAN, Susan L</creatorcontrib><creatorcontrib>LINDSTROM, Yoshi I</creatorcontrib><creatorcontrib>CLARKE, Stephen H</creatorcontrib><creatorcontrib>FALK, Ronald J</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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of the American Society of Nephrology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>BUNCH, Donna O</au><au>SILVER, Jonathan S</au><au>NACHMAN, Patrick H</au><au>MAJURE, Melanie C</au><au>SULLIVAN, Pamela</au><au>ALCORTA, David A</au><au>CHIN, Hyunsook</au><au>HOGAN, Susan L</au><au>LINDSTROM, Yoshi I</au><au>CLARKE, Stephen H</au><au>FALK, Ronald J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Maintenance of Tolerance by Regulation of Anti-myeloperoxidase B Cells</atitle><jtitle>Journal of the American Society of Nephrology</jtitle><addtitle>J Am Soc Nephrol</addtitle><date>2008-09-01</date><risdate>2008</risdate><volume>19</volume><issue>9</issue><spage>1763</spage><epage>1773</epage><pages>1763-1773</pages><issn>1046-6673</issn><eissn>1533-3450</eissn><coden>JASNEU</coden><abstract>Anti-neutrophil cytoplasmic autoantibodies directed toward myeloperoxidase or proteinase 3 are detected in sera of patients with small vessel vasculitis and participate in the pathogenesis of this disease. Autoantibodies develop when self-reactive B cells escape the regulation that ensures self-tolerance. In this study, regulation of anti-myeloperoxidase B cells was examined in mice that express an anti-myeloperoxidase Vkappa1C-Jkappa5 light-chain transgene, which confers anti-myeloperoxidase specificity when combined with a variety of heavy chains. Vkappa1C-Jkappa5 transgenic mice have splenic anti-myeloperoxidase B cells but do not produce circulating anti-myeloperoxidase antibodies. Two groups of transgenic mice that differed by their relative dosage of the transgene were compared; high-copy mice had a mean relative transgene dosage of 1.92 compared with 1.02 in the low-copy mice. These mice exhibited a 90 and 60% decrease in mature follicular B cells, respectively. High-copy mice were characterized by a large population of anti-myeloperoxidase B cells, a preponderance of B-1 cells, and an increased percentage of apoptotic myeloperoxidase-binding B cells. Low-copy mice had similar changes in B cell phenotype with the exception of an expanded marginal zone population. B cells from low-copy mice but not high-copy mice produced anti-myeloperoxidase antibodies after stimulation with lipopolysaccharide. These results indicate that tolerance to myeloperoxidase is maintained by central and peripheral deletion and that some myeloperoxidase-binding B cells are positively selected into the marginal zone and B-1 B cell subsets. A defect in these regulatory pathways could result in autoimmune disease.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams &amp; Wilkins</pub><pmid>18650487</pmid><doi>10.1681/ASN.2007030382</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1046-6673
ispartof Journal of the American Society of Nephrology, 2008-09, Vol.19 (9), p.1763-1773
issn 1046-6673
1533-3450
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2518447
source MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central
subjects Animals
Antibodies - metabolism
Apoptosis
Autoimmune Diseases - metabolism
B-Lymphocytes - immunology
B-Lymphocytes - metabolism
Basic Research
Biological and medical sciences
Bone Marrow Cells - cytology
Cell Count
Fundamental and applied biological sciences. Psychology
Fundamental immunology
Immune Tolerance
Immunobiology
Immunoglobulin kappa-Chains - genetics
Immunoglobulin kappa-Chains - metabolism
Immunological tolerance
Medical sciences
Mice
Mice, Transgenic
Nephrology. Urinary tract diseases
Peroxidase - immunology
Spleen - cytology
title Maintenance of Tolerance by Regulation of Anti-myeloperoxidase B Cells
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T17%3A42%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Maintenance%20of%20Tolerance%20by%20Regulation%20of%20Anti-myeloperoxidase%20B%20Cells&rft.jtitle=Journal%20of%20the%20American%20Society%20of%20Nephrology&rft.au=BUNCH,%20Donna%20O&rft.date=2008-09-01&rft.volume=19&rft.issue=9&rft.spage=1763&rft.epage=1773&rft.pages=1763-1773&rft.issn=1046-6673&rft.eissn=1533-3450&rft.coden=JASNEU&rft_id=info:doi/10.1681/ASN.2007030382&rft_dat=%3Cproquest_pubme%3E69476597%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=69476597&rft_id=info:pmid/18650487&rfr_iscdi=true