Neutrophils from ANCA-associated vasculitis patients show an increased capacity to activate the complement system via the alternative pathway after ANCA stimulation
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), are autoimmune conditions associated with small vessel inflammation. Earlier studies indicate that complement activation via the alternative...
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| Veröffentlicht in: | PloS one 2019-06, Vol.14 (6), p.e0218272-e0218272 |
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| creator | Ohlsson, Sophie Holm, Lisa Hansson, Christina Ohlsson, Susanne M Gunnarsson, Lena Pettersson, Åsa Skattum, Lillemor |
| description | Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), are autoimmune conditions associated with small vessel inflammation. Earlier studies indicate that complement activation via the alternative pathway plays a major role in the pathogenesis. In this study we have investigated if ANCA-activation of neutrophils from AAV patients leads to activation of the alternative complement pathway. C5a-primed neutrophils (PMN) from 10 AAV patients and 10 healthy controls (HC) were stimulated with PMA or IgG purified from PR3-ANCA positive patients (ANCA IgG). The supernatants were analyzed for release of complement proteins and markers of different granules by ELISA, and release of microparticles (MP) by flow cytometry. The ability of the supernatants to activate the alternative complement pathway was determined by incubation with normal serum and C3bBbP and C5a were measured by ELISA. MP were analyzed by flow cytometry and removed by centrifugation. The supernatants from the AAV patients' neutrophils produced significantly more C3bBbP compared with HCs (p = 0.0001). C3bBbP levels correlated with the number of MP. After removal of MP from the supernatants, alternative pathway activation was significantly lower. This study shows that primed and ANCA-stimulated neutrophils from AAV patients have a greater ability to activate the alternative complement pathway compared to primed neutrophils from healthy controls. This finding emphasizes the role of complement in the pathogenesis of AAV - underlining the therapeutic potential of C5a and other complement blockade. |
| doi_str_mv | 10.1371/journal.pone.0218272 |
| format | Article |
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Earlier studies indicate that complement activation via the alternative pathway plays a major role in the pathogenesis. In this study we have investigated if ANCA-activation of neutrophils from AAV patients leads to activation of the alternative complement pathway. C5a-primed neutrophils (PMN) from 10 AAV patients and 10 healthy controls (HC) were stimulated with PMA or IgG purified from PR3-ANCA positive patients (ANCA IgG). The supernatants were analyzed for release of complement proteins and markers of different granules by ELISA, and release of microparticles (MP) by flow cytometry. The ability of the supernatants to activate the alternative complement pathway was determined by incubation with normal serum and C3bBbP and C5a were measured by ELISA. MP were analyzed by flow cytometry and removed by centrifugation. The supernatants from the AAV patients' neutrophils produced significantly more C3bBbP compared with HCs (p = 0.0001). C3bBbP levels correlated with the number of MP. After removal of MP from the supernatants, alternative pathway activation was significantly lower. This study shows that primed and ANCA-stimulated neutrophils from AAV patients have a greater ability to activate the alternative complement pathway compared to primed neutrophils from healthy controls. This finding emphasizes the role of complement in the pathogenesis of AAV - underlining the therapeutic potential of C5a and other complement blockade.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0218272</identifier><identifier>PMID: 31216309</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation analysis ; Aged ; Alternative pathway ; Animals ; Annan klinisk medicin ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - blood ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - immunology ; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - pathology ; Antibodies ; Antibodies, Antineutrophil Cytoplasmic - immunology ; Antineutrophil cytoplasmic antibodies ; Arthritis ; Biology and Life Sciences ; Blood vessels ; Cell activation ; Centrifugation ; Clinical Medicine ; Complement ; Complement activation ; Complement Activation - drug effects ; Complement Activation - immunology ; Complement C5a - immunology ; Complement component C5a ; Disease ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow cytometry ; Genetic aspects ; Granulomatosis ; Granulomatosis with Polyangiitis - blood ; Granulomatosis with Polyangiitis - immunology ; Granulomatosis with Polyangiitis - pathology ; Humans ; Immunoglobulin G ; Immunoglobulin G - administration & dosage ; Immunoglobulin G - immunology ; Immunology ; Inflammation ; Inflammation - blood ; Inflammation - immunology ; Inflammation - pathology ; Kinases ; Klinisk medicin ; Laboratories ; Leukocytes (neutrophilic) ; Male ; Medical and Health Sciences ; Medical research ; Medicin och hälsovetenskap ; Medicine ; Medicine and Health Sciences ; Microparticles ; Microscopic Polyangiitis - blood ; Microscopic Polyangiitis - immunology ; Microscopic Polyangiitis - pathology ; Nephrology ; Neutrophils ; Neutrophils - immunology ; Neutrophils - pathology ; Other Clinical Medicine ; Pathogenesis ; Proteins ; Research and Analysis Methods ; Rheumatology ; Risk factors ; Somatotropin ; Vasculitis</subject><ispartof>PloS one, 2019-06, Vol.14 (6), p.e0218272-e0218272</ispartof><rights>COPYRIGHT 2019 Public Library of Science</rights><rights>2019 Ohlsson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2019 Ohlsson et al 2019 Ohlsson et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c827t-22886ac20b95ffb76c0baabf303f02fc246c47629096288a445805120320bd283</citedby><cites>FETCH-LOGICAL-c827t-22886ac20b95ffb76c0baabf303f02fc246c47629096288a445805120320bd283</cites><orcidid>0000-0002-5253-1650 ; 0000-0002-5636-6592</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583988/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583988/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,552,727,780,784,864,885,2100,2926,23865,27923,27924,53790,53792,79371,79372</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31216309$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/85ae491a-a04d-4bc2-ad37-b0698cff9cd3$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><contributor>Palaniyar, Nades</contributor><creatorcontrib>Ohlsson, Sophie</creatorcontrib><creatorcontrib>Holm, Lisa</creatorcontrib><creatorcontrib>Hansson, Christina</creatorcontrib><creatorcontrib>Ohlsson, Susanne M</creatorcontrib><creatorcontrib>Gunnarsson, Lena</creatorcontrib><creatorcontrib>Pettersson, Åsa</creatorcontrib><creatorcontrib>Skattum, Lillemor</creatorcontrib><title>Neutrophils from ANCA-associated vasculitis patients show an increased capacity to activate the complement system via the alternative pathway after ANCA stimulation</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), are autoimmune conditions associated with small vessel inflammation. Earlier studies indicate that complement activation via the alternative pathway plays a major role in the pathogenesis. In this study we have investigated if ANCA-activation of neutrophils from AAV patients leads to activation of the alternative complement pathway. C5a-primed neutrophils (PMN) from 10 AAV patients and 10 healthy controls (HC) were stimulated with PMA or IgG purified from PR3-ANCA positive patients (ANCA IgG). The supernatants were analyzed for release of complement proteins and markers of different granules by ELISA, and release of microparticles (MP) by flow cytometry. The ability of the supernatants to activate the alternative complement pathway was determined by incubation with normal serum and C3bBbP and C5a were measured by ELISA. MP were analyzed by flow cytometry and removed by centrifugation. The supernatants from the AAV patients' neutrophils produced significantly more C3bBbP compared with HCs (p = 0.0001). C3bBbP levels correlated with the number of MP. After removal of MP from the supernatants, alternative pathway activation was significantly lower. This study shows that primed and ANCA-stimulated neutrophils from AAV patients have a greater ability to activate the alternative complement pathway compared to primed neutrophils from healthy controls. This finding emphasizes the role of complement in the pathogenesis of AAV - underlining the therapeutic potential of C5a and other complement blockade.</description><subject>Activation analysis</subject><subject>Aged</subject><subject>Alternative pathway</subject><subject>Animals</subject><subject>Annan klinisk medicin</subject><subject>Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - blood</subject><subject>Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - immunology</subject><subject>Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - pathology</subject><subject>Antibodies</subject><subject>Antibodies, Antineutrophil Cytoplasmic - immunology</subject><subject>Antineutrophil cytoplasmic antibodies</subject><subject>Arthritis</subject><subject>Biology and Life Sciences</subject><subject>Blood vessels</subject><subject>Cell activation</subject><subject>Centrifugation</subject><subject>Clinical Medicine</subject><subject>Complement</subject><subject>Complement activation</subject><subject>Complement Activation - drug effects</subject><subject>Complement Activation - immunology</subject><subject>Complement C5a - immunology</subject><subject>Complement component C5a</subject><subject>Disease</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Female</subject><subject>Flow cytometry</subject><subject>Genetic aspects</subject><subject>Granulomatosis</subject><subject>Granulomatosis with Polyangiitis - blood</subject><subject>Granulomatosis with Polyangiitis - immunology</subject><subject>Granulomatosis with Polyangiitis - pathology</subject><subject>Humans</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulin G - administration & dosage</subject><subject>Immunoglobulin G - immunology</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Inflammation - blood</subject><subject>Inflammation - immunology</subject><subject>Inflammation - pathology</subject><subject>Kinases</subject><subject>Klinisk medicin</subject><subject>Laboratories</subject><subject>Leukocytes (neutrophilic)</subject><subject>Male</subject><subject>Medical and Health Sciences</subject><subject>Medical research</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Microparticles</subject><subject>Microscopic Polyangiitis - blood</subject><subject>Microscopic Polyangiitis - immunology</subject><subject>Microscopic Polyangiitis - pathology</subject><subject>Nephrology</subject><subject>Neutrophils</subject><subject>Neutrophils - immunology</subject><subject>Neutrophils - pathology</subject><subject>Other Clinical Medicine</subject><subject>Pathogenesis</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Rheumatology</subject><subject>Risk factors</subject><subject>Somatotropin</subject><subject>Vasculitis</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>D8T</sourceid><sourceid>DOA</sourceid><recordid>eNqNk81q3DAUhU1padK0b1BaQaG0i5nKkizbm8IQ-hMICfRvK65laawgW44lTzrv0wetPDMJccmiGGFz9Z0j6Vg3SV6meJnSPP1w5cahA7vsXaeWmKQFycmj5DgtKVlwgunje99HyTPvrzDOaMH50-SIpiTlFJfHyZ8LNYbB9Y2xHunBtWh1cbpagPdOGgiqRhvwcrQmGI96CEZ1wSPfuBsEHTKdHBT4SEnoQZqwRcEhkMFsohaFRiHp2t6qNsqQ3_qgWrQxsJsBG1Q8QWTV5NzcwBaBjrXdFpAPph1tnHbd8-SJBuvVi8P7JPn5-dOP06-L88svZ6er84WMhw8LQoqCgyS4KjOtq5xLXAFUmmKqMdGSMC5ZzkmJSx5RYCwrcJbGfKKkJgU9SV7vfXvrvDgE7AUhjDLOOGaRONsTtYMr0Q-mhWErHBixK7hhLWAIRlolJM0zKWXJsa6YJnXFMfCq0AXRcXMVj17ney9_o_qxmrnZsY-jikN4JYoMFCtTEIBZLVgliYCa5qLCvCyk1qWsabT7eNj8WLWqljHxAezMdT7TmUas3UbwrKBlMZ3-3cFgcNej8kG0xktlLXTKjbsYWEpplk1rvfkHfTisA7WGmIfptIvryslUrLKizBnLSRap5QNUfGrVGhkvtzaxPhO8nwkiE9TvsIbRe3H2_dv_s5e_5uzbe2yj4v1svLPjdAP9HGR7UA7O-0Hpu5BTLKbevE1DTL0pDr0ZZa_u_6A70W0z0r9kWje8</recordid><startdate>20190619</startdate><enddate>20190619</enddate><creator>Ohlsson, Sophie</creator><creator>Holm, Lisa</creator><creator>Hansson, Christina</creator><creator>Ohlsson, Susanne M</creator><creator>Gunnarsson, Lena</creator><creator>Pettersson, Åsa</creator><creator>Skattum, Lillemor</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>ADTPV</scope><scope>AGCHP</scope><scope>AOWAS</scope><scope>D8T</scope><scope>D95</scope><scope>ZZAVC</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-5253-1650</orcidid><orcidid>https://orcid.org/0000-0002-5636-6592</orcidid></search><sort><creationdate>20190619</creationdate><title>Neutrophils from ANCA-associated vasculitis patients show an increased capacity to activate the complement system via the alternative pathway after ANCA stimulation</title><author>Ohlsson, Sophie ; Holm, Lisa ; Hansson, Christina ; Ohlsson, Susanne M ; Gunnarsson, Lena ; Pettersson, Åsa ; Skattum, Lillemor</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c827t-22886ac20b95ffb76c0baabf303f02fc246c47629096288a445805120320bd283</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Activation analysis</topic><topic>Aged</topic><topic>Alternative pathway</topic><topic>Animals</topic><topic>Annan klinisk medicin</topic><topic>Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - blood</topic><topic>Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - immunology</topic><topic>Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - pathology</topic><topic>Antibodies</topic><topic>Antibodies, Antineutrophil Cytoplasmic - immunology</topic><topic>Antineutrophil cytoplasmic antibodies</topic><topic>Arthritis</topic><topic>Biology and Life Sciences</topic><topic>Blood vessels</topic><topic>Cell activation</topic><topic>Centrifugation</topic><topic>Clinical Medicine</topic><topic>Complement</topic><topic>Complement activation</topic><topic>Complement Activation - drug effects</topic><topic>Complement Activation - immunology</topic><topic>Complement C5a - immunology</topic><topic>Complement component C5a</topic><topic>Disease</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Female</topic><topic>Flow cytometry</topic><topic>Genetic aspects</topic><topic>Granulomatosis</topic><topic>Granulomatosis with Polyangiitis - blood</topic><topic>Granulomatosis with Polyangiitis - 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pathology</topic><topic>Other Clinical Medicine</topic><topic>Pathogenesis</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>Rheumatology</topic><topic>Risk factors</topic><topic>Somatotropin</topic><topic>Vasculitis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ohlsson, Sophie</creatorcontrib><creatorcontrib>Holm, Lisa</creatorcontrib><creatorcontrib>Hansson, Christina</creatorcontrib><creatorcontrib>Ohlsson, Susanne M</creatorcontrib><creatorcontrib>Gunnarsson, Lena</creatorcontrib><creatorcontrib>Pettersson, Åsa</creatorcontrib><creatorcontrib>Skattum, Lillemor</creatorcontrib><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: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology 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>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>SwePub</collection><collection>SWEPUB Lunds universitet full text</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Lunds universitet</collection><collection>SwePub Articles full text</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ohlsson, Sophie</au><au>Holm, Lisa</au><au>Hansson, Christina</au><au>Ohlsson, Susanne M</au><au>Gunnarsson, Lena</au><au>Pettersson, Åsa</au><au>Skattum, Lillemor</au><au>Palaniyar, Nades</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Neutrophils from ANCA-associated vasculitis patients show an increased capacity to activate the complement system via the alternative pathway after ANCA stimulation</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2019-06-19</date><risdate>2019</risdate><volume>14</volume><issue>6</issue><spage>e0218272</spage><epage>e0218272</epage><pages>e0218272-e0218272</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), are autoimmune conditions associated with small vessel inflammation. Earlier studies indicate that complement activation via the alternative pathway plays a major role in the pathogenesis. In this study we have investigated if ANCA-activation of neutrophils from AAV patients leads to activation of the alternative complement pathway. C5a-primed neutrophils (PMN) from 10 AAV patients and 10 healthy controls (HC) were stimulated with PMA or IgG purified from PR3-ANCA positive patients (ANCA IgG). The supernatants were analyzed for release of complement proteins and markers of different granules by ELISA, and release of microparticles (MP) by flow cytometry. The ability of the supernatants to activate the alternative complement pathway was determined by incubation with normal serum and C3bBbP and C5a were measured by ELISA. MP were analyzed by flow cytometry and removed by centrifugation. The supernatants from the AAV patients' neutrophils produced significantly more C3bBbP compared with HCs (p = 0.0001). C3bBbP levels correlated with the number of MP. After removal of MP from the supernatants, alternative pathway activation was significantly lower. This study shows that primed and ANCA-stimulated neutrophils from AAV patients have a greater ability to activate the alternative complement pathway compared to primed neutrophils from healthy controls. This finding emphasizes the role of complement in the pathogenesis of AAV - underlining the therapeutic potential of C5a and other complement blockade.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>31216309</pmid><doi>10.1371/journal.pone.0218272</doi><tpages>e0218272</tpages><orcidid>https://orcid.org/0000-0002-5253-1650</orcidid><orcidid>https://orcid.org/0000-0002-5636-6592</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2019-06, Vol.14 (6), p.e0218272-e0218272 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2243464604 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; SWEPUB Freely available online; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation analysis Aged Alternative pathway Animals Annan klinisk medicin Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - blood Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - immunology Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - pathology Antibodies Antibodies, Antineutrophil Cytoplasmic - immunology Antineutrophil cytoplasmic antibodies Arthritis Biology and Life Sciences Blood vessels Cell activation Centrifugation Clinical Medicine Complement Complement activation Complement Activation - drug effects Complement Activation - immunology Complement C5a - immunology Complement component C5a Disease Enzyme-Linked Immunosorbent Assay Female Flow cytometry Genetic aspects Granulomatosis Granulomatosis with Polyangiitis - blood Granulomatosis with Polyangiitis - immunology Granulomatosis with Polyangiitis - pathology Humans Immunoglobulin G Immunoglobulin G - administration & dosage Immunoglobulin G - immunology Immunology Inflammation Inflammation - blood Inflammation - immunology Inflammation - pathology Kinases Klinisk medicin Laboratories Leukocytes (neutrophilic) Male Medical and Health Sciences Medical research Medicin och hälsovetenskap Medicine Medicine and Health Sciences Microparticles Microscopic Polyangiitis - blood Microscopic Polyangiitis - immunology Microscopic Polyangiitis - pathology Nephrology Neutrophils Neutrophils - immunology Neutrophils - pathology Other Clinical Medicine Pathogenesis Proteins Research and Analysis Methods Rheumatology Risk factors Somatotropin Vasculitis |
| title | Neutrophils from ANCA-associated vasculitis patients show an increased capacity to activate the complement system via the alternative pathway after ANCA stimulation |
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