The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity
Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic...
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| Veröffentlicht in: | The Journal of clinical investigation 2018-09, Vol.128 (9), p.4057-4073 |
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| creator | Swystun, Laura L Lai, Jesse D Notley, Colleen Georgescu, Ilinca Paine, A Simonne Mewburn, Jeff Nesbitt, Kate Schledzewski, Kai Géraud, Cyrill Kzhyshkowska, Julia Goerdt, Sergij Hopman, Wilma Montgomery, Robert R James, Paula D Lillicrap, David |
| description | Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates. |
| doi_str_mv | 10.1172/jci96400 |
| format | Article |
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Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/jci96400</identifier><identifier>PMID: 30124466</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Adolescent ; Adult ; Aged ; Animals ; Antigens ; Biomedical research ; Blood platelets ; Cell Adhesion Molecules, Neuronal - deficiency ; Cell Adhesion Molecules, Neuronal - genetics ; Cell Adhesion Molecules, Neuronal - metabolism ; Cell receptors ; Child ; Child, Preschool ; Coagulation factors ; Disease ; Drug Combinations ; Endocytosis ; Endothelial cells ; Endothelial Cells - immunology ; Endothelial Cells - metabolism ; Endothelium ; Factor VIII - chemistry ; Factor VIII - immunology ; Factor VIII - metabolism ; Factor VIII - pharmacokinetics ; Female ; Genetic aspects ; Genetic Variation ; Genomes ; Half-Life ; Health aspects ; Hemophilia ; Humans ; Hyaluronic acid ; Immune clearance ; Immune response ; Immunogenicity ; Immunoglobulins ; Immunoregulation ; Infant ; Kinases ; Liver ; Liver - cytology ; Liver - metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Middle Aged ; Mutation ; Phagocytes ; Plasma levels ; Protein Binding ; Protein Stability ; Scavenger receptors ; Studies ; Systematic review ; Thrombosis ; Von Willebrand factor ; von Willebrand Factor - chemistry ; von Willebrand Factor - immunology ; von Willebrand Factor - metabolism ; von Willebrand Factor - pharmacokinetics ; Young Adult</subject><ispartof>The Journal of clinical investigation, 2018-09, Vol.128 (9), p.4057-4073</ispartof><rights>COPYRIGHT 2018 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Sep 2018</rights><rights>Copyright © 2018, American Society for Clinical Investigation 2018 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c670t-3702a9af81c5252694924e298504584e935adc0e3f82fd0b544ec9ab701fdf43</citedby><cites>FETCH-LOGICAL-c670t-3702a9af81c5252694924e298504584e935adc0e3f82fd0b544ec9ab701fdf43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118640/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118640/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30124466$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Swystun, Laura L</creatorcontrib><creatorcontrib>Lai, Jesse D</creatorcontrib><creatorcontrib>Notley, Colleen</creatorcontrib><creatorcontrib>Georgescu, Ilinca</creatorcontrib><creatorcontrib>Paine, A Simonne</creatorcontrib><creatorcontrib>Mewburn, Jeff</creatorcontrib><creatorcontrib>Nesbitt, Kate</creatorcontrib><creatorcontrib>Schledzewski, Kai</creatorcontrib><creatorcontrib>Géraud, Cyrill</creatorcontrib><creatorcontrib>Kzhyshkowska, Julia</creatorcontrib><creatorcontrib>Goerdt, Sergij</creatorcontrib><creatorcontrib>Hopman, Wilma</creatorcontrib><creatorcontrib>Montgomery, Robert R</creatorcontrib><creatorcontrib>James, Paula D</creatorcontrib><creatorcontrib>Lillicrap, David</creatorcontrib><title>The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Aged</subject><subject>Animals</subject><subject>Antigens</subject><subject>Biomedical research</subject><subject>Blood platelets</subject><subject>Cell Adhesion Molecules, Neuronal - deficiency</subject><subject>Cell Adhesion Molecules, Neuronal - genetics</subject><subject>Cell Adhesion Molecules, Neuronal - metabolism</subject><subject>Cell receptors</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Coagulation factors</subject><subject>Disease</subject><subject>Drug Combinations</subject><subject>Endocytosis</subject><subject>Endothelial cells</subject><subject>Endothelial Cells - immunology</subject><subject>Endothelial Cells - metabolism</subject><subject>Endothelium</subject><subject>Factor VIII - chemistry</subject><subject>Factor VIII - immunology</subject><subject>Factor VIII - metabolism</subject><subject>Factor VIII - pharmacokinetics</subject><subject>Female</subject><subject>Genetic aspects</subject><subject>Genetic Variation</subject><subject>Genomes</subject><subject>Half-Life</subject><subject>Health aspects</subject><subject>Hemophilia</subject><subject>Humans</subject><subject>Hyaluronic acid</subject><subject>Immune clearance</subject><subject>Immune response</subject><subject>Immunogenicity</subject><subject>Immunoglobulins</subject><subject>Immunoregulation</subject><subject>Infant</subject><subject>Kinases</subject><subject>Liver</subject><subject>Liver - cytology</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Phagocytes</subject><subject>Plasma levels</subject><subject>Protein Binding</subject><subject>Protein Stability</subject><subject>Scavenger receptors</subject><subject>Studies</subject><subject>Systematic review</subject><subject>Thrombosis</subject><subject>Von Willebrand factor</subject><subject>von Willebrand Factor - chemistry</subject><subject>von Willebrand Factor - immunology</subject><subject>von Willebrand Factor - metabolism</subject><subject>von Willebrand Factor - pharmacokinetics</subject><subject>Young Adult</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkt-L1DAQx4so3noK_gVSEEQfeuZn27wIx-Jq5eBAl_UxZNPpNkua7DWp3P33ZnU9b2UfZB4Ck898M_nOZNlLjC4wrsj7rTaiZAg9ymaY87qoCa0fZzOECC5EReuz7FkIW4QwY5w9zc4owoSxspxlatlDDq71sQdrlM01WJuPoGEX_ZiHqNbGGleQlNtMVkUI-er7olismqbJtR92Fm7zXtmusKaDXLk2N8MwOb8BZ7SJd8-zJ52yAV4czvNsufi4nH8urq4_NfPLq0KXFYoFrRBRQnU11pxwUgomCAMiao4YrxkIylWrEdCuJl2L1pwx0EKtK4S7tmP0PPvwW3Y3rQdoNbg4Kit3oxnUeCe9MvL4xplebvwPWWJcJ--SwNuDwOhvJghRDibs3VAO_BQkQQJRnFoTCX39D7r10-jS7yTBiCdzU_ylNsqCNK7z6V29F5WXnNOKC0FooooTVDIPUpPeQWdS-oi_OMGnaGEw-mTBu6OCxES4jRs1hSCbb1__n71eHbNvHrA9KBv74O0UjXfhGDwYq0cfwgjd_VAwkvv1lV_mza_1Teirh0O8B__sK_0JP3_lYw</recordid><startdate>20180901</startdate><enddate>20180901</enddate><creator>Swystun, Laura L</creator><creator>Lai, Jesse D</creator><creator>Notley, Colleen</creator><creator>Georgescu, Ilinca</creator><creator>Paine, A Simonne</creator><creator>Mewburn, Jeff</creator><creator>Nesbitt, Kate</creator><creator>Schledzewski, Kai</creator><creator>Géraud, Cyrill</creator><creator>Kzhyshkowska, Julia</creator><creator>Goerdt, Sergij</creator><creator>Hopman, Wilma</creator><creator>Montgomery, Robert R</creator><creator>James, Paula D</creator><creator>Lillicrap, David</creator><general>American Society for Clinical Investigation</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>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</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>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20180901</creationdate><title>The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity</title><author>Swystun, Laura L ; Lai, Jesse D ; Notley, Colleen ; Georgescu, Ilinca ; Paine, A Simonne ; Mewburn, Jeff ; Nesbitt, Kate ; Schledzewski, Kai ; Géraud, Cyrill ; Kzhyshkowska, Julia ; Goerdt, Sergij ; Hopman, Wilma ; Montgomery, Robert R ; James, Paula D ; Lillicrap, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c670t-3702a9af81c5252694924e298504584e935adc0e3f82fd0b544ec9ab701fdf43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Aged</topic><topic>Animals</topic><topic>Antigens</topic><topic>Biomedical research</topic><topic>Blood platelets</topic><topic>Cell Adhesion Molecules, Neuronal - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Swystun, Laura L</au><au>Lai, Jesse D</au><au>Notley, Colleen</au><au>Georgescu, Ilinca</au><au>Paine, A Simonne</au><au>Mewburn, Jeff</au><au>Nesbitt, Kate</au><au>Schledzewski, Kai</au><au>Géraud, Cyrill</au><au>Kzhyshkowska, Julia</au><au>Goerdt, Sergij</au><au>Hopman, Wilma</au><au>Montgomery, Robert R</au><au>James, Paula D</au><au>Lillicrap, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2018-09-01</date><risdate>2018</risdate><volume>128</volume><issue>9</issue><spage>4057</spage><epage>4073</epage><pages>4057-4073</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><abstract>Quantitative abnormalities of the von Willebrand factor-factor VIII (VWF-FVIII) complex associate with inherited bleeding or thrombotic disorders. Receptor-mediated interactions between plasma VWF-FVIII and phagocytic or immune cells can influence their hemostatic and immunogenic activities. Genetic association studies have demonstrated that variants in the STAB2 gene, which encodes the scavenger receptor stabilin-2, associate with plasma levels of VWF-FVIII. However, the mechanistic basis and pathophysiological consequences of this association are unknown. We have demonstrated that stabilin-2-expressing cells bind and internalize human VWF and FVIII in a VWF-dependent manner, and stabilin-2-deficient mice displayed prolonged human VWF-FVIII half-life compared with controls. The stabilin-2 variant p.E2377K significantly decreased stabilin-2 expression and impaired VWF endocytosis in a heterologous expression system, and common STAB2 variants associated with plasma VWF levels in type 1 von Willebrand disease patients. STAB2-deficient mice displayed a decreased immunogenic response to human VWF-FVIII complex, while coinfusion of human VWF-FVIII with the stabilin-2 ligand hyaluronic acid attenuated the immune response to exogenous FVIII. Collectively, these data suggest that stabilin-2 functions as both a clearance and an immunoregulatory receptor for VWF-FVIII, making stabilin-2 a novel molecular target for modification of the half-life of VWF-FVIII and the immune response to VWF-FVIII concentrates.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>30124466</pmid><doi>10.1172/jci96400</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | The Journal of clinical investigation, 2018-09, Vol.128 (9), p.4057-4073 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6118640 |
| source | MEDLINE; Journals@Ovid Complete; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Adolescent Adult Aged Animals Antigens Biomedical research Blood platelets Cell Adhesion Molecules, Neuronal - deficiency Cell Adhesion Molecules, Neuronal - genetics Cell Adhesion Molecules, Neuronal - metabolism Cell receptors Child Child, Preschool Coagulation factors Disease Drug Combinations Endocytosis Endothelial cells Endothelial Cells - immunology Endothelial Cells - metabolism Endothelium Factor VIII - chemistry Factor VIII - immunology Factor VIII - metabolism Factor VIII - pharmacokinetics Female Genetic aspects Genetic Variation Genomes Half-Life Health aspects Hemophilia Humans Hyaluronic acid Immune clearance Immune response Immunogenicity Immunoglobulins Immunoregulation Infant Kinases Liver Liver - cytology Liver - metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Mutation Phagocytes Plasma levels Protein Binding Protein Stability Scavenger receptors Studies Systematic review Thrombosis Von Willebrand factor von Willebrand Factor - chemistry von Willebrand Factor - immunology von Willebrand Factor - metabolism von Willebrand Factor - pharmacokinetics Young Adult |
| title | The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T20%3A31%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=The%20endothelial%20cell%20receptor%20stabilin-2%20regulates%20VWF-FVIII%20complex%20half-life%20and%20immunogenicity&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Swystun,%20Laura%20L&rft.date=2018-09-01&rft.volume=128&rft.issue=9&rft.spage=4057&rft.epage=4073&rft.pages=4057-4073&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/jci96400&rft_dat=%3Cgale_pubme%3EA553759923%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2105012121&rft_id=info:pmid/30124466&rft_galeid=A553759923&rfr_iscdi=true |