Lipid presentation by the protein C receptor links coagulation with autoimmunity
Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen reco...
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| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2021-03, Vol.371 (6534) |
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| creator | Müller-Calleja, Nadine Hollerbach, Anne Royce, Jennifer Ritter, Svenja Pedrosa, Denise Madhusudhan, Thati Teifel, Sina Meineck, Myriam Häuser, Friederike Canisius, Antje Nguyen, T Son Braun, Johannes Bruns, Kai Etzold, Anna Zechner, Ulrich Strand, Susanne Radsak, Markus Strand, Dennis Gu, Jian-Ming Weinmann-Menke, Julia Esmon, Charles T Teyton, Luc Lackner, Karl J Ruf, Wolfram |
| description | Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways. |
| doi_str_mv | 10.1126/science.abc0956 |
| format | Article |
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Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.abc0956</identifier><identifier>PMID: 33707237</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Acids ; ALG-2-interacting protein ; Animals ; Antibodies ; Antibodies, Antiphospholipid - biosynthesis ; Antigen Presentation ; Antigens ; Antiinfectives and antibacterials ; Antiphospholipid antibodies ; Antiphospholipid syndrome ; Autoantibodies ; Autoantibodies - biosynthesis ; Autocrine signalling ; Autoimmune diseases ; Autoimmunity ; Binding ; Blocking antibodies ; Blood Coagulation - immunology ; Cascades ; CD1d antigen ; Cell surface ; Chronic conditions ; Coagulation ; Complement ; Complement activation ; Complications ; Dendritic cells ; Dendritic structure ; Disease Models, Animal ; Embryo Loss - immunology ; Endosomes - immunology ; Endothelial Protein C Receptor - genetics ; Endothelial Protein C Receptor - immunology ; Exchanging ; Expansion ; Fetuses ; Humans ; Immune system ; Immunity, Innate ; Infectious diseases ; Inflammation ; Interferon ; Internalization ; Intersections ; Kidneys ; Lecithin ; Lipids ; Lupus ; Lupus Erythematosus, Systemic - blood ; Lupus Erythematosus, Systemic - immunology ; Lysophospholipids - immunology ; Mice ; Mice, Mutant Strains ; Monocytes ; Monoglycerides - immunology ; Mutagenesis ; Pathology ; Phosphatidylcholine ; Pregnancy ; Pregnancy complications ; Protein C ; Proteins ; Receptors ; Signaling ; Sphingomyelin Phosphodiesterase - metabolism ; Stereoselectivity ; Stroke ; Systemic lupus erythematosus ; Thromboembolism ; Thrombosis ; Thrombosis - immunology ; Toll-Like Receptor 7 - immunology ; Toll-like receptors ; α-Interferon</subject><ispartof>Science (American Association for the Advancement of Science), 2021-03, Vol.371 (6534)</ispartof><rights>Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c421t-56830fb5aa2b201c007cc78d9c8ae2a584092e1f8909a67fd8c81ee4c791a5523</citedby><cites>FETCH-LOGICAL-c421t-56830fb5aa2b201c007cc78d9c8ae2a584092e1f8909a67fd8c81ee4c791a5523</cites><orcidid>0000-0002-7851-3354 ; 0000-0002-4049-1583 ; 0000-0001-9348-3141 ; 0000-0001-7344-8381 ; 0000-0002-6064-2166 ; 0000-0002-3243-2540 ; 0000-0003-3324-7088 ; 0000-0002-1985-7931 ; 0000-0002-1353-4074 ; 0000-0002-0409-7474 ; 0000-0002-8903-843X ; 0000-0001-6099-6952 ; 0000-0001-9100-9542</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,2884,2885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33707237$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Müller-Calleja, Nadine</creatorcontrib><creatorcontrib>Hollerbach, Anne</creatorcontrib><creatorcontrib>Royce, Jennifer</creatorcontrib><creatorcontrib>Ritter, Svenja</creatorcontrib><creatorcontrib>Pedrosa, Denise</creatorcontrib><creatorcontrib>Madhusudhan, Thati</creatorcontrib><creatorcontrib>Teifel, Sina</creatorcontrib><creatorcontrib>Meineck, Myriam</creatorcontrib><creatorcontrib>Häuser, Friederike</creatorcontrib><creatorcontrib>Canisius, Antje</creatorcontrib><creatorcontrib>Nguyen, T Son</creatorcontrib><creatorcontrib>Braun, Johannes</creatorcontrib><creatorcontrib>Bruns, Kai</creatorcontrib><creatorcontrib>Etzold, Anna</creatorcontrib><creatorcontrib>Zechner, Ulrich</creatorcontrib><creatorcontrib>Strand, Susanne</creatorcontrib><creatorcontrib>Radsak, Markus</creatorcontrib><creatorcontrib>Strand, Dennis</creatorcontrib><creatorcontrib>Gu, Jian-Ming</creatorcontrib><creatorcontrib>Weinmann-Menke, Julia</creatorcontrib><creatorcontrib>Esmon, Charles T</creatorcontrib><creatorcontrib>Teyton, Luc</creatorcontrib><creatorcontrib>Lackner, Karl J</creatorcontrib><creatorcontrib>Ruf, Wolfram</creatorcontrib><title>Lipid presentation by the protein C receptor links coagulation with autoimmunity</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.</description><subject>Acids</subject><subject>ALG-2-interacting protein</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Antibodies, Antiphospholipid - biosynthesis</subject><subject>Antigen Presentation</subject><subject>Antigens</subject><subject>Antiinfectives and antibacterials</subject><subject>Antiphospholipid antibodies</subject><subject>Antiphospholipid syndrome</subject><subject>Autoantibodies</subject><subject>Autoantibodies - biosynthesis</subject><subject>Autocrine signalling</subject><subject>Autoimmune diseases</subject><subject>Autoimmunity</subject><subject>Binding</subject><subject>Blocking antibodies</subject><subject>Blood Coagulation - immunology</subject><subject>Cascades</subject><subject>CD1d antigen</subject><subject>Cell surface</subject><subject>Chronic conditions</subject><subject>Coagulation</subject><subject>Complement</subject><subject>Complement activation</subject><subject>Complications</subject><subject>Dendritic cells</subject><subject>Dendritic structure</subject><subject>Disease Models, Animal</subject><subject>Embryo Loss - immunology</subject><subject>Endosomes - immunology</subject><subject>Endothelial Protein C Receptor - genetics</subject><subject>Endothelial Protein C Receptor - immunology</subject><subject>Exchanging</subject><subject>Expansion</subject><subject>Fetuses</subject><subject>Humans</subject><subject>Immune system</subject><subject>Immunity, Innate</subject><subject>Infectious diseases</subject><subject>Inflammation</subject><subject>Interferon</subject><subject>Internalization</subject><subject>Intersections</subject><subject>Kidneys</subject><subject>Lecithin</subject><subject>Lipids</subject><subject>Lupus</subject><subject>Lupus Erythematosus, Systemic - blood</subject><subject>Lupus Erythematosus, Systemic - immunology</subject><subject>Lysophospholipids - immunology</subject><subject>Mice</subject><subject>Mice, Mutant Strains</subject><subject>Monocytes</subject><subject>Monoglycerides - immunology</subject><subject>Mutagenesis</subject><subject>Pathology</subject><subject>Phosphatidylcholine</subject><subject>Pregnancy</subject><subject>Pregnancy complications</subject><subject>Protein C</subject><subject>Proteins</subject><subject>Receptors</subject><subject>Signaling</subject><subject>Sphingomyelin Phosphodiesterase - metabolism</subject><subject>Stereoselectivity</subject><subject>Stroke</subject><subject>Systemic lupus erythematosus</subject><subject>Thromboembolism</subject><subject>Thrombosis</subject><subject>Thrombosis - immunology</subject><subject>Toll-Like Receptor 7 - immunology</subject><subject>Toll-like receptors</subject><subject>α-Interferon</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUFr3DAQhUVpaLZpz70FQy-5OBlJK8u6BMKSpIWF9NCehawdZ5XakiPJCfvvq7DbkPY0MPPN4808Qr5QOKeUNRfJOvQWz01nQYnmHVnQUmvFgL8nCwDe1C1IcUw-pvQAUGaKfyDHnEuQjMsF-bF2k9tUU8SEPpvsgq-6XZW3WHoho_PVqopoccohVoPzv1Nlg7mfhz377PK2MnMObhxn7_LuEznqzZDw86GekF831z9X3-r13e331dW6tktGcy2alkPfCWNYx4BaAGmtbDfKtgaZEe0SFEPatwqUaWS_aW1LEZdWKmqEYPyEXO51p7kbcWOL-2gGPUU3mrjTwTj978S7rb4PT1oBXTImisDZQSCGxxlT1qNLFofBeAxz0kxA-TAVIAv69T_0IczRl_NeKCh2yr8LdbGnbAwpRexfzVDQL2npQ1r6kFbZOH17wyv_Nx7-B1iGlAw</recordid><startdate>20210312</startdate><enddate>20210312</enddate><creator>Müller-Calleja, Nadine</creator><creator>Hollerbach, Anne</creator><creator>Royce, Jennifer</creator><creator>Ritter, Svenja</creator><creator>Pedrosa, Denise</creator><creator>Madhusudhan, Thati</creator><creator>Teifel, Sina</creator><creator>Meineck, Myriam</creator><creator>Häuser, Friederike</creator><creator>Canisius, Antje</creator><creator>Nguyen, T Son</creator><creator>Braun, Johannes</creator><creator>Bruns, Kai</creator><creator>Etzold, Anna</creator><creator>Zechner, Ulrich</creator><creator>Strand, Susanne</creator><creator>Radsak, Markus</creator><creator>Strand, Dennis</creator><creator>Gu, Jian-Ming</creator><creator>Weinmann-Menke, Julia</creator><creator>Esmon, Charles T</creator><creator>Teyton, Luc</creator><creator>Lackner, Karl J</creator><creator>Ruf, Wolfram</creator><general>The American Association for the Advancement of Science</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>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-7851-3354</orcidid><orcidid>https://orcid.org/0000-0002-4049-1583</orcidid><orcidid>https://orcid.org/0000-0001-9348-3141</orcidid><orcidid>https://orcid.org/0000-0001-7344-8381</orcidid><orcidid>https://orcid.org/0000-0002-6064-2166</orcidid><orcidid>https://orcid.org/0000-0002-3243-2540</orcidid><orcidid>https://orcid.org/0000-0003-3324-7088</orcidid><orcidid>https://orcid.org/0000-0002-1985-7931</orcidid><orcidid>https://orcid.org/0000-0002-1353-4074</orcidid><orcidid>https://orcid.org/0000-0002-0409-7474</orcidid><orcidid>https://orcid.org/0000-0002-8903-843X</orcidid><orcidid>https://orcid.org/0000-0001-6099-6952</orcidid><orcidid>https://orcid.org/0000-0001-9100-9542</orcidid></search><sort><creationdate>20210312</creationdate><title>Lipid presentation by the protein C receptor links coagulation with autoimmunity</title><author>Müller-Calleja, Nadine ; Hollerbach, Anne ; Royce, Jennifer ; Ritter, Svenja ; Pedrosa, Denise ; Madhusudhan, Thati ; Teifel, Sina ; Meineck, Myriam ; Häuser, Friederike ; Canisius, Antje ; Nguyen, T Son ; Braun, Johannes ; Bruns, Kai ; Etzold, Anna ; Zechner, Ulrich ; Strand, Susanne ; Radsak, Markus ; Strand, Dennis ; Gu, Jian-Ming ; Weinmann-Menke, Julia ; Esmon, Charles T ; Teyton, Luc ; Lackner, Karl J ; Ruf, Wolfram</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c421t-56830fb5aa2b201c007cc78d9c8ae2a584092e1f8909a67fd8c81ee4c791a5523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acids</topic><topic>ALG-2-interacting protein</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Antibodies, Antiphospholipid - biosynthesis</topic><topic>Antigen Presentation</topic><topic>Antigens</topic><topic>Antiinfectives and antibacterials</topic><topic>Antiphospholipid antibodies</topic><topic>Antiphospholipid syndrome</topic><topic>Autoantibodies</topic><topic>Autoantibodies - biosynthesis</topic><topic>Autocrine signalling</topic><topic>Autoimmune diseases</topic><topic>Autoimmunity</topic><topic>Binding</topic><topic>Blocking antibodies</topic><topic>Blood Coagulation - immunology</topic><topic>Cascades</topic><topic>CD1d antigen</topic><topic>Cell surface</topic><topic>Chronic conditions</topic><topic>Coagulation</topic><topic>Complement</topic><topic>Complement activation</topic><topic>Complications</topic><topic>Dendritic cells</topic><topic>Dendritic structure</topic><topic>Disease Models, Animal</topic><topic>Embryo Loss - immunology</topic><topic>Endosomes - immunology</topic><topic>Endothelial Protein C Receptor - genetics</topic><topic>Endothelial Protein C Receptor - immunology</topic><topic>Exchanging</topic><topic>Expansion</topic><topic>Fetuses</topic><topic>Humans</topic><topic>Immune system</topic><topic>Immunity, Innate</topic><topic>Infectious diseases</topic><topic>Inflammation</topic><topic>Interferon</topic><topic>Internalization</topic><topic>Intersections</topic><topic>Kidneys</topic><topic>Lecithin</topic><topic>Lipids</topic><topic>Lupus</topic><topic>Lupus Erythematosus, Systemic - blood</topic><topic>Lupus Erythematosus, Systemic - immunology</topic><topic>Lysophospholipids - immunology</topic><topic>Mice</topic><topic>Mice, Mutant Strains</topic><topic>Monocytes</topic><topic>Monoglycerides - immunology</topic><topic>Mutagenesis</topic><topic>Pathology</topic><topic>Phosphatidylcholine</topic><topic>Pregnancy</topic><topic>Pregnancy complications</topic><topic>Protein C</topic><topic>Proteins</topic><topic>Receptors</topic><topic>Signaling</topic><topic>Sphingomyelin Phosphodiesterase - metabolism</topic><topic>Stereoselectivity</topic><topic>Stroke</topic><topic>Systemic lupus erythematosus</topic><topic>Thromboembolism</topic><topic>Thrombosis</topic><topic>Thrombosis - immunology</topic><topic>Toll-Like Receptor 7 - immunology</topic><topic>Toll-like receptors</topic><topic>α-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Müller-Calleja, Nadine</creatorcontrib><creatorcontrib>Hollerbach, Anne</creatorcontrib><creatorcontrib>Royce, Jennifer</creatorcontrib><creatorcontrib>Ritter, Svenja</creatorcontrib><creatorcontrib>Pedrosa, Denise</creatorcontrib><creatorcontrib>Madhusudhan, Thati</creatorcontrib><creatorcontrib>Teifel, Sina</creatorcontrib><creatorcontrib>Meineck, Myriam</creatorcontrib><creatorcontrib>Häuser, Friederike</creatorcontrib><creatorcontrib>Canisius, Antje</creatorcontrib><creatorcontrib>Nguyen, T Son</creatorcontrib><creatorcontrib>Braun, Johannes</creatorcontrib><creatorcontrib>Bruns, Kai</creatorcontrib><creatorcontrib>Etzold, Anna</creatorcontrib><creatorcontrib>Zechner, Ulrich</creatorcontrib><creatorcontrib>Strand, Susanne</creatorcontrib><creatorcontrib>Radsak, Markus</creatorcontrib><creatorcontrib>Strand, Dennis</creatorcontrib><creatorcontrib>Gu, Jian-Ming</creatorcontrib><creatorcontrib>Weinmann-Menke, Julia</creatorcontrib><creatorcontrib>Esmon, Charles T</creatorcontrib><creatorcontrib>Teyton, Luc</creatorcontrib><creatorcontrib>Lackner, Karl J</creatorcontrib><creatorcontrib>Ruf, Wolfram</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Müller-Calleja, Nadine</au><au>Hollerbach, Anne</au><au>Royce, Jennifer</au><au>Ritter, Svenja</au><au>Pedrosa, Denise</au><au>Madhusudhan, Thati</au><au>Teifel, Sina</au><au>Meineck, Myriam</au><au>Häuser, Friederike</au><au>Canisius, Antje</au><au>Nguyen, T Son</au><au>Braun, Johannes</au><au>Bruns, Kai</au><au>Etzold, Anna</au><au>Zechner, Ulrich</au><au>Strand, Susanne</au><au>Radsak, Markus</au><au>Strand, Dennis</au><au>Gu, Jian-Ming</au><au>Weinmann-Menke, Julia</au><au>Esmon, Charles T</au><au>Teyton, Luc</au><au>Lackner, Karl J</au><au>Ruf, Wolfram</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lipid presentation by the protein C receptor links coagulation with autoimmunity</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2021-03-12</date><risdate>2021</risdate><volume>371</volume><issue>6534</issue><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>Antiphospholipid antibodies (aPLs) cause severe autoimmune disease characterized by vascular pathologies and pregnancy complications. Here, we identify endosomal lysobisphosphatidic acid (LBPA) presented by the CD1d-like endothelial protein C receptor (EPCR) as a pathogenic cell surface antigen recognized by aPLs for induction of thrombosis and endosomal inflammatory signaling. The engagement of aPLs with EPCR-LBPA expressed on innate immune cells sustains interferon- and toll-like receptor 7-dependent B1a cell expansion and autoantibody production. Specific pharmacological interruption of EPCR-LBPA signaling attenuates major aPL-elicited pathologies and the development of autoimmunity in a mouse model of systemic lupus erythematosus. Thus, aPLs recognize a single cell surface lipid-protein receptor complex to perpetuate a self-amplifying autoimmune signaling loop dependent on the cooperation with the innate immune complement and coagulation pathways.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>33707237</pmid><doi>10.1126/science.abc0956</doi><orcidid>https://orcid.org/0000-0002-7851-3354</orcidid><orcidid>https://orcid.org/0000-0002-4049-1583</orcidid><orcidid>https://orcid.org/0000-0001-9348-3141</orcidid><orcidid>https://orcid.org/0000-0001-7344-8381</orcidid><orcidid>https://orcid.org/0000-0002-6064-2166</orcidid><orcidid>https://orcid.org/0000-0002-3243-2540</orcidid><orcidid>https://orcid.org/0000-0003-3324-7088</orcidid><orcidid>https://orcid.org/0000-0002-1985-7931</orcidid><orcidid>https://orcid.org/0000-0002-1353-4074</orcidid><orcidid>https://orcid.org/0000-0002-0409-7474</orcidid><orcidid>https://orcid.org/0000-0002-8903-843X</orcidid><orcidid>https://orcid.org/0000-0001-6099-6952</orcidid><orcidid>https://orcid.org/0000-0001-9100-9542</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2021-03, Vol.371 (6534) |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9014225 |
| source | MEDLINE; Science Magazine |
| subjects | Acids ALG-2-interacting protein Animals Antibodies Antibodies, Antiphospholipid - biosynthesis Antigen Presentation Antigens Antiinfectives and antibacterials Antiphospholipid antibodies Antiphospholipid syndrome Autoantibodies Autoantibodies - biosynthesis Autocrine signalling Autoimmune diseases Autoimmunity Binding Blocking antibodies Blood Coagulation - immunology Cascades CD1d antigen Cell surface Chronic conditions Coagulation Complement Complement activation Complications Dendritic cells Dendritic structure Disease Models, Animal Embryo Loss - immunology Endosomes - immunology Endothelial Protein C Receptor - genetics Endothelial Protein C Receptor - immunology Exchanging Expansion Fetuses Humans Immune system Immunity, Innate Infectious diseases Inflammation Interferon Internalization Intersections Kidneys Lecithin Lipids Lupus Lupus Erythematosus, Systemic - blood Lupus Erythematosus, Systemic - immunology Lysophospholipids - immunology Mice Mice, Mutant Strains Monocytes Monoglycerides - immunology Mutagenesis Pathology Phosphatidylcholine Pregnancy Pregnancy complications Protein C Proteins Receptors Signaling Sphingomyelin Phosphodiesterase - metabolism Stereoselectivity Stroke Systemic lupus erythematosus Thromboembolism Thrombosis Thrombosis - immunology Toll-Like Receptor 7 - immunology Toll-like receptors α-Interferon |
| title | Lipid presentation by the protein C receptor links coagulation with autoimmunity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-21T05%3A52%3A54IST&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=Lipid%20presentation%20by%20the%20protein%20C%20receptor%20links%20coagulation%20with%20autoimmunity&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=M%C3%BCller-Calleja,%20Nadine&rft.date=2021-03-12&rft.volume=371&rft.issue=6534&rft.issn=0036-8075&rft.eissn=1095-9203&rft_id=info:doi/10.1126/science.abc0956&rft_dat=%3Cproquest_pubme%3E2500552203%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=2500552203&rft_id=info:pmid/33707237&rfr_iscdi=true |