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Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein
The optimal clinical management of patients with antiphospholipid antibody syndrome (APS) is uncertain because of a lack of an underlying hypothesis to explain why antiphospholipid autoantibodies (aPL) form to such ubiquitous compounds as phospholipids (PL). In this paper, we demonstrate that many,...
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| Published in: | The Journal of clinical investigation 1996-08, Vol.98 (3), p.815-825 |
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| Main Authors: | , , , , , , , , , , |
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| container_end_page | 825 |
| container_issue | 3 |
| container_start_page | 815 |
| container_title | The Journal of clinical investigation |
| container_volume | 98 |
| creator | Hörkkö, S Miller, E Dudl, E Reaven, P Curtiss, L K Zvaifler, N J Terkeltaub, R Pierangeli, S S Branch, D W Palinski, W Witztum, J L |
| description | The optimal clinical management of patients with antiphospholipid antibody syndrome (APS) is uncertain because of a lack of an underlying hypothesis to explain why antiphospholipid autoantibodies (aPL) form to such ubiquitous compounds as phospholipids (PL). In this paper, we demonstrate that many, if not most, aPL are actually directed at neoepitopes of oxidized PL, or neoepitopes generated by adduct formation between breakdown products of oxidized PL and associated proteins. Each cardiolipin (CL) molecule contains four unsaturated fatty acids and is highly susceptible to oxidation, particularly upon exposure to air. Yet, standard anticardiolipin antibodies (aCL) immunoassays routinely bind CL to microtiter wells by evaporation of the ethanol solvent overnight at 4 degrees C. Using a variety of techniques, we demonstrated that rapid oxidation occurs when CL is plated and exposed to air. Sera from apo E-deficient mice, which have high autoantibody titers to oxidized low density lipoprotein, showed a striking time-dependent increase in binding to CL that was exposed to air for increasing periods of time. Monoclonal antibodies to oxidized LDL, cloned from the apo E-deficient mice, also bound to oxidized CL. Both sera and affinity-purified aCL-IgG from APS patients bound to CL progressively as it was oxidized. However, the monoclonal antibodies from apo E-deficient mice, or sera or aCL-IgG from APS patients did not bind to a reduced CL analog that was unable to undergo peroxidation. These data demonstrate that many aPL are directed at neoepitopes of oxidized phospholipids, and suggest that oxidative events may be important in the pathophysiology of APS. In turn, this suggests new therapeutic strategies, possibly including intensive antioxidant therapy. |
| doi_str_mv | 10.1172/jci118854 |
| format | article |
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Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein</title><source>PubMed Central</source><source>EZB Electronic Journals Library</source><creator>Hörkkö, S ; Miller, E ; Dudl, E ; Reaven, P ; Curtiss, L K ; Zvaifler, N J ; Terkeltaub, R ; Pierangeli, S S ; Branch, D W ; Palinski, W ; Witztum, J L</creator><creatorcontrib>Hörkkö, S ; Miller, E ; Dudl, E ; Reaven, P ; Curtiss, L K ; Zvaifler, N J ; Terkeltaub, R ; Pierangeli, S S ; Branch, D W ; Palinski, W ; Witztum, J L</creatorcontrib><description>The optimal clinical management of patients with antiphospholipid antibody syndrome (APS) is uncertain because of a lack of an underlying hypothesis to explain why antiphospholipid autoantibodies (aPL) form to such ubiquitous compounds as phospholipids (PL). In this paper, we demonstrate that many, if not most, aPL are actually directed at neoepitopes of oxidized PL, or neoepitopes generated by adduct formation between breakdown products of oxidized PL and associated proteins. Each cardiolipin (CL) molecule contains four unsaturated fatty acids and is highly susceptible to oxidation, particularly upon exposure to air. Yet, standard anticardiolipin antibodies (aCL) immunoassays routinely bind CL to microtiter wells by evaporation of the ethanol solvent overnight at 4 degrees C. Using a variety of techniques, we demonstrated that rapid oxidation occurs when CL is plated and exposed to air. Sera from apo E-deficient mice, which have high autoantibody titers to oxidized low density lipoprotein, showed a striking time-dependent increase in binding to CL that was exposed to air for increasing periods of time. Monoclonal antibodies to oxidized LDL, cloned from the apo E-deficient mice, also bound to oxidized CL. Both sera and affinity-purified aCL-IgG from APS patients bound to CL progressively as it was oxidized. However, the monoclonal antibodies from apo E-deficient mice, or sera or aCL-IgG from APS patients did not bind to a reduced CL analog that was unable to undergo peroxidation. These data demonstrate that many aPL are directed at neoepitopes of oxidized phospholipids, and suggest that oxidative events may be important in the pathophysiology of APS. In turn, this suggests new therapeutic strategies, possibly including intensive antioxidant therapy.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/jci118854</identifier><identifier>PMID: 8698874</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Antibodies, Anticardiolipin - immunology ; Antibodies, Monoclonal - immunology ; Antiphospholipid Syndrome - blood ; Antiphospholipid Syndrome - etiology ; Apolipoproteins E - deficiency ; Cardiolipins - analysis ; Cardiolipins - immunology ; Cardiolipins - metabolism ; Epitopes ; Female ; Humans ; Lipoproteins, LDL - immunology ; Mice ; Mice, Inbred C57BL ; Oxidation-Reduction</subject><ispartof>The Journal of clinical investigation, 1996-08, Vol.98 (3), p.815-825</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c435t-b8871f9585157af3b47592cec5e2d66a4df68e3b909f21a81f8bb30e9967c6cf3</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/PMC507492/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC507492/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8698874$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hörkkö, S</creatorcontrib><creatorcontrib>Miller, E</creatorcontrib><creatorcontrib>Dudl, E</creatorcontrib><creatorcontrib>Reaven, P</creatorcontrib><creatorcontrib>Curtiss, L K</creatorcontrib><creatorcontrib>Zvaifler, N J</creatorcontrib><creatorcontrib>Terkeltaub, R</creatorcontrib><creatorcontrib>Pierangeli, S S</creatorcontrib><creatorcontrib>Branch, D W</creatorcontrib><creatorcontrib>Palinski, W</creatorcontrib><creatorcontrib>Witztum, J L</creatorcontrib><title>Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>The optimal clinical management of patients with antiphospholipid antibody syndrome (APS) is uncertain because of a lack of an underlying hypothesis to explain why antiphospholipid autoantibodies (aPL) form to such ubiquitous compounds as phospholipids (PL). In this paper, we demonstrate that many, if not most, aPL are actually directed at neoepitopes of oxidized PL, or neoepitopes generated by adduct formation between breakdown products of oxidized PL and associated proteins. Each cardiolipin (CL) molecule contains four unsaturated fatty acids and is highly susceptible to oxidation, particularly upon exposure to air. Yet, standard anticardiolipin antibodies (aCL) immunoassays routinely bind CL to microtiter wells by evaporation of the ethanol solvent overnight at 4 degrees C. Using a variety of techniques, we demonstrated that rapid oxidation occurs when CL is plated and exposed to air. Sera from apo E-deficient mice, which have high autoantibody titers to oxidized low density lipoprotein, showed a striking time-dependent increase in binding to CL that was exposed to air for increasing periods of time. Monoclonal antibodies to oxidized LDL, cloned from the apo E-deficient mice, also bound to oxidized CL. Both sera and affinity-purified aCL-IgG from APS patients bound to CL progressively as it was oxidized. However, the monoclonal antibodies from apo E-deficient mice, or sera or aCL-IgG from APS patients did not bind to a reduced CL analog that was unable to undergo peroxidation. These data demonstrate that many aPL are directed at neoepitopes of oxidized phospholipids, and suggest that oxidative events may be important in the pathophysiology of APS. In turn, this suggests new therapeutic strategies, possibly including intensive antioxidant therapy.</description><subject>Animals</subject><subject>Antibodies, Anticardiolipin - immunology</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antiphospholipid Syndrome - blood</subject><subject>Antiphospholipid Syndrome - etiology</subject><subject>Apolipoproteins E - deficiency</subject><subject>Cardiolipins - analysis</subject><subject>Cardiolipins - immunology</subject><subject>Cardiolipins - metabolism</subject><subject>Epitopes</subject><subject>Female</subject><subject>Humans</subject><subject>Lipoproteins, LDL - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Oxidation-Reduction</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><recordid>eNptkc-KFDEQxoMo67h68AGEnAQPvSbdSXdy8LAM_llZEETPTTpdPVtLT6pNMur4ZD6eWWdYRvBQFNT3q68SPsaeS3EhZVe_vvUopTFaPWArqbWpTN2Yh2wlRC0r2zXmMXuS0q0QUimtztiZaa0xnVqx35ch43JDqdSMC47clcFAI0LiLgIfMYLPUOYbhyFlDgtmWopKE6efOOKvIp46pAv-GTxtAmakcId5F0f8KwY-7PmWAvmZgptPj2X6v_VMP_gIIWHe82JBS6QMGJ6yR5ObEzw79nP29d3bL-sP1fWn91fry-vKq0bnaijflJPVRkvduakZVKdt7cFrqMe2dWqcWgPNYIWdaumMnMwwNAKsbTvf-qk5Z28Ovstu2MLoIeTo5n6JuHVx35PD_l8l4E2_oe-9Fp2yddl_edyP9G0HKfdbTB7m2QWgXeo7U9dWKF3AVwfQR0opwnR_Q4r-LuX-4_rqkHJhX5w-6p48xtr8AbNUqqc</recordid><startdate>19960801</startdate><enddate>19960801</enddate><creator>Hörkkö, S</creator><creator>Miller, E</creator><creator>Dudl, E</creator><creator>Reaven, P</creator><creator>Curtiss, L K</creator><creator>Zvaifler, N J</creator><creator>Terkeltaub, R</creator><creator>Pierangeli, S S</creator><creator>Branch, D W</creator><creator>Palinski, W</creator><creator>Witztum, J L</creator><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>19960801</creationdate><title>Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein</title><author>Hörkkö, S ; Miller, E ; Dudl, E ; Reaven, P ; Curtiss, L K ; Zvaifler, N J ; Terkeltaub, R ; Pierangeli, S S ; Branch, D W ; Palinski, W ; Witztum, J L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c435t-b8871f9585157af3b47592cec5e2d66a4df68e3b909f21a81f8bb30e9967c6cf3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Animals</topic><topic>Antibodies, Anticardiolipin - immunology</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antiphospholipid Syndrome - blood</topic><topic>Antiphospholipid Syndrome - etiology</topic><topic>Apolipoproteins E - deficiency</topic><topic>Cardiolipins - analysis</topic><topic>Cardiolipins - immunology</topic><topic>Cardiolipins - metabolism</topic><topic>Epitopes</topic><topic>Female</topic><topic>Humans</topic><topic>Lipoproteins, LDL - immunology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Oxidation-Reduction</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hörkkö, S</creatorcontrib><creatorcontrib>Miller, E</creatorcontrib><creatorcontrib>Dudl, E</creatorcontrib><creatorcontrib>Reaven, P</creatorcontrib><creatorcontrib>Curtiss, L K</creatorcontrib><creatorcontrib>Zvaifler, N J</creatorcontrib><creatorcontrib>Terkeltaub, R</creatorcontrib><creatorcontrib>Pierangeli, S S</creatorcontrib><creatorcontrib>Branch, D W</creatorcontrib><creatorcontrib>Palinski, W</creatorcontrib><creatorcontrib>Witztum, J L</creatorcontrib><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>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hörkkö, S</au><au>Miller, E</au><au>Dudl, E</au><au>Reaven, P</au><au>Curtiss, L K</au><au>Zvaifler, N J</au><au>Terkeltaub, R</au><au>Pierangeli, S S</au><au>Branch, D W</au><au>Palinski, W</au><au>Witztum, J L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>1996-08-01</date><risdate>1996</risdate><volume>98</volume><issue>3</issue><spage>815</spage><epage>825</epage><pages>815-825</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><abstract>The optimal clinical management of patients with antiphospholipid antibody syndrome (APS) is uncertain because of a lack of an underlying hypothesis to explain why antiphospholipid autoantibodies (aPL) form to such ubiquitous compounds as phospholipids (PL). In this paper, we demonstrate that many, if not most, aPL are actually directed at neoepitopes of oxidized PL, or neoepitopes generated by adduct formation between breakdown products of oxidized PL and associated proteins. Each cardiolipin (CL) molecule contains four unsaturated fatty acids and is highly susceptible to oxidation, particularly upon exposure to air. Yet, standard anticardiolipin antibodies (aCL) immunoassays routinely bind CL to microtiter wells by evaporation of the ethanol solvent overnight at 4 degrees C. Using a variety of techniques, we demonstrated that rapid oxidation occurs when CL is plated and exposed to air. Sera from apo E-deficient mice, which have high autoantibody titers to oxidized low density lipoprotein, showed a striking time-dependent increase in binding to CL that was exposed to air for increasing periods of time. Monoclonal antibodies to oxidized LDL, cloned from the apo E-deficient mice, also bound to oxidized CL. Both sera and affinity-purified aCL-IgG from APS patients bound to CL progressively as it was oxidized. However, the monoclonal antibodies from apo E-deficient mice, or sera or aCL-IgG from APS patients did not bind to a reduced CL analog that was unable to undergo peroxidation. These data demonstrate that many aPL are directed at neoepitopes of oxidized phospholipids, and suggest that oxidative events may be important in the pathophysiology of APS. In turn, this suggests new therapeutic strategies, possibly including intensive antioxidant therapy.</abstract><cop>United States</cop><pmid>8698874</pmid><doi>10.1172/jci118854</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 0021-9738 |
| ispartof | The Journal of clinical investigation, 1996-08, Vol.98 (3), p.815-825 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_507492 |
| source | PubMed Central; EZB Electronic Journals Library |
| subjects | Animals Antibodies, Anticardiolipin - immunology Antibodies, Monoclonal - immunology Antiphospholipid Syndrome - blood Antiphospholipid Syndrome - etiology Apolipoproteins E - deficiency Cardiolipins - analysis Cardiolipins - immunology Cardiolipins - metabolism Epitopes Female Humans Lipoproteins, LDL - immunology Mice Mice, Inbred C57BL Oxidation-Reduction |
| title | Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein |
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