Chimeric CD46/DAF molecules reveal a cryptic functional role for SCR1 of DAF in regulating complement activation
Identifieur interne : 001881 ( Istex/Corpus ); précédent : 001880; suivant : 001882Chimeric CD46/DAF molecules reveal a cryptic functional role for SCR1 of DAF in regulating complement activation
Auteurs : Dale Christiansen ; Bruce Loveland ; Peter Kyriakou ; Marc Lanteri ; Eric Rubinstein ; Denis GerlierSource :
- Molecular Immunology [ 0161-5890 ] ; 2001.
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Abstract
Chimeric proteins using membrane cofactor (CD46) and decay accelerating factor (DAF or CD55) were generated to further investigate the functional domains involved in the regulation of human serum complement. Following activation of the classical pathway, the isolated substitution of CD46 SCR III (×3DAF) exhibited a modest regulatory activity comparable to that of CD46. The isolated substitution of CD46 SCR IV (×4DAF), and the combined CD46 SCR III+IV substitutions (×3/4DAF) were essentially as efficient as DAF. No regulation of C3b deposition was observed with the combined CD46 SCR I+II substitutions (×1/2DAF). When tested after activation of the alternative pathway, both the ×3DAF and ×3/4DAF chimeras failed to regulate C3b deposition, while the ×4DAF chimera still displayed some activity. In contrast to that observed following classical pathway activation, the ×1/2DAF chimera exhibited a similar efficiency to wild type CD46 and DAF in controlling C3b deposition. Using SCR specific antibodies, the regulatory activity of the ×1/2DAF chimera against the alternative pathway was mapped to the first three distal SCR (i.e. DAF 1, DAF 2 and CD46 III). These data demonstrate that several combinations of SCR domains from two related complement regulators can result in functional molecules, and reveal a novel and cryptic functional role for DAF SCR1.
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DOI: 10.1016/S0161-5890(01)00002-5
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Tel.: +33-4-78778618; fax: +33-4-78778754</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: gerlier@laennec.univ-lyonl.fr</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:8F09E47111AE44C0F32A60F48A68E5D6BB932E99</idno><date when="2001" year="2001">2001</date><idno type="doi">10.1016/S0161-5890(01)00002-5</idno><idno type="url">https://api.istex.fr/document/8F09E47111AE44C0F32A60F48A68E5D6BB932E99/fulltext/pdf</idno><idno type="wicri:Area/Istex/Corpus">001881</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001881</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main" xml:lang="en">Chimeric CD46/DAF molecules reveal a cryptic functional role for SCR1 of DAF in regulating complement activation</title><author><name sortKey="Christiansen, Dale" sort="Christiansen, Dale" uniqKey="Christiansen D" first="Dale" last="Christiansen">Dale Christiansen</name><affiliation><mods:affiliation>Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France</mods:affiliation></affiliation></author><author><name sortKey="Loveland, Bruce" sort="Loveland, Bruce" uniqKey="Loveland B" first="Bruce" last="Loveland">Bruce Loveland</name><affiliation><mods:affiliation>The Austin Research Institute, Heidelberg, Vic 3084, Australia</mods:affiliation></affiliation></author><author><name sortKey="Kyriakou, Peter" sort="Kyriakou, Peter" uniqKey="Kyriakou P" first="Peter" last="Kyriakou">Peter Kyriakou</name><affiliation><mods:affiliation>The Austin Research Institute, Heidelberg, Vic 3084, Australia</mods:affiliation></affiliation></author><author><name sortKey="Lanteri, Marc" sort="Lanteri, Marc" uniqKey="Lanteri M" first="Marc" last="Lanteri">Marc Lanteri</name><affiliation><mods:affiliation>The Austin Research Institute, Heidelberg, Vic 3084, Australia</mods:affiliation></affiliation></author><author><name sortKey="Rubinstein, Eric" sort="Rubinstein, Eric" uniqKey="Rubinstein E" first="Eric" last="Rubinstein">Eric Rubinstein</name><affiliation><mods:affiliation>INSERM U268, Hopital Paul Brousse, Villejuif, France</mods:affiliation></affiliation></author><author><name sortKey="Gerlier, Denis" sort="Gerlier, Denis" uniqKey="Gerlier D" first="Denis" last="Gerlier">Denis Gerlier</name><affiliation><mods:affiliation>Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France</mods:affiliation></affiliation><affiliation><mods:affiliation>Corresponding author. Tel.: +33-4-78778618; fax: +33-4-78778754</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: gerlier@laennec.univ-lyonl.fr</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j">Molecular Immunology</title><title level="j" type="abbrev">MIMM</title><idno type="ISSN">0161-5890</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="2001">2001</date><biblScope unit="volume">37</biblScope><biblScope unit="issue">12–13</biblScope><biblScope unit="page" from="687">687</biblScope><biblScope unit="page" to="696">696</biblScope></imprint><idno type="ISSN">0161-5890</idno></series><idno type="istex">8F09E47111AE44C0F32A60F48A68E5D6BB932E99</idno><idno type="DOI">10.1016/S0161-5890(01)00002-5</idno><idno type="PII">S0161-5890(01)00002-5</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0161-5890</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>C3b deposition</term><term>CD46</term><term>CD55</term><term>Membrane cofactor protein</term></keywords></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Chimeric proteins using membrane cofactor (CD46) and decay accelerating factor (DAF or CD55) were generated to further investigate the functional domains involved in the regulation of human serum complement. Following activation of the classical pathway, the isolated substitution of CD46 SCR III (×3DAF) exhibited a modest regulatory activity comparable to that of CD46. The isolated substitution of CD46 SCR IV (×4DAF), and the combined CD46 SCR III+IV substitutions (×3/4DAF) were essentially as efficient as DAF. No regulation of C3b deposition was observed with the combined CD46 SCR I+II substitutions (×1/2DAF). When tested after activation of the alternative pathway, both the ×3DAF and ×3/4DAF chimeras failed to regulate C3b deposition, while the ×4DAF chimera still displayed some activity. In contrast to that observed following classical pathway activation, the ×1/2DAF chimera exhibited a similar efficiency to wild type CD46 and DAF in controlling C3b deposition. Using SCR specific antibodies, the regulatory activity of the ×1/2DAF chimera against the alternative pathway was mapped to the first three distal SCR (i.e. DAF 1, DAF 2 and CD46 III). These data demonstrate that several combinations of SCR domains from two related complement regulators can result in functional molecules, and reveal a novel and cryptic functional role for DAF SCR1.</div></front></TEI><istex><corpusName>elsevier</corpusName><author><json:item><name>Dale Christiansen</name><affiliations><json:string>Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France</json:string></affiliations></json:item><json:item><name>Bruce Loveland</name><affiliations><json:string>The Austin Research Institute, Heidelberg, Vic 3084, Australia</json:string></affiliations></json:item><json:item><name>Peter Kyriakou</name><affiliations><json:string>The Austin Research Institute, Heidelberg, Vic 3084, Australia</json:string></affiliations></json:item><json:item><name>Marc Lanteri</name><affiliations><json:string>The Austin Research Institute, Heidelberg, Vic 3084, Australia</json:string></affiliations></json:item><json:item><name>Eric Rubinstein</name><affiliations><json:string>INSERM U268, Hopital Paul Brousse, Villejuif, France</json:string></affiliations></json:item><json:item><name>Denis Gerlier</name><affiliations><json:string>Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France</json:string><json:string>Corresponding author. Tel.: +33-4-78778618; fax: +33-4-78778754</json:string><json:string>E-mail: gerlier@laennec.univ-lyonl.fr</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>CD46</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CD55</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>C3b deposition</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Membrane cofactor protein</value></json:item></subject><language><json:string>eng</json:string></language><originalGenre><json:string>Full-length article</json:string></originalGenre><abstract>Chimeric proteins using membrane cofactor (CD46) and decay accelerating factor (DAF or CD55) were generated to further investigate the functional domains involved in the regulation of human serum complement. Following activation of the classical pathway, the isolated substitution of CD46 SCR III (×3DAF) exhibited a modest regulatory activity comparable to that of CD46. The isolated substitution of CD46 SCR IV (×4DAF), and the combined CD46 SCR III+IV substitutions (×3/4DAF) were essentially as efficient as DAF. No regulation of C3b deposition was observed with the combined CD46 SCR I+II substitutions (×1/2DAF). When tested after activation of the alternative pathway, both the ×3DAF and ×3/4DAF chimeras failed to regulate C3b deposition, while the ×4DAF chimera still displayed some activity. In contrast to that observed following classical pathway activation, the ×1/2DAF chimera exhibited a similar efficiency to wild type CD46 and DAF in controlling C3b deposition. Using SCR specific antibodies, the regulatory activity of the ×1/2DAF chimera against the alternative pathway was mapped to the first three distal SCR (i.e. DAF 1, DAF 2 and CD46 III). These data demonstrate that several combinations of SCR domains from two related complement regulators can result in functional molecules, and reveal a novel and cryptic functional role for DAF SCR1.</abstract><qualityIndicators><score>7.448</score><pdfVersion>1.2</pdfVersion><pdfPageSize>552 x 768 pts</pdfPageSize><refBibsNative>true</refBibsNative><keywordCount>4</keywordCount><abstractCharCount>1363</abstractCharCount><pdfWordCount>6018</pdfWordCount><pdfCharCount>36544</pdfCharCount><pdfPageCount>10</pdfPageCount><abstractWordCount>204</abstractWordCount></qualityIndicators><title>Chimeric CD46/DAF molecules reveal a cryptic functional role for SCR1 of DAF in regulating complement activation</title><pii><json:string>S0161-5890(01)00002-5</json:string></pii><refBibs><json:item><author><json:item><name>P. Accardo</name></json:item><json:item><name>P. Sanchez-Corral</name></json:item><json:item><name>O. Criado</name></json:item><json:item><name>E. 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Cells were incubated with 67% factor B depleted serum and anti-CHO Ab diluted 1:50 for 30 min at 37°C. C3b deposition was determined by flow cytometry after immunolabelling with the anti-C3b mAb WM1. Results are expressed as the percentage of deposition relative to CHO cells, which was defined as 100%. The data show the means (±S.D.) of three experiments.</note><note type="content">Fig. 2: C3b deposition following alternative pathway activation. Cells were incubated with 67% normal human serum and MgCT2/EGTA for 30 min at 37°C. C3b deposition was determined by flow cytometry as described above. Results are expressed as the percentage of deposition relative to CHO cells, which was defined as 100%. The data show the means (±S.D.) of three experiments.</note><note type="content">Fig. 3: C3b deposition following antibody pre-incubation and alternative complement activation. (A) CD46 expressing cells, (B) DAF expressing cells or (C) ×1/2DAF expressing cells were preincubated with either anti-CD46 or anti-DAF mAb for 30 min at 4°C, subsequently 67% normal human serum and MgCT2/EGTA were added for 30 min at 37°C and C3b deposition was determined. Relevant antibodies to each cell type are denoted by the grey filled bars, irrelevant antibodies by spotted bars, and the no antibody controls by the empty bars. Target epitopes for each of the mAb are shown in the figure. The data show the means (±S.D.) of three experiments.</note><note type="content">Fig. 4: Summary of the functional properties of the chimeric CD46/DAF proteins. The combination of SCR affecting regulation of C3b deposition derived from either the alternative (AP) or classical pathway (CP) is shown by the dotted lines. Note the use of the three proximal SCRs (DAF SCR 1+2 CD46 SCR III) in the case of ×1/2DAF. The regulatory efficiency of each chimeric proteins was summarized according to the arbitrary scale: +++, 0–25% C3b deposition (compared with CHO control); ++ 26–50% C3b deposition; + 51–75% C3b deposition, and 76–100% C3b deposition.</note></notesStmt><sourceDesc><biblStruct type="inbook"><analytic><title level="a" type="main" xml:lang="en">Chimeric CD46/DAF molecules reveal a cryptic functional role for SCR1 of DAF in regulating complement activation</title><author xml:id="author-1"><persName><forename type="first">Dale</forename><surname>Christiansen</surname></persName><affiliation>Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France</affiliation></author><author xml:id="author-2"><persName><forename type="first">Bruce</forename><surname>Loveland</surname></persName><affiliation>The Austin Research Institute, Heidelberg, Vic 3084, Australia</affiliation></author><author xml:id="author-3"><persName><forename type="first">Peter</forename><surname>Kyriakou</surname></persName><affiliation>The Austin Research Institute, Heidelberg, Vic 3084, Australia</affiliation></author><author xml:id="author-4"><persName><forename type="first">Marc</forename><surname>Lanteri</surname></persName><affiliation>The Austin Research Institute, Heidelberg, Vic 3084, Australia</affiliation></author><author xml:id="author-5"><persName><forename type="first">Eric</forename><surname>Rubinstein</surname></persName><affiliation>INSERM U268, Hopital Paul Brousse, Villejuif, France</affiliation></author><author xml:id="author-6"><persName><forename type="first">Denis</forename><surname>Gerlier</surname></persName><email>gerlier@laennec.univ-lyonl.fr</email><affiliation>Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France</affiliation><affiliation>Corresponding author. Tel.: +33-4-78778618; fax: +33-4-78778754</affiliation></author></analytic><monogr><title level="j">Molecular Immunology</title><title level="j" type="abbrev">MIMM</title><idno type="pISSN">0161-5890</idno><idno type="PII">S0161-5890(00)X0081-8</idno><imprint><publisher>ELSEVIER</publisher><date type="published" when="2001"></date><biblScope unit="volume">37</biblScope><biblScope unit="issue">12–13</biblScope><biblScope unit="page" from="687">687</biblScope><biblScope unit="page" to="696">696</biblScope></imprint></monogr><idno type="istex">8F09E47111AE44C0F32A60F48A68E5D6BB932E99</idno><idno type="DOI">10.1016/S0161-5890(01)00002-5</idno><idno type="PII">S0161-5890(01)00002-5</idno></biblStruct></sourceDesc></fileDesc><profileDesc><creation><date>2001</date></creation><langUsage><language ident="en">en</language></langUsage><abstract xml:lang="en"><p>Chimeric proteins using membrane cofactor (CD46) and decay accelerating factor (DAF or CD55) were generated to further investigate the functional domains involved in the regulation of human serum complement. Following activation of the classical pathway, the isolated substitution of CD46 SCR III (×3DAF) exhibited a modest regulatory activity comparable to that of CD46. The isolated substitution of CD46 SCR IV (×4DAF), and the combined CD46 SCR III+IV substitutions (×3/4DAF) were essentially as efficient as DAF. No regulation of C3b deposition was observed with the combined CD46 SCR I+II substitutions (×1/2DAF). When tested after activation of the alternative pathway, both the ×3DAF and ×3/4DAF chimeras failed to regulate C3b deposition, while the ×4DAF chimera still displayed some activity. In contrast to that observed following classical pathway activation, the ×1/2DAF chimera exhibited a similar efficiency to wild type CD46 and DAF in controlling C3b deposition. Using SCR specific antibodies, the regulatory activity of the ×1/2DAF chimera against the alternative pathway was mapped to the first three distal SCR (i.e. DAF 1, DAF 2 and CD46 III). These data demonstrate that several combinations of SCR domains from two related complement regulators can result in functional molecules, and reveal a novel and cryptic functional role for DAF SCR1.</p></abstract><textClass xml:lang="en"><keywords scheme="keyword"><list><head>Keywords</head><item><term>CD46</term></item><item><term>CD55</term></item><item><term>C3b deposition</term></item><item><term>Membrane cofactor protein</term></item></list></keywords></textClass></profileDesc><revisionDesc><change when="2001">Published</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/document/8F09E47111AE44C0F32A60F48A68E5D6BB932E99/fulltext/txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="Elsevier, elements deleted: ce:floats; body; tail"><istex:xmlDeclaration>version="1.0" encoding="utf-8"</istex:xmlDeclaration><istex:docType PUBLIC="-//ES//DTD journal article DTD version 4.5.2//EN//XML" URI="art452.dtd" name="istex:docType"><istex:entity SYSTEM="gr1" NDATA="IMAGE" name="gr1"></istex:entity><istex:entity SYSTEM="gr2" NDATA="IMAGE" name="gr2"></istex:entity><istex:entity SYSTEM="gr3" NDATA="IMAGE" name="gr3"></istex:entity><istex:entity SYSTEM="gr4" NDATA="IMAGE" name="gr4"></istex:entity></istex:docType><istex:document><converted-article version="4.5.2" docsubtype="fla" xml:lang="en"><item-info><jid>MIMM</jid><aid>974</aid><ce:pii>S0161-5890(01)00002-5</ce:pii><ce:doi>10.1016/S0161-5890(01)00002-5</ce:doi><ce:copyright type="full-transfer" year="2001">Elsevier Science Ltd</ce:copyright></item-info><head><ce:title>Chimeric CD46/DAF molecules reveal a cryptic functional role for SCR1 of DAF in regulating complement activation</ce:title><ce:author-group><ce:author><ce:given-name>Dale</ce:given-name><ce:surname>Christiansen</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>a</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Bruce</ce:given-name><ce:surname>Loveland</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>b</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Peter</ce:given-name><ce:surname>Kyriakou</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>b</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Marc</ce:given-name><ce:surname>Lanteri</ce:surname><ce:cross-ref refid="AFF2"><ce:sup>b</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Eric</ce:given-name><ce:surname>Rubinstein</ce:surname><ce:cross-ref refid="AFF3"><ce:sup>c</ce:sup></ce:cross-ref></ce:author><ce:author><ce:given-name>Denis</ce:given-name><ce:surname>Gerlier</ce:surname><ce:cross-ref refid="AFF1"><ce:sup>a</ce:sup></ce:cross-ref><ce:cross-ref refid="CORR1">*</ce:cross-ref><ce:e-address>gerlier@laennec.univ-lyonl.fr</ce:e-address></ce:author><ce:affiliation id="AFF1"><ce:label>a</ce:label><ce:textfn>Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France</ce:textfn></ce:affiliation><ce:affiliation id="AFF2"><ce:label>b</ce:label><ce:textfn>The Austin Research Institute, Heidelberg, Vic 3084, Australia</ce:textfn></ce:affiliation><ce:affiliation id="AFF3"><ce:label>c</ce:label><ce:textfn>INSERM U268, Hopital Paul Brousse, Villejuif, France</ce:textfn></ce:affiliation><ce:correspondence id="CORR1"><ce:label>*</ce:label><ce:text>Corresponding author. Tel.: +33-4-78778618; fax: +33-4-78778754</ce:text></ce:correspondence></ce:author-group><ce:date-received day="30" month="10" year="2000"></ce:date-received><ce:date-accepted day="19" month="12" year="2000"></ce:date-accepted><ce:abstract><ce:section-title>Abstract</ce:section-title><ce:abstract-sec><ce:simple-para>Chimeric proteins using membrane cofactor (CD46) and decay accelerating factor (DAF or CD55) were generated to further investigate the functional domains involved in the regulation of human serum complement. Following activation of the classical pathway, the isolated substitution of CD46 SCR III (×3DAF) exhibited a modest regulatory activity comparable to that of CD46. The isolated substitution of CD46 SCR IV (×4DAF), and the combined CD46 SCR III+IV substitutions (×3/4DAF) were essentially as efficient as DAF. No regulation of C3b deposition was observed with the combined CD46 SCR I+II substitutions (×1/2DAF). When tested after activation of the alternative pathway, both the ×3DAF and ×3/4DAF chimeras failed to regulate C3b deposition, while the ×4DAF chimera still displayed some activity. In contrast to that observed following classical pathway activation, the ×1/2DAF chimera exhibited a similar efficiency to wild type CD46 and DAF in controlling C3b deposition. Using SCR specific antibodies, the regulatory activity of the ×1/2DAF chimera against the alternative pathway was mapped to the first three distal SCR (i.e. DAF 1, DAF 2 and CD46 III). These data demonstrate that several combinations of SCR domains from two related complement regulators can result in functional molecules, and reveal a novel and cryptic functional role for DAF SCR1.</ce:simple-para></ce:abstract-sec></ce:abstract><ce:keywords class="keyword"><ce:section-title>Keywords</ce:section-title><ce:keyword><ce:text>CD46</ce:text></ce:keyword><ce:keyword><ce:text>CD55</ce:text></ce:keyword><ce:keyword><ce:text>C3b deposition</ce:text></ce:keyword><ce:keyword><ce:text>Membrane cofactor protein</ce:text></ce:keyword></ce:keywords></head></converted-article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Chimeric CD46/DAF molecules reveal a cryptic functional role for SCR1 of DAF in regulating complement activation</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Chimeric CD46/DAF molecules reveal a cryptic functional role for SCR1 of DAF in regulating complement activation</title></titleInfo><name type="personal"><namePart type="given">Dale</namePart><namePart type="family">Christiansen</namePart><affiliation>Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bruce</namePart><namePart type="family">Loveland</namePart><affiliation>The Austin Research Institute, Heidelberg, Vic 3084, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Peter</namePart><namePart type="family">Kyriakou</namePart><affiliation>The Austin Research Institute, Heidelberg, Vic 3084, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Marc</namePart><namePart type="family">Lanteri</namePart><affiliation>The Austin Research Institute, Heidelberg, Vic 3084, Australia</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Eric</namePart><namePart type="family">Rubinstein</namePart><affiliation>INSERM U268, Hopital Paul Brousse, Villejuif, France</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Denis</namePart><namePart type="family">Gerlier</namePart><affiliation>Immunité and Infections Virales, V.P.V., CNRS-UCBL UMR 5537, Faculté de Médecine Laennec, 69372 Lyon Cedex 08, France</affiliation><affiliation>Corresponding author. Tel.: +33-4-78778618; fax: +33-4-78778754</affiliation><affiliation>E-mail: gerlier@laennec.univ-lyonl.fr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="Full-length article"></genre><originInfo><publisher>ELSEVIER</publisher><dateIssued encoding="w3cdtf">2001</dateIssued><copyrightDate encoding="w3cdtf">2001</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><physicalDescription><internetMediaType>text/html</internetMediaType></physicalDescription><abstract lang="en">Chimeric proteins using membrane cofactor (CD46) and decay accelerating factor (DAF or CD55) were generated to further investigate the functional domains involved in the regulation of human serum complement. Following activation of the classical pathway, the isolated substitution of CD46 SCR III (×3DAF) exhibited a modest regulatory activity comparable to that of CD46. The isolated substitution of CD46 SCR IV (×4DAF), and the combined CD46 SCR III+IV substitutions (×3/4DAF) were essentially as efficient as DAF. No regulation of C3b deposition was observed with the combined CD46 SCR I+II substitutions (×1/2DAF). When tested after activation of the alternative pathway, both the ×3DAF and ×3/4DAF chimeras failed to regulate C3b deposition, while the ×4DAF chimera still displayed some activity. In contrast to that observed following classical pathway activation, the ×1/2DAF chimera exhibited a similar efficiency to wild type CD46 and DAF in controlling C3b deposition. Using SCR specific antibodies, the regulatory activity of the ×1/2DAF chimera against the alternative pathway was mapped to the first three distal SCR (i.e. DAF 1, DAF 2 and CD46 III). These data demonstrate that several combinations of SCR domains from two related complement regulators can result in functional molecules, and reveal a novel and cryptic functional role for DAF SCR1.</abstract><note type="content">Fig. 1: C3b deposition derived exclusively following classical pathway activation. Cells were incubated with 67% factor B depleted serum and anti-CHO Ab diluted 1:50 for 30 min at 37°C. C3b deposition was determined by flow cytometry after immunolabelling with the anti-C3b mAb WM1. Results are expressed as the percentage of deposition relative to CHO cells, which was defined as 100%. The data show the means (±S.D.) of three experiments.</note><note type="content">Fig. 2: C3b deposition following alternative pathway activation. Cells were incubated with 67% normal human serum and MgCT2/EGTA for 30 min at 37°C. C3b deposition was determined by flow cytometry as described above. Results are expressed as the percentage of deposition relative to CHO cells, which was defined as 100%. The data show the means (±S.D.) of three experiments.</note><note type="content">Fig. 3: C3b deposition following antibody pre-incubation and alternative complement activation. (A) CD46 expressing cells, (B) DAF expressing cells or (C) ×1/2DAF expressing cells were preincubated with either anti-CD46 or anti-DAF mAb for 30 min at 4°C, subsequently 67% normal human serum and MgCT2/EGTA were added for 30 min at 37°C and C3b deposition was determined. Relevant antibodies to each cell type are denoted by the grey filled bars, irrelevant antibodies by spotted bars, and the no antibody controls by the empty bars. Target epitopes for each of the mAb are shown in the figure. The data show the means (±S.D.) of three experiments.</note><note type="content">Fig. 4: Summary of the functional properties of the chimeric CD46/DAF proteins. The combination of SCR affecting regulation of C3b deposition derived from either the alternative (AP) or classical pathway (CP) is shown by the dotted lines. Note the use of the three proximal SCRs (DAF SCR 1+2 CD46 SCR III) in the case of ×1/2DAF. The regulatory efficiency of each chimeric proteins was summarized according to the arbitrary scale: +++, 0–25% C3b deposition (compared with CHO control); ++ 26–50% C3b deposition; + 51–75% C3b deposition, and 76–100% C3b deposition.</note><subject lang="en"><genre>Keywords</genre><topic>CD46</topic><topic>CD55</topic><topic>C3b deposition</topic><topic>Membrane cofactor protein</topic></subject><relatedItem type="host"><titleInfo><title>Molecular Immunology</title></titleInfo><titleInfo type="abbreviated"><title>MIMM</title></titleInfo><genre type="journal">journal</genre><originInfo><dateIssued encoding="w3cdtf">20000901</dateIssued></originInfo><identifier type="ISSN">0161-5890</identifier><identifier type="PII">S0161-5890(00)X0081-8</identifier><part><date>20000901</date><detail type="volume"><number>37</number><caption>vol.</caption></detail><detail type="issue"><number>12–13</number><caption>no.</caption></detail><extent unit="issue pages"><start>687</start><end>801</end></extent><extent unit="pages"><start>687</start><end>696</end></extent></part></relatedItem><identifier type="istex">8F09E47111AE44C0F32A60F48A68E5D6BB932E99</identifier><identifier type="DOI">10.1016/S0161-5890(01)00002-5</identifier><identifier type="PII">S0161-5890(01)00002-5</identifier><accessCondition type="use and reproduction" contentType="copyright">©2001 Elsevier Science Ltd</accessCondition><recordInfo><recordContentSource>ELSEVIER</recordContentSource><recordOrigin>Elsevier Science Ltd, ©2001</recordOrigin></recordInfo></mods></metadata><serie></serie></istex></record>Pour manipuler ce document sous Unix (Dilib)
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