Congenital heart block maternal sera autoantibodies target an extracellular epitope on the α1G T-type calcium channel in human fetal hearts
Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subun...
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| Veröffentlicht in: | PloS one 2013-09, Vol.8 (9), p.e72668-e72668 |
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| creator | Strandberg, Linn S Cui, Xuezhi Rath, Arianna Liu, Jie Silverman, Earl D Liu, Xiaoru Siragam, Vinayakumar Ackerley, Cameron Su, Brenda Bin Yan, Jane Yuqing Capecchi, Marco Biavati, Luca Accorroni, Alice Yuen, William Quattrone, Filippo Lung, Kalvin Jaeggi, Edgar T Backx, Peter H Deber, Charles M Hamilton, Robert M |
| description | Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB.
We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Using human fetal hearts (20-22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.
Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets. |
| doi_str_mv | 10.1371/journal.pone.0072668 |
| format | Article |
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We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Using human fetal hearts (20-22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.
Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0072668</identifier><identifier>PMID: 24039792</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Amino Acid Sequence ; Amino acids ; Animals ; Antibodies ; Atrioventricular Node - drug effects ; Atrioventricular Node - metabolism ; Autoantibodies ; Autoantibodies - blood ; Autoantibodies - immunology ; Autoantigens - immunology ; Calcium ; Calcium Channel Blockers - pharmacology ; Calcium channels ; Calcium channels (T-type) ; Calcium Channels, T-Type - chemistry ; Calcium Channels, T-Type - genetics ; Calcium Channels, T-Type - immunology ; Cardiac arrhythmia ; Cardiomyocytes ; Congenital diseases ; Congenital heart block ; Electrophysiology ; Enzyme-linked immunosorbent assay ; Epitope Mapping ; Epitopes ; Epitopes - immunology ; Extracellular Space ; Female ; Fetal Heart - drug effects ; Fetal Heart - immunology ; Fetal Heart - metabolism ; Fetuses ; Gene Expression ; Gestation ; Heart ; Heart Block - congenital ; Heart Block - genetics ; Heart Block - immunology ; Homology ; Humans ; Immunofluorescence ; Immunoglobulins ; Immunoprecipitation ; Male ; Maternal-Fetal Exchange - immunology ; Medicine ; Mice ; Molecular Sequence Data ; Molecular structure ; Myocytes, Cardiac - immunology ; Myocytes, Cardiac - metabolism ; Peptides - immunology ; Physiology ; Pregnancy ; Proteins ; Rabbits ; Reactivity ; Ro(SSA) antigen ; Rodents ; Sinuses ; Xenopus</subject><ispartof>PloS one, 2013-09, Vol.8 (9), p.e72668-e72668</ispartof><rights>2013 Strandberg et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Strandberg et al 2013 Strandberg et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-d29d0b3bf61b4db5b5c213c8384988c902715dbebcfc2e130e699f22d1e78e6a3</citedby><cites>FETCH-LOGICAL-c526t-d29d0b3bf61b4db5b5c213c8384988c902715dbebcfc2e130e699f22d1e78e6a3</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/PMC3767782/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3767782/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24039792$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Strandberg, Linn S</creatorcontrib><creatorcontrib>Cui, Xuezhi</creatorcontrib><creatorcontrib>Rath, Arianna</creatorcontrib><creatorcontrib>Liu, Jie</creatorcontrib><creatorcontrib>Silverman, Earl D</creatorcontrib><creatorcontrib>Liu, Xiaoru</creatorcontrib><creatorcontrib>Siragam, Vinayakumar</creatorcontrib><creatorcontrib>Ackerley, Cameron</creatorcontrib><creatorcontrib>Su, Brenda Bin</creatorcontrib><creatorcontrib>Yan, Jane Yuqing</creatorcontrib><creatorcontrib>Capecchi, Marco</creatorcontrib><creatorcontrib>Biavati, Luca</creatorcontrib><creatorcontrib>Accorroni, Alice</creatorcontrib><creatorcontrib>Yuen, William</creatorcontrib><creatorcontrib>Quattrone, Filippo</creatorcontrib><creatorcontrib>Lung, Kalvin</creatorcontrib><creatorcontrib>Jaeggi, Edgar T</creatorcontrib><creatorcontrib>Backx, Peter H</creatorcontrib><creatorcontrib>Deber, Charles M</creatorcontrib><creatorcontrib>Hamilton, Robert M</creatorcontrib><title>Congenital heart block maternal sera autoantibodies target an extracellular epitope on the α1G T-type calcium channel in human fetal hearts</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB.
We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Using human fetal hearts (20-22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.
Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.</description><subject>Amino Acid Sequence</subject><subject>Amino acids</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Atrioventricular Node - drug effects</subject><subject>Atrioventricular Node - metabolism</subject><subject>Autoantibodies</subject><subject>Autoantibodies - blood</subject><subject>Autoantibodies - immunology</subject><subject>Autoantigens - immunology</subject><subject>Calcium</subject><subject>Calcium Channel Blockers - pharmacology</subject><subject>Calcium channels</subject><subject>Calcium channels (T-type)</subject><subject>Calcium Channels, T-Type - chemistry</subject><subject>Calcium Channels, T-Type - genetics</subject><subject>Calcium Channels, T-Type - immunology</subject><subject>Cardiac arrhythmia</subject><subject>Cardiomyocytes</subject><subject>Congenital diseases</subject><subject>Congenital heart block</subject><subject>Electrophysiology</subject><subject>Enzyme-linked immunosorbent assay</subject><subject>Epitope Mapping</subject><subject>Epitopes</subject><subject>Epitopes - immunology</subject><subject>Extracellular Space</subject><subject>Female</subject><subject>Fetal Heart - drug effects</subject><subject>Fetal Heart - immunology</subject><subject>Fetal Heart - metabolism</subject><subject>Fetuses</subject><subject>Gene Expression</subject><subject>Gestation</subject><subject>Heart</subject><subject>Heart Block - congenital</subject><subject>Heart Block - genetics</subject><subject>Heart Block - immunology</subject><subject>Homology</subject><subject>Humans</subject><subject>Immunofluorescence</subject><subject>Immunoglobulins</subject><subject>Immunoprecipitation</subject><subject>Male</subject><subject>Maternal-Fetal Exchange - immunology</subject><subject>Medicine</subject><subject>Mice</subject><subject>Molecular Sequence Data</subject><subject>Molecular structure</subject><subject>Myocytes, Cardiac - immunology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Peptides - immunology</subject><subject>Physiology</subject><subject>Pregnancy</subject><subject>Proteins</subject><subject>Rabbits</subject><subject>Reactivity</subject><subject>Ro(SSA) 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heart block maternal sera autoantibodies target an extracellular epitope on the α1G T-type calcium channel in human fetal hearts</title><author>Strandberg, Linn S ; Cui, Xuezhi ; Rath, Arianna ; Liu, Jie ; Silverman, Earl D ; Liu, Xiaoru ; Siragam, Vinayakumar ; Ackerley, Cameron ; Su, Brenda Bin ; Yan, Jane Yuqing ; Capecchi, Marco ; Biavati, Luca ; Accorroni, Alice ; Yuen, William ; Quattrone, Filippo ; Lung, Kalvin ; Jaeggi, Edgar T ; Backx, Peter H ; Deber, Charles M ; Hamilton, Robert M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-d29d0b3bf61b4db5b5c213c8384988c902715dbebcfc2e130e699f22d1e78e6a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amino Acid Sequence</topic><topic>Amino acids</topic><topic>Animals</topic><topic>Antibodies</topic><topic>Atrioventricular Node - drug effects</topic><topic>Atrioventricular Node - 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Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Strandberg, Linn S</au><au>Cui, Xuezhi</au><au>Rath, Arianna</au><au>Liu, Jie</au><au>Silverman, Earl D</au><au>Liu, Xiaoru</au><au>Siragam, Vinayakumar</au><au>Ackerley, Cameron</au><au>Su, Brenda Bin</au><au>Yan, Jane Yuqing</au><au>Capecchi, Marco</au><au>Biavati, Luca</au><au>Accorroni, Alice</au><au>Yuen, William</au><au>Quattrone, Filippo</au><au>Lung, Kalvin</au><au>Jaeggi, Edgar T</au><au>Backx, Peter H</au><au>Deber, Charles M</au><au>Hamilton, Robert M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Congenital heart block maternal sera autoantibodies target an extracellular epitope on the α1G T-type calcium channel in human fetal hearts</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-09-09</date><risdate>2013</risdate><volume>8</volume><issue>9</issue><spage>e72668</spage><epage>e72668</epage><pages>e72668-e72668</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB.
We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Using human fetal hearts (20-22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells.
Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24039792</pmid><doi>10.1371/journal.pone.0072668</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-09, Vol.8 (9), p.e72668-e72668 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1431102506 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Amino Acid Sequence Amino acids Animals Antibodies Atrioventricular Node - drug effects Atrioventricular Node - metabolism Autoantibodies Autoantibodies - blood Autoantibodies - immunology Autoantigens - immunology Calcium Calcium Channel Blockers - pharmacology Calcium channels Calcium channels (T-type) Calcium Channels, T-Type - chemistry Calcium Channels, T-Type - genetics Calcium Channels, T-Type - immunology Cardiac arrhythmia Cardiomyocytes Congenital diseases Congenital heart block Electrophysiology Enzyme-linked immunosorbent assay Epitope Mapping Epitopes Epitopes - immunology Extracellular Space Female Fetal Heart - drug effects Fetal Heart - immunology Fetal Heart - metabolism Fetuses Gene Expression Gestation Heart Heart Block - congenital Heart Block - genetics Heart Block - immunology Homology Humans Immunofluorescence Immunoglobulins Immunoprecipitation Male Maternal-Fetal Exchange - immunology Medicine Mice Molecular Sequence Data Molecular structure Myocytes, Cardiac - immunology Myocytes, Cardiac - metabolism Peptides - immunology Physiology Pregnancy Proteins Rabbits Reactivity Ro(SSA) antigen Rodents Sinuses Xenopus |
| title | Congenital heart block maternal sera autoantibodies target an extracellular epitope on the α1G T-type calcium channel in human fetal hearts |
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