Analysis of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study
In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as γ-H2AX. Formation of γ-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand br...
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| Veröffentlicht in: | PloS one 2016-01, Vol.11 (1), p.e0147968-e0147968 |
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| creator | Rasche, Ludwig Heiserich, Lisa Behrens, Janina Ruth Lenz, Klaus Pfuhl, Catherina Wakonig, Katharina Gieß, René Markus Freitag, Erik Eberle, Caroline Wuerfel, Jens Dörr, Jan Bauer, Peter Bellmann-Strobl, Judith Paul, Friedemann Roggenbuck, Dirk Ruprecht, Klemens |
| description | In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as γ-H2AX. Formation of γ-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. γ-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS).
To evaluate the significance of γ-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated γ-H2AX and 53BP1 foci detection.
Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with γ-H2AX and 53BP1 specific antibodies. Nuclear γ-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of γ-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. γ-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls.
The median (range) number of γ-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0-0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, γ-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. γ-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although γ-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, γ-H2AX values of both groups overlapped and γ-H2AX did not correlate with the number or volume of CEL.
γ-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS. |
| doi_str_mv | 10.1371/journal.pone.0147968 |
| format | Article |
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To evaluate the significance of γ-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated γ-H2AX and 53BP1 foci detection.
Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with γ-H2AX and 53BP1 specific antibodies. Nuclear γ-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of γ-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. γ-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls.
The median (range) number of γ-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0-0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, γ-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. γ-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although γ-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, γ-H2AX values of both groups overlapped and γ-H2AX did not correlate with the number or volume of CEL.
γ-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0147968</identifier><identifier>PMID: 26820970</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Antibodies ; Autoimmune diseases ; Automatic control ; Automation ; Biology and Life Sciences ; Biomarkers ; Biomarkers - metabolism ; Case-Control Studies ; Cell cycle ; Damage detection ; Deoxyribonucleic acid ; Development and progression ; Diagnostic systems ; DNA ; DNA Damage ; Female ; Gene expression ; Genetic aspects ; Histones - metabolism ; Humans ; Immunocytochemistry ; Intracellular Signaling Peptides and Proteins - metabolism ; Lesions ; Leukocytes (mononuclear) ; Lymphocytes ; Lymphocytes - metabolism ; Magnetic resonance ; Magnetic resonance imaging ; Male ; Medical diagnosis ; Medicine and Health Sciences ; Microscopy ; Middle Aged ; Multiple sclerosis ; Multiple Sclerosis - genetics ; Multiple Sclerosis - metabolism ; Multiple Sclerosis - pathology ; Neurology ; NMR ; Nuclear magnetic resonance ; Oxidative stress ; p53 Protein ; Pathogenesis ; Patients ; Peripheral blood mononuclear cells ; Physiological aspects ; Recruitment ; Research and Analysis Methods ; Serine ; Technology application ; Tumor Suppressor p53-Binding Protein 1 ; Young Adult</subject><ispartof>PloS one, 2016-01, Vol.11 (1), p.e0147968-e0147968</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Rasche et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://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>2016 Rasche et al 2016 Rasche et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-64e1c8cc58bcba1d2870afd0f8f524dd875818101de0d50432882b5e7fdd31203</citedby><cites>FETCH-LOGICAL-c692t-64e1c8cc58bcba1d2870afd0f8f524dd875818101de0d50432882b5e7fdd31203</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/PMC4731473/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731473/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26820970$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Reindl, Markus</contributor><creatorcontrib>Rasche, Ludwig</creatorcontrib><creatorcontrib>Heiserich, Lisa</creatorcontrib><creatorcontrib>Behrens, Janina Ruth</creatorcontrib><creatorcontrib>Lenz, Klaus</creatorcontrib><creatorcontrib>Pfuhl, Catherina</creatorcontrib><creatorcontrib>Wakonig, Katharina</creatorcontrib><creatorcontrib>Gieß, René Markus</creatorcontrib><creatorcontrib>Freitag, Erik</creatorcontrib><creatorcontrib>Eberle, Caroline</creatorcontrib><creatorcontrib>Wuerfel, Jens</creatorcontrib><creatorcontrib>Dörr, Jan</creatorcontrib><creatorcontrib>Bauer, Peter</creatorcontrib><creatorcontrib>Bellmann-Strobl, Judith</creatorcontrib><creatorcontrib>Paul, Friedemann</creatorcontrib><creatorcontrib>Roggenbuck, Dirk</creatorcontrib><creatorcontrib>Ruprecht, Klemens</creatorcontrib><title>Analysis of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as γ-H2AX. Formation of γ-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. γ-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS).
To evaluate the significance of γ-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated γ-H2AX and 53BP1 foci detection.
Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with γ-H2AX and 53BP1 specific antibodies. Nuclear γ-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of γ-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. γ-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls.
The median (range) number of γ-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0-0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, γ-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. γ-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although γ-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, γ-H2AX values of both groups overlapped and γ-H2AX did not correlate with the number or volume of CEL.
γ-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS.</description><subject>Adult</subject><subject>Antibodies</subject><subject>Autoimmune diseases</subject><subject>Automatic control</subject><subject>Automation</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Biomarkers - metabolism</subject><subject>Case-Control Studies</subject><subject>Cell cycle</subject><subject>Damage detection</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>Diagnostic systems</subject><subject>DNA</subject><subject>DNA Damage</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Immunocytochemistry</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>Lesions</subject><subject>Leukocytes (mononuclear)</subject><subject>Lymphocytes</subject><subject>Lymphocytes - metabolism</subject><subject>Magnetic resonance</subject><subject>Magnetic resonance imaging</subject><subject>Male</subject><subject>Medical diagnosis</subject><subject>Medicine and Health Sciences</subject><subject>Microscopy</subject><subject>Middle Aged</subject><subject>Multiple sclerosis</subject><subject>Multiple Sclerosis - genetics</subject><subject>Multiple Sclerosis - metabolism</subject><subject>Multiple Sclerosis - pathology</subject><subject>Neurology</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Oxidative stress</subject><subject>p53 Protein</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Peripheral blood mononuclear cells</subject><subject>Physiological aspects</subject><subject>Recruitment</subject><subject>Research and Analysis Methods</subject><subject>Serine</subject><subject>Technology application</subject><subject>Tumor Suppressor p53-Binding Protein 1</subject><subject>Young 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of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study</title><author>Rasche, Ludwig ; Heiserich, Lisa ; Behrens, Janina Ruth ; Lenz, Klaus ; Pfuhl, Catherina ; Wakonig, Katharina ; Gieß, René Markus ; Freitag, Erik ; Eberle, Caroline ; Wuerfel, Jens ; Dörr, Jan ; Bauer, Peter ; Bellmann-Strobl, Judith ; Paul, Friedemann ; Roggenbuck, Dirk ; Ruprecht, Klemens</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-64e1c8cc58bcba1d2870afd0f8f524dd875818101de0d50432882b5e7fdd31203</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adult</topic><topic>Antibodies</topic><topic>Autoimmune diseases</topic><topic>Automatic control</topic><topic>Automation</topic><topic>Biology and Life Sciences</topic><topic>Biomarkers</topic><topic>Biomarkers - metabolism</topic><topic>Case-Control Studies</topic><topic>Cell 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Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Rasche, Ludwig</au><au>Heiserich, Lisa</au><au>Behrens, Janina Ruth</au><au>Lenz, Klaus</au><au>Pfuhl, Catherina</au><au>Wakonig, Katharina</au><au>Gieß, René Markus</au><au>Freitag, Erik</au><au>Eberle, Caroline</au><au>Wuerfel, Jens</au><au>Dörr, Jan</au><au>Bauer, Peter</au><au>Bellmann-Strobl, Judith</au><au>Paul, Friedemann</au><au>Roggenbuck, Dirk</au><au>Ruprecht, Klemens</au><au>Reindl, Markus</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-01-28</date><risdate>2016</risdate><volume>11</volume><issue>1</issue><spage>e0147968</spage><epage>e0147968</epage><pages>e0147968-e0147968</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as γ-H2AX. Formation of γ-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. γ-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS).
To evaluate the significance of γ-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated γ-H2AX and 53BP1 foci detection.
Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with γ-H2AX and 53BP1 specific antibodies. Nuclear γ-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of γ-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. γ-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls.
The median (range) number of γ-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0-0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, γ-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. γ-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although γ-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, γ-H2AX values of both groups overlapped and γ-H2AX did not correlate with the number or volume of CEL.
γ-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26820970</pmid><doi>10.1371/journal.pone.0147968</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-01, Vol.11 (1), p.e0147968-e0147968 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1761076283 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adult Antibodies Autoimmune diseases Automatic control Automation Biology and Life Sciences Biomarkers Biomarkers - metabolism Case-Control Studies Cell cycle Damage detection Deoxyribonucleic acid Development and progression Diagnostic systems DNA DNA Damage Female Gene expression Genetic aspects Histones - metabolism Humans Immunocytochemistry Intracellular Signaling Peptides and Proteins - metabolism Lesions Leukocytes (mononuclear) Lymphocytes Lymphocytes - metabolism Magnetic resonance Magnetic resonance imaging Male Medical diagnosis Medicine and Health Sciences Microscopy Middle Aged Multiple sclerosis Multiple Sclerosis - genetics Multiple Sclerosis - metabolism Multiple Sclerosis - pathology Neurology NMR Nuclear magnetic resonance Oxidative stress p53 Protein Pathogenesis Patients Peripheral blood mononuclear cells Physiological aspects Recruitment Research and Analysis Methods Serine Technology application Tumor Suppressor p53-Binding Protein 1 Young Adult |
| title | Analysis of Lymphocytic DNA Damage in Early Multiple Sclerosis by Automated Gamma-H2AX and 53BP1 Foci Detection: A Case Control Study |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-26T10%3A37%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Analysis%20of%20Lymphocytic%20DNA%20Damage%20in%20Early%20Multiple%20Sclerosis%20by%20Automated%20Gamma-H2AX%20and%2053BP1%20Foci%20Detection:%20A%20Case%20Control%20Study&rft.jtitle=PloS%20one&rft.au=Rasche,%20Ludwig&rft.date=2016-01-28&rft.volume=11&rft.issue=1&rft.spage=e0147968&rft.epage=e0147968&rft.pages=e0147968-e0147968&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0147968&rft_dat=%3Cgale_plos_%3EA441646842%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1761076283&rft_id=info:pmid/26820970&rft_galeid=A441646842&rft_doaj_id=oai_doaj_org_article_65d7438056b149d29e45545d44831cac&rfr_iscdi=true |