Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products
The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain injuries is recognized but not well understood. In this study, a systematic investigation was performed to identify serum autoantibody responses to brain-specific proteins after TBI in humans. TBI autoan...
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| Veröffentlicht in: | PloS one 2014-03, Vol.9 (3), p.e92698-e92698 |
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| creator | Zhang, Zhiqun Zoltewicz, J Susie Mondello, Stefania Newsom, Kimberly J Yang, Zhihui Yang, Boxuan Kobeissy, Firas Guingab, Joy Glushakova, Olena Robicsek, Steven Heaton, Shelley Buki, Andras Hannay, Julia Gold, Mark S Rubenstein, Richard Lu, Xi-Chun May Dave, Jitendra R Schmid, Kara Tortella, Frank Robertson, Claudia S Wang, Kevin K W |
| description | The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain injuries is recognized but not well understood. In this study, a systematic investigation was performed to identify serum autoantibody responses to brain-specific proteins after TBI in humans. TBI autoantibodies showed predominant immunoreactivity against a cluster of bands from 38-50 kDa on human brain immunoblots, which were identified as GFAP and GFAP breakdown products. GFAP autoantibody levels increased by 7 days after injury, and were of the IgG subtype predominantly. Results from in vitro tests and rat TBI experiments also indicated that calpain was responsible for removing the amino and carboxyl termini of GFAP to yield a 38 kDa fragment. Additionally, TBI autoantibody staining co-localized with GFAP in injured rat brain and in primary rat astrocytes. These results suggest that GFAP breakdown products persist within degenerating astrocytes in the brain. Anti-GFAP autoantibody also can enter living astroglia cells in culture and its presence appears to compromise glial cell health. TBI patients showed an average 3.77 fold increase in anti-GFAP autoantibody levels from early (0-1 days) to late (7-10 days) times post injury. Changes in autoantibody levels were negatively correlated with outcome as measured by GOS-E score at 6 months, suggesting that TBI patients with greater anti-GFAP immune-responses had worse outcomes. Due to the long lasting nature of IgG, a test to detect anti-GFAP autoantibodies is likely to prolong the temporal window for assessment of brain damage in human patients. |
| doi_str_mv | 10.1371/journal.pone.0092698 |
| format | Article |
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In this study, a systematic investigation was performed to identify serum autoantibody responses to brain-specific proteins after TBI in humans. TBI autoantibodies showed predominant immunoreactivity against a cluster of bands from 38-50 kDa on human brain immunoblots, which were identified as GFAP and GFAP breakdown products. GFAP autoantibody levels increased by 7 days after injury, and were of the IgG subtype predominantly. Results from in vitro tests and rat TBI experiments also indicated that calpain was responsible for removing the amino and carboxyl termini of GFAP to yield a 38 kDa fragment. Additionally, TBI autoantibody staining co-localized with GFAP in injured rat brain and in primary rat astrocytes. These results suggest that GFAP breakdown products persist within degenerating astrocytes in the brain. Anti-GFAP autoantibody also can enter living astroglia cells in culture and its presence appears to compromise glial cell health. TBI patients showed an average 3.77 fold increase in anti-GFAP autoantibody levels from early (0-1 days) to late (7-10 days) times post injury. Changes in autoantibody levels were negatively correlated with outcome as measured by GOS-E score at 6 months, suggesting that TBI patients with greater anti-GFAP immune-responses had worse outcomes. Due to the long lasting nature of IgG, a test to detect anti-GFAP autoantibodies is likely to prolong the temporal window for assessment of brain damage in human patients.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0092698</identifier><identifier>PMID: 24667434</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Animal experimentation ; Animals ; Antigens ; Apoptosis ; Astrocytes ; Astrocytes - immunology ; Astrocytes - metabolism ; Astrocytes - pathology ; Autoantibodies ; Autoantibodies - blood ; Autoantibodies - immunology ; Autoimmunity ; Biology and Life Sciences ; Biomarkers ; Brain ; Brain damage ; Brain injuries ; Brain Injuries - blood ; Brain Injuries - immunology ; Brain Injuries - pathology ; Brain research ; Breakdown ; Calpain ; Cell culture ; Correlation analysis ; Damage assessment ; Disease ; Female ; Glial fibrillary acidic protein ; Glial Fibrillary Acidic Protein - immunology ; Head injuries ; Health care ; Humans ; Immune response ; Immunoglobulin G ; Immunoglobulin G - blood ; Immunoglobulin G - immunology ; Immunoglobulins ; Immunoreactivity ; In vitro methods and tests ; Intermediate filament proteins ; Male ; Medicine and Health Sciences ; Multiple sclerosis ; Nervous system ; Neurosciences ; Neurosurgery ; Patients ; Proteins ; Psychiatry ; Rats ; Rats, Sprague-Dawley ; Research and Analysis Methods ; Time Factors ; Trauma ; Traumatic brain injury</subject><ispartof>PloS one, 2014-03, Vol.9 (3), p.e92698-e92698</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Zhang 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>2014 Zhang et al 2014 Zhang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c796t-9dc0e2f1ceec1c9571c5e63951de50569244de128ef3e7d2eecc94a7d17895523</citedby><cites>FETCH-LOGICAL-c796t-9dc0e2f1ceec1c9571c5e63951de50569244de128ef3e7d2eecc94a7d17895523</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/PMC3965455/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3965455/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,550,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79342,79343</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24667434$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-113590$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Zhiqun</creatorcontrib><creatorcontrib>Zoltewicz, J Susie</creatorcontrib><creatorcontrib>Mondello, Stefania</creatorcontrib><creatorcontrib>Newsom, Kimberly J</creatorcontrib><creatorcontrib>Yang, Zhihui</creatorcontrib><creatorcontrib>Yang, Boxuan</creatorcontrib><creatorcontrib>Kobeissy, Firas</creatorcontrib><creatorcontrib>Guingab, Joy</creatorcontrib><creatorcontrib>Glushakova, Olena</creatorcontrib><creatorcontrib>Robicsek, Steven</creatorcontrib><creatorcontrib>Heaton, Shelley</creatorcontrib><creatorcontrib>Buki, Andras</creatorcontrib><creatorcontrib>Hannay, Julia</creatorcontrib><creatorcontrib>Gold, Mark S</creatorcontrib><creatorcontrib>Rubenstein, Richard</creatorcontrib><creatorcontrib>Lu, Xi-Chun May</creatorcontrib><creatorcontrib>Dave, Jitendra R</creatorcontrib><creatorcontrib>Schmid, Kara</creatorcontrib><creatorcontrib>Tortella, Frank</creatorcontrib><creatorcontrib>Robertson, Claudia S</creatorcontrib><creatorcontrib>Wang, Kevin K W</creatorcontrib><title>Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain injuries is recognized but not well understood. In this study, a systematic investigation was performed to identify serum autoantibody responses to brain-specific proteins after TBI in humans. TBI autoantibodies showed predominant immunoreactivity against a cluster of bands from 38-50 kDa on human brain immunoblots, which were identified as GFAP and GFAP breakdown products. GFAP autoantibody levels increased by 7 days after injury, and were of the IgG subtype predominantly. Results from in vitro tests and rat TBI experiments also indicated that calpain was responsible for removing the amino and carboxyl termini of GFAP to yield a 38 kDa fragment. Additionally, TBI autoantibody staining co-localized with GFAP in injured rat brain and in primary rat astrocytes. These results suggest that GFAP breakdown products persist within degenerating astrocytes in the brain. Anti-GFAP autoantibody also can enter living astroglia cells in culture and its presence appears to compromise glial cell health. TBI patients showed an average 3.77 fold increase in anti-GFAP autoantibody levels from early (0-1 days) to late (7-10 days) times post injury. Changes in autoantibody levels were negatively correlated with outcome as measured by GOS-E score at 6 months, suggesting that TBI patients with greater anti-GFAP immune-responses had worse outcomes. Due to the long lasting nature of IgG, a test to detect anti-GFAP autoantibodies is likely to prolong the temporal window for assessment of brain damage in human patients.</description><subject>Adult</subject><subject>Animal experimentation</subject><subject>Animals</subject><subject>Antigens</subject><subject>Apoptosis</subject><subject>Astrocytes</subject><subject>Astrocytes - immunology</subject><subject>Astrocytes - metabolism</subject><subject>Astrocytes - pathology</subject><subject>Autoantibodies</subject><subject>Autoantibodies - blood</subject><subject>Autoantibodies - immunology</subject><subject>Autoimmunity</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Brain</subject><subject>Brain damage</subject><subject>Brain injuries</subject><subject>Brain Injuries - blood</subject><subject>Brain Injuries - immunology</subject><subject>Brain Injuries - pathology</subject><subject>Brain research</subject><subject>Breakdown</subject><subject>Calpain</subject><subject>Cell culture</subject><subject>Correlation analysis</subject><subject>Damage assessment</subject><subject>Disease</subject><subject>Female</subject><subject>Glial fibrillary acidic protein</subject><subject>Glial Fibrillary Acidic Protein - immunology</subject><subject>Head injuries</subject><subject>Health care</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulin G - blood</subject><subject>Immunoglobulin G - immunology</subject><subject>Immunoglobulins</subject><subject>Immunoreactivity</subject><subject>In vitro methods and tests</subject><subject>Intermediate filament proteins</subject><subject>Male</subject><subject>Medicine and Health Sciences</subject><subject>Multiple sclerosis</subject><subject>Nervous 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traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products</title><author>Zhang, Zhiqun ; Zoltewicz, J Susie ; Mondello, Stefania ; Newsom, Kimberly J ; Yang, Zhihui ; Yang, Boxuan ; Kobeissy, Firas ; Guingab, Joy ; Glushakova, Olena ; Robicsek, Steven ; Heaton, Shelley ; Buki, Andras ; Hannay, Julia ; Gold, Mark S ; Rubenstein, Richard ; Lu, Xi-Chun May ; Dave, Jitendra R ; Schmid, Kara ; Tortella, Frank ; Robertson, Claudia S ; Wang, Kevin K W</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c796t-9dc0e2f1ceec1c9571c5e63951de50569244de128ef3e7d2eecc94a7d17895523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Animal experimentation</topic><topic>Animals</topic><topic>Antigens</topic><topic>Apoptosis</topic><topic>Astrocytes</topic><topic>Astrocytes - immunology</topic><topic>Astrocytes - 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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>SWEPUB Örebro universitet full text</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SWEPUB Örebro universitet</collection><collection>SwePub Articles full text</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>Zhang, Zhiqun</au><au>Zoltewicz, J Susie</au><au>Mondello, Stefania</au><au>Newsom, Kimberly J</au><au>Yang, Zhihui</au><au>Yang, Boxuan</au><au>Kobeissy, Firas</au><au>Guingab, Joy</au><au>Glushakova, Olena</au><au>Robicsek, Steven</au><au>Heaton, Shelley</au><au>Buki, Andras</au><au>Hannay, Julia</au><au>Gold, Mark S</au><au>Rubenstein, Richard</au><au>Lu, Xi-Chun May</au><au>Dave, Jitendra R</au><au>Schmid, Kara</au><au>Tortella, Frank</au><au>Robertson, Claudia S</au><au>Wang, Kevin K W</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-03-25</date><risdate>2014</risdate><volume>9</volume><issue>3</issue><spage>e92698</spage><epage>e92698</epage><pages>e92698-e92698</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The role of systemic autoimmunity in human traumatic brain injury (TBI) and other forms of brain injuries is recognized but not well understood. In this study, a systematic investigation was performed to identify serum autoantibody responses to brain-specific proteins after TBI in humans. TBI autoantibodies showed predominant immunoreactivity against a cluster of bands from 38-50 kDa on human brain immunoblots, which were identified as GFAP and GFAP breakdown products. GFAP autoantibody levels increased by 7 days after injury, and were of the IgG subtype predominantly. Results from in vitro tests and rat TBI experiments also indicated that calpain was responsible for removing the amino and carboxyl termini of GFAP to yield a 38 kDa fragment. Additionally, TBI autoantibody staining co-localized with GFAP in injured rat brain and in primary rat astrocytes. These results suggest that GFAP breakdown products persist within degenerating astrocytes in the brain. Anti-GFAP autoantibody also can enter living astroglia cells in culture and its presence appears to compromise glial cell health. TBI patients showed an average 3.77 fold increase in anti-GFAP autoantibody levels from early (0-1 days) to late (7-10 days) times post injury. Changes in autoantibody levels were negatively correlated with outcome as measured by GOS-E score at 6 months, suggesting that TBI patients with greater anti-GFAP immune-responses had worse outcomes. Due to the long lasting nature of IgG, a test to detect anti-GFAP autoantibodies is likely to prolong the temporal window for assessment of brain damage in human patients.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24667434</pmid><doi>10.1371/journal.pone.0092698</doi><tpages>e92698</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-03, Vol.9 (3), p.e92698-e92698 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1510195285 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; SWEPUB Freely available online; Free Full-Text Journals in Chemistry; Public Library of Science (PLoS) |
| subjects | Adult Animal experimentation Animals Antigens Apoptosis Astrocytes Astrocytes - immunology Astrocytes - metabolism Astrocytes - pathology Autoantibodies Autoantibodies - blood Autoantibodies - immunology Autoimmunity Biology and Life Sciences Biomarkers Brain Brain damage Brain injuries Brain Injuries - blood Brain Injuries - immunology Brain Injuries - pathology Brain research Breakdown Calpain Cell culture Correlation analysis Damage assessment Disease Female Glial fibrillary acidic protein Glial Fibrillary Acidic Protein - immunology Head injuries Health care Humans Immune response Immunoglobulin G Immunoglobulin G - blood Immunoglobulin G - immunology Immunoglobulins Immunoreactivity In vitro methods and tests Intermediate filament proteins Male Medicine and Health Sciences Multiple sclerosis Nervous system Neurosciences Neurosurgery Patients Proteins Psychiatry Rats Rats, Sprague-Dawley Research and Analysis Methods Time Factors Trauma Traumatic brain injury |
| title | Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products |
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