title: Human traumatic brain injury induces autoantibody response against glial fibrillary acidic protein and its breakdown products.
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.
authors.affiliation: Banyan Biomarkers Inc., Alachua, Florida, United States of America.
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Psychiatry, Center for Neuroproteomics and Biomarker Research, University of Florida, Gainesville, Florida, United States of America.
authors.forename: J Susie
authors.initials: JS
authors.lastname: Zoltewicz
authors.affiliation: University of Messina, Messina, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Mondello
authors.affiliation: Department of Psychiatry, Center for Neuroproteomics and Biomarker Research, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Newsom
authors.affiliation: Banyan Biomarkers Inc., Alachua, Florida, United States of America.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Psychiatry, Center for Neuroproteomics and Biomarker Research, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Boxuan
authors.initials: B
authors.lastname: Yang
authors.affiliation: Banyan Biomarkers Inc., Alachua, Florida, United States of America.
authors.forename: Firas
authors.initials: F
authors.lastname: Kobeissy
authors.affiliation: Department of Psychiatry, Center for Neuroproteomics and Biomarker Research, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Joy
authors.initials: J
authors.lastname: Guingab
authors.affiliation: Department of Psychiatry, Center for Neuroproteomics and Biomarker Research, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Olena
authors.initials: O
authors.lastname: Glushakova
authors.affiliation: Department of Anesthesiology, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Robicsek
authors.affiliation: Clinical and Health Psychology, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Shelley
authors.initials: S
authors.lastname: Heaton
authors.affiliation: Department of Neurosurgery, University of Pécs and Clinical Neuroscience Image Center of Hungarian Academy of Sciences (HAS) Pécs, Hungary.
authors.forename: Andras
authors.initials: A
authors.lastname: Buki
authors.affiliation: Department of Psychology, University of Houston, Houston, Texas, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Hannay
authors.affiliation: University of Messina, Messina, Italy.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gold
authors.affiliation: Laboratory of Neurodegenerative Disease and CNS Biomarkers, Departments of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Rubenstein
authors.affiliation: Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Xi-Chun May
authors.initials: XC
authors.lastname: Lu
authors.affiliation: Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Jitendra R
authors.initials: JR
authors.lastname: Dave
authors.affiliation: Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Kara
authors.initials: K
authors.lastname: Schmid
authors.affiliation: Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.
authors.forename: Frank
authors.initials: F
authors.lastname: Tortella
authors.affiliation: Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Robertson
authors.affiliation: Banyan Biomarkers Inc., Alachua, Florida, United States of America.
authors.forename: Kevin K W
authors.initials: KK
authors.lastname: Wang
mesh_terms: D000328:Adult; D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D001930:Brain Injuries / Q000097:blood* / Q000276:immunology* / Q000473:pathology; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D005904:Glial Fibrillary Acidic Protein; D007074:Immunoglobulin G