title: Is peripheral immunity regulated by blood-brain barrier permeability changes?
abstract: S100B is a reporter of blood-brain barrier (BBB) integrity which appears in blood when the BBB is breached. Circulating S100B derives from either extracranial sources or release into circulation by normal fluctuations in BBB integrity or pathologic BBB disruption (BBBD). Elevated S100B matches the clinical presence of indices of BBBD (gadolinium enhancement or albumin coefficient). After repeated sub-concussive episodes, serum S100B triggers an antigen-driven production of anti-S100B autoantibodies. We tested the hypothesis that the presence of S100B in extracranial tissue is due to peripheral cellular uptake of serum S100B by antigen presenting cells, which may induce the production of auto antibodies against S100B. To test this hypothesis, we used animal models of seizures, enrolled patients undergoing repeated BBBD, and collected serum samples from epileptic patients. We employed a broad array of techniques, including immunohistochemistry, RNA analysis, tracer injection and serum analysis. mRNA for S100B was segregated to barrier organs (testis, kidney and brain) but S100B protein was detected in immunocompetent cells in spleen, thymus and lymph nodes, in resident immune cells (Langerhans, satellite cells in heart muscle, etc.) and BBB endothelium. Uptake of labeled S100B by rat spleen CD4+ or CD8+ and CD86+ dendritic cells was exacerbated by pilocarpine-induced status epilepticus which is accompanied by BBBD. Clinical seizures were preceded by a surge of serum S100B. In patients undergoing repeated therapeutic BBBD, an autoimmune response against S100B was measured. In addition to its role in the central nervous system and its diagnostic value as a BBBD reporter, S100B may integrate blood-brain barrier disruption to the control of systemic immunity by a mechanism involving the activation of immune cells. We propose a scenario where extravasated S100B may trigger a pathologic autoimmune reaction linking systemic and CNS immune responses.
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Erin
authors.initials: E
authors.lastname: Bargerstock
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Department of Neurosurgery, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Department of Biomedical Engineering, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Vikram
authors.initials: V
authors.lastname: Puvenna
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Kent State University, Kent, Ohio, United States of America.
authors.forename: Philip
authors.initials: P
authors.lastname: Iffland
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Department of Psychiatry, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Falcone
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Department of Neurosurgery, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Department of Biomedical Engineering, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hossain
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Vetter
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Shumei
authors.initials: S
authors.lastname: Man
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Leah
authors.initials: L
authors.lastname: Dickstein
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchi
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Department of Neurosurgery, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Department of Biomedical Engineering, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Chaitali
authors.initials: C
authors.lastname: Ghosh
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America.
authors.forename: Juliana
authors.initials: J
authors.lastname: Carvalho-Tavares
authors.affiliation: Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Department of Neurosurgery, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Department of Biomedical Engineering, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, United States of America; Flocel, Inc. Cleveland, Ohio, United States of America.
authors.forename: Damir
authors.initials: D
authors.lastname: Janigro
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity; D001812:Blood-Brain Barrier / Q000276:immunology / Q000378:metabolism*; D002199:Capillary Permeability; D006801:Humans; D007111:Immunity, Cellular; D008297:Male; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D017207:Rats, Sprague-Dawley; D064568:S100 Calcium Binding Protein beta Subunit / Q000032:analysis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D012640:Seizures / Q000276:immunology / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D064568:S100 Calcium Binding Protein beta Subunit