Journal Article

Is Peripheral Immunity Regulated by Blood-Brain Barrier Permeability Changes?

Vetter, Stephen, Carvalho-Tavares, Juliana, Dickstein, Leah, Janigro, Damir, Puvenna, Vikram, Iffland, Philip, Bargerstock, Erin, Man, Shumei, Marchi, Nicola, Ghosh, Chaitali, Hossain, Mohammad, Falcone, Tatiana

2014

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino Acid Sequence / Analysis / Animal models / Animals / Antibodies / Antigen-presenting cells / Antigens / Autoantibodies / Autoimmunity / Biology and Life Sciences / Biomedical engineering / Blood circulation / Blood-brain barrier / Blood-Brain Barrier - immunology / Blood-Brain Barrier - metabolism / Brain / Brain research / Capillary Permeability / Cardiac muscle / CD4 antigen / CD8 antigen / CD86 antigen / Cells (biology) / Central nervous system / Dendritic cells / Diagnostic systems / Endothelium / Engineering / Epilepsy / Gadolinium / Heart / Humans / Hypotheses / Immune response / Immune system / Immunity / Immunity, Cellular / Immunohistochemistry / Integrity / Kidneys / Lymph nodes / Male / Medicine / Medicine and Health Sciences / Membrane permeability / Molecular Sequence Data / mRNA / Muscles / Neurosurgery / Organs / Pathology / Patients / Permeability / Physicians / Pilocarpine / Proteins / Rats, Sprague-Dawley / Research and Analysis Methods / Ribonucleic acid / RNA / RNA, Messenger - genetics / Rodents / S100 Calcium Binding Protein beta Subunit - analysis / S100 Calcium Binding Protein beta Subunit - genetics / S100 Calcium Binding Protein beta Subunit - immunology / S100 Calcium Binding Protein beta Subunit - metabolism / S100b protein / Satellite cells / Seizures / Seizures (Medicine) / Seizures - immunology / Seizures - metabolism / Spleen / Thymus