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.
Highlights
There is overwhelming evidence showing that systemic immunity is regulated by brain activity [1] and that this axis can be exploited therapeutically to treat CNS disease [2]
Of the 5 animals used for protein uptake, one was injected with an equal part mixture of S100B and S100A1; the remaining animals were used for experiments of distribution of labeled S100B
S100B mRNA expression is limited to barrier organs Messenger RNA analysis was performed on tissue samples isolated from the same animals used for immunohistochemistry experiments
Summary
There is overwhelming evidence showing that systemic immunity is regulated by brain activity [1] and that this axis can be exploited therapeutically to treat CNS disease [2]. A recent report has linked the extravasation in serum of the astrocytic protein S100B to an autoimmune response after subconcussion-induced serum level surges [37]. These results pointed to altered BBB function as a mechanism of long-lasting neurological sequelae. Given the fact that BBBD and subsequent S100B appearance is serum is a hallmark of many acute or chronic neurological diseases [39,40,41,42,43,44,45] as well as in animal model of seizures [13] or in human epilepsy [46], we wished to determine the fate of circulating S100B in control or post-status epilepticus animals. We tested the hypothesis that S100B after accomplishing its role as reporter of BBBD acts as a trigger of autoimmunity due to its preferential homing into immune cells
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