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.

S100B blood levels and childhood trauma in adolescent inpatients

“…Authors concluded that the stress of combat training increases inflammatory mediators and propose alterations in the BBB permeability as one of the mechanisms for cognitive dysfunction under stress (Li et al, 2014). The role of peripheral immunity in regulating BBB permeability has also been reported (Bargerstock et al, 2014). The findings of our study are in accordance with previous studies in animal models, which demonstrated that chronic trauma during early development produced increased levels of S100B (Sharma and Dey, 1981; Diehl et al, 2007; Margis et al, 2004; Scaccianoce et al, 2004; Friedman et al, 1996).…”

Inflammatory mechanisms contribute to the neurological manifestations of tuberous sclerosis complex

“…This breakdown of the blood brain barrier can lead to infiltration of pathogenic systemic inflammatory mediators, immune cells or other toxic substances into the brain that may promote epileptogenesis (Fabene et al, 2008; Ivens et al, 2007). In fact, astrocytic proteins may be involved in triggering peripheral immune responses in the context of brain injury and blood brain barrier breakdown (Bargerstock et al 2014; Marchi et al 2013; Zhang et al 2014). In contrast to epilepsy related to acquired brain injuries, much less is known about a potential role of systemic inflammation in genetic epilepsies such as TSC.…”

Blood–brain barrier, bulk flow, and interstitial clearance in epilepsy

“…Available tools include microangiography (Cavaglia et al, 2001), 2-photon microscopy (Iliff et al, 2013b), magnetic resonance imaging (MRI) and serum markers (Bargerstock et al, 2014; Janigro et al, 2013b; Kanner et al, 2003; Marchi et al, 2012b). Fluorescent Dextrans or Albumin has been used to visualize regional cerebrovascular morphology, damage and the pattern of interstitial protein accumulation (Boussadia et al, 2014; Cavaglia et al, 2001; Fan et al, 2008; Hallene et al, 2006).…”