Elsevier

Neuroscience

Volume 158, Issue 3, 6 February 2009, Pages 1090-1097
Neuroscience

Review
Sensitization and tolerization to brain antigens in stroke

https://doi.org/10.1016/j.neuroscience.2008.07.027Get rights and content

Abstract

Despite encounter of novel brain antigens by the systemic immune system following stroke, autoimmune responses to these antigens do not seem to occur. In rats, a systemic inflammatory response at the time of stroke, however, provokes changes that increase the likelihood of developing detrimental autoimmunity. These findings may help to explain why infections in the post-stroke period are associated with worse outcome. In addition, data suggest that the immune response can be manipulated in an antigen specific fashion to improve stroke outcome. Together these data argue that the nature of the post-ischemic immune response influences neurological recovery from stroke.

Section snippets

CNS autoimmune responses in experimental stroke

For all of the experiments described in this manuscript, Lewis rats were subjected to 3 h of middle cerebral artery occlusion (MCAO) followed by varying periods of reperfusion; the cellular immune response to MBP, a prototypical CNS antigen, was analyzed by performing ELISPOT assays on mononuclear cells extracted from the spleen and the ischemic hemisphere of the brain. The number of cells secreting interferon (IFN)-γ in response to stimulation with MBP (relative to the number of unstimulated

Antigen specific modulation of the immune response improves outcome

In a previous study we showed that induction of “mucosal tolerance” to MBP (characterized as a Th3/Treg response to the antigen) could improve outcome in an animal model of stroke (Becker et al 1997, Becker et al 2003). In these experiments, regulatory T cells to MBP were induced by mucosal administration of MBP prior to MCAO. If an animal is “tolerized” to a given CNS antigen prior to stroke, re-encounter with that antigen after stroke leads to secretion of cytokines (TGF-β1 or IL-10) that

Systemic inflammation is associated with worse stroke outcome

In our animal model, a Th1(+) response to MBP induced by systemic inflammation (i.e. administration of LPS) is associated with worse outcome up to 1 month after MCAO (Becker et al., 2005). Given that neurological outcome is worse in patients who develop an infection following stroke, the possibility that the infection contributes to this worsened outcome (and is not just a marker for stroke severity) must be entertained (Davenport et al 1996, Georgilis et al 1999, Grau et al 1999, Langhorne et

The nature of CNS autoimmune response influences outcome

Based on our experimental data and the fact that infection (and the attendant inflammatory response that occurs in response to infection) is so common following stroke, the circumstances that favor the development of an immune response to previously sequestered brain antigens exist in many stroke patients. Preventing infection could potentially limit the chances of developing an autoimmune response, but strategies to prevent infection following stroke have not yet been demonstrated to be

Pathological effects of CNS autoimmunity

Our data thus show that induction of mucosal tolerance to a brain antigen (MBP) can modulate the post-ischemic inflammatory response to improve outcome; it also limits the chance of developing a detrimental Th1(+) response to brain antigens in animals subjected to a systemic inflammatory response following stroke. The mechanisms by which a Th1(+) immune response to MBP worsens outcome from stroke, however, are not completely clear. Potential contributing factors include the fact that activated

Conclusions

Our data demonstrate that an inflammatory insult (i.e. LPS) after stroke onset is associated with worse outcome. LPS initiates the innate immune response through stimulation of TLR4 and sets the stage for the adaptive immune response by creating an environment that promotes lymphocyte sensitization to antigens; if one of these antigens is a brain antigen, a CNS autoimmune response may occur. The long-term consequences of this autoimmune response are unclear, but it appears that it is associated

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