ReviewSensitization and tolerization to brain antigens in 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
References (86)
- et al.
Systemic LPS injection leads to granulocyte influx into normal and injured brain: effects of ICAM-1 deficiency
Exp Neurol
(2001) - et al.
The influence of cytokines on the integrity of the blood-brain barrier in vitro
J Neuroimmunol
(1996) - et al.
Neuroprotection by IL-10-producing MOG CD4+ T cells following ischemic stroke
J Neurol Sci
(2005) - et al.
Fever and infection early after ischemic stroke
J Neurol Sci
(1999) - et al.
Neurotoxic consequences of central long-term administration of interleukin-2 in rats
Neuroscience
(1997) - et al.
Cytokine-mediated neuronal apoptosis
Neurochem Int
(1997) - et al.
The B7 and CD28 receptor families
Immunol Today
(1994) - et al.
Stroke-induced immunodepression and post-stroke infections: Lessons from the PANTHERIS trial
Neuroscience
(2009) - et al.
Effect of lipopolysaccharide on the morphology and integrin immunoreactivity of ramified microglia in the mouse brain and in cell culture
Exp Neurol
(2001) - et al.
The right place at the right time: novel B7 family members regulate effector T cell responses
Curr Opin Immunol
(2002)
Toll like receptor signaling in endogenous neuroprotection and stroke
Neuroscience
Analysis of the immune response against tetanus toxoid: enumeration of specific T helper cells by the Elispot assay
Immunobiology
Systemic infection, inflammation and acute ischaemic stroke
Neuroscience
Serum anti-GFAP and anti-S100 autoantibodies in brain aging, Alzheimer's disease and vascular dementia
J Neuroimmunol
Effect of experimental stroke on peripheral immunity: CNS ischemia induces profound immunosuppression
Neuroscience
Catheter associated urinary tract infections in neurology and neurosurgical units
J Infect
Active killing of neurons during development and following stress: a role for p75(NTR) and Fas?
Curr Opin Neurobiol
A randomized, double blind study in young healthy adults comparing cell mediated and humoral immune responses induced by influenza ISCOM vaccines and conventional vaccines
Vaccine
T-cell costimulatory molecules B7-1 (CD80) and B7-2 (CD86) are expressed in human microglia but not in astrocytes in culture
Brain Res
Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion
J Neuroimmunol
How do cytotoxic lymphocytes kill their targets?
Curr Opin Immunol
Systemic infection and inflammation in acute CNS injury and chronic neurodegeneration: underlying mechanisms
Neuroscience
Autoantibodies in neurodegenerative diseases: antigen-specific frequencies and intrathecal analysis
Neurobiol Aging
Harms and benefits of lymphocyte subpopulations in patients with acute stroke
Neuroscience
Serum S-100 protein, relationship to clinical outcome in acute stroke
Ann Clin Biochem
Pneumonia and urinary tract infection after acute ischaemic stroke: a tertiary analysis of the GAIN International trial
Eur J Neurol
Direct NK cell-mediated lysis of syngenic dorsal root ganglia neurons in vitro
J Immunol
Tumor necrosis factor-alphaA mediator of focal ischemic brain injury
Stroke
Adoptive transfer of myelin basic protein-tolerized splenocytes to naive animals reduces infarct size: a role for lymphocytes in ischemic brain injury?
Stroke
Sensitization to brain antigens after stroke is augmented by lipopolysaccharide
J Cereb Blood Flow Metab
Immunologic tolerance to myelin basic protein decreases stroke size after transient focal cerebral ischemia
Proc Natl Acad Sci U S A
Protein S-100B: a serum marker for ischemic and infectious injury of cerebral tissue
Clin Chem Lab Med
Destruction of neurons by cytotoxic T cells: a new pathogenic mechanism in Rasmussen's encephalitis
Ann Neurol
Antibodies to brain antigens following stroke
Neurology
Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia
Mol Med
Spatiotemporal relationship of apoptotic cell death to lymphomonocytic infiltration in photochemically induced focal ischemia of the rat cerebral cortex
Acta Neuropathol (Berl)
The Early Systemic Prophylaxis of Infection After Stroke study: a randomized clinical trial
Stroke
Neurons reduce glial responses to lipopolysaccharide (LPS) and prevent injury of microglial cells from over-activation by LPS
J Neurochem
Mucosal tolerance to E-selectin provides cell-mediated protection against ischemic brain injury
Proc Natl Acad Sci U S A
Accessory molecule and costimulation requirements for CD4 T cell response
Crit Rev Immunol
Serum neurone-specific enolase as an indicator of stroke volume
Eur J Clin Invest
Signal integration following Toll-like receptor triggering
Crit Rev Immunol
Cited by (47)
CNS border-associated macrophages in the homeostatic and ischaemic brain
2022, Pharmacology and TherapeuticsThe impact of sex and age on T cell immunity and ischemic stroke outcomes
2019, Cellular ImmunologyCitation Excerpt :Whether brain antigen specific T cells are protective or not could also depend on the time-course of the concomitant activation of regulatory T cells. Work by Becker and others have demonstrated that increased tolerance to myelin basic protein characterized by a Treg response improves outcome after stroke in pre-clinical models [89–92]. Tregs are a subpopulation of CD4+ T cells characterized by nuclear expression of the transcription factor FoxP3.
Contrasting roles of immune cells in tissue injury and repair in stroke: The dark and bright side of immunity in the brain
2017, Neurochemistry InternationalDynamics of T cell responses after stroke
2016, Current Opinion in PharmacologyCitation Excerpt :As part of the adaptive immune system, canonical T cell receptor mediated T cell responses are generally considered to be antigen-specific. The topic of autoimmunity to self-antigens in stroke remains contentious [2,63,64]. While it is clear that adoptive transfer of pro-inflammatory lymphocytes directed against myelin proteins worsens outcomes [65,66••], it remains debated whether any self-antigen-specific T cells arising in vivo after stroke are of pathological consequence or indeed protective [67••].
Inflammation and Immune Response
2015, Stroke: Pathophysiology, Diagnosis, and Management