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Autoimmune responses to the brain after stroke are associated with worse outcome.

ABSTRACT: Immune responses to brain antigens occur after stroke, and experimental studies show that the likelihood of developing a detrimental autoimmune response to these antigens is increased by systemic inflammation at the time of stroke. The aim of this study was to determine if patients who developed infection in the poststroke period would be similarly predisposed to develop autoimmune responses to central nervous system antigens.We enrolled 114 patients within 72 hours of ischemic stroke. Clinical and demographic data were obtained, and cellular immune responses to a panel of central nervous system antigens were assessed during the initial week and again at Day 90. Outcome was assessed using the modified Rankin Scale.Patients who developed an infection, especially pneumonia, in the 15 days after stroke were more likely to evidence a Th1(+) response to myelin basic protein and glial fibrillary acidic protein (P=0.019 and P=0.039, respectively) at 90 days after stroke. Further, more robust Th1 responses to myelin basic protein at 90 days were associated with a decreased likelihood of good outcome, even after adjusting for baseline stroke severity and patient age (OR, 0.477; 95% CI, 0.244 to 0.935; P=0.031).This study demonstrates that immune responses to brain antigens occur after stroke. Although these responses are likely to be an epiphenomenon of ischemic brain injury, the response to myelin basic protein appears to have clinical consequences. The potential role of postischemic autoimmune-mediated brain injury deserves further investigation.

SUBMITTER: Becker KJ

PROVIDER: S-EPMC3183403 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Autoimmune responses to the brain after stroke are associated with worse outcome.

Becker Kyra J KJ Kalil Angela J AJ Tanzi Pat P Zierath Dannielle K DK Savos Anna V AV Gee J Michael JM Hadwin Jessica J Carter Kelly T KT Shibata Dean D Cain Kevin C KC

Stroke 20110728 10

<h4>Background and purpose</h4>Immune responses to brain antigens occur after stroke, and experimental studies show that the likelihood of developing a detrimental autoimmune response to these antigens is increased by systemic inflammation at the time of stroke. The aim of this study was to determine if patients who developed infection in the poststroke period would be similarly predisposed to develop autoimmune responses to central nervous system antigens.<h4>Methods</h4>We enrolled 114 patient ...[more]

PMID: 21799171

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Project description:Prenatal alcohol exposure (PAE) is linked to elevated risk for systemic adult-onset diseases like hypertension, impaired glucose and immune regulation, and in animal models, to impaired recovery from acute onset diseases like cerebrovascular ischemic stroke. Recent evidence suggests that the gastrointestinal system rapidly becomes dysbiotic following cerebrovascular stroke, resulting in systemic inflammation. We hypothesized that a history of PAE would modify the systemic effects of stroke, and transduce exposure-dependent transcriptomic changes in downstream sentinel tissues of the enteric portal circulation that have previously been linked to biobehavioral outcomes in rodent PAE models. Pregnant Sprague Dawley rats were exposed to repeated episodes of vaporized ethanol or room air from gestational day 8 to 19. At 5 months, progeny from each treatment condition were subjected to unilateral endothelin-1 induced occlusion of the middle cerebral artery and outcomes evaluated after 2 days while other progeny stayed stroke-naïve. Stroke induced disabilities were assessed by behavioral assays (adhesive removal, Vibrissae evoked fore-limb placement, circling) and infarct size. The mesenteric adipose tissue and liver transcriptomes were assessed by sequencing, from age-matched stroke-exposed and stroke-naïve offspring. In stroke-naïve animals, pathway analysis identified rRNA processing as downregulated and citric acid cycle as upregulated in mesenteric adipose. Weighted gene correlation network analysis (WGCNA) identified, in the liver of stoke-naïve animals, a moderate but significant correlation between PAE status and necroptosis, a proinflammatory form of programmed cell death (Pearson’s r=0.554, p<0.05). Two days after a stroke, PAE rats exhibited worse neurological scores compared to controls (p<0.05). WGCNA after stroke identified an adipose gene network associated with B cell differentiation and NF-kappa B signaling as moderately correlated with post-stroke neurological function (Pearson's r=0.52, p=0.05). Post-stroke WGCNA also identified a liver proinflammatory gene network strongly correlated with post-stroke neurological function (Pearson's r=-0.63, p<0.01). PAE persistently alters the transcriptome of afferent tissue targets of enteric circulation in adult rat offspring. Moreover, PAE-linked enteric inflammation is correlated to worse outcomes following cerebrovascular ischemic stroke in adulthood. Enteric disturbances may mediate adverse brain health outcomes due to PAE in adulthood.

Project description:BackgroundTraumatic brain injury (TBI) is the leading cause of death and disability in children, but effective tools for predicting outcome remain elusive. Although many pediatric patients receive early magnetic resonance imaging (MRI), data on its utility in prognostication are lacking. Diffuse axonal injury (DAI) is a hallmark of TBI detected on early MRI and was shown previously to improve prognostication in adult patients with TBI. In this exploratory study, we investigated whether DAI grade correlates with functional outcome and improves prognostic accuracy when combined with core clinical variables and computed tomography (CT) biomarkers in pediatric patients with moderate-severe TBI (msTBI).MethodsPediatric patients (≤ 19 years) who were admitted to two regional level one trauma centers with a diagnosis of msTBI (Glasgow Coma Scale [GCS] score < 13) between 2011 and 2019 were identified through retrospective chart review. Patients who underwent brain MRI within 30 days of injury and had documented clinical follow-up after discharge were included. Age, pupil reactivity, and initial motor GCS score were collected as part of the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) model. Imaging was reviewed to calculate the Rotterdam score (CT) and DAI grade (MRI) and to evaluate for presence of hypoxic-ischemic injury (MRI). The primary outcome measure was the Pediatric Cerebral Performance Category Scale (PCPCS) score at 6 months after TBI, with favorable outcome defined as PCPCS scores 1-3 and unfavorable outcome defined as PCPCS scores 4-6. The secondary outcome measure was discharge disposition to home versus to an inpatient rehabilitation facility.ResultOf 55 patients included in the study, 45 (82%) had severe TBI. The most common mechanism of injury was motor vehicle collision (71%). Initial head CT scans showed acute hemorrhage in 84% of patients. MRI was acquired a median of 5 days after injury, and hemorrhagic DAI lesions were detected in 87% of patients. Each 1-point increase in DAI grade increased the odds of unfavorable functional outcome by 2.4-fold. When controlling for core IMPACT clinical variables, neither the DAI grade nor the Rotterdam score was independently correlated with outcome and neither significantly improved outcome prediction over the IMPACT model alone.ConclusionsA higher DAI grade on early MRI is associated with worse 6-month functional outcome and with discharge to inpatient rehabilitation in children with acute msTBI in a univariate analysis but does not independently correlate with outcome when controlling for the GCS score. Addition of the DAI grade to the core IMPACT model does not significantly improve prediction of poor neurological outcome. Further study is needed to elucidate the utility of early MRI in children with msTBI.

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Autoimmune responses to the brain after stroke are associated with worse outcome.

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Autoimmune responses to the brain after stroke are associated with worse outcome.

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