Focal transient CNS vessel leak provides a tissue niche for sequential immune cell accumulation during the asymptomatic phase of EAE induction

Barkauskas, Deborah S.; Dorand, Rodney Dixon; Myers, Jay; Evans, Teresa A.; Barkauskas, Kestutis J.; Askew, David; Purgert, Robert; Huang, Alex Y.

doi:10.1016/j.expneurol.2015.02.018

Cited by 33 publications

(23 citation statements)

References 71 publications

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“…Based on the distribution of the T-cells, which were initially concentrated proximal to the root entry zone, we conclude that the T-cells infiltrate sensory ganglia via their central branch. It follows that the T-cells must gain access to the CNS before accessing the PNS (Barkauskas et al, 2015; Reboldi et al, 2009). Basedon localized demyelination at this transition zone, Thorburn et al came to a comparable conclusion (Thorburn et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Peripheral and central neuronal ATF3 precedes CD4+ T-cell infiltration in EAE

Frezel¹,

Sohet²,

Daneman³

et al. 2016

Experimental Neurology

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Experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis produced by immunization with myelin oligodendrocyte glycoprotein (MOG) and adjuvants, results from profound T-cell mediated CNS demyelination. EAE is characterized by progressive, ascending motor dysfunction and symptoms of ongoing pain and hypersensitivity, in some cases preceding or concomitant with the motor deficits. In this regard, the EAE model mimics major features of multiple sclerosis, where a central neuropathic pain state is common. Although the latter condition is presumed to arise from a CNS loss of inhibitory controls secondary to the demyelination, dysfunction of sensory neurons may also contribute. Based on our previous studies that demonstrated the utility of monitoring expression of activating transcription factor 3 (ATF3), a sensitive marker of injured sensory neurons, here we followed both ATF3 and CD4+ T cells invasion of sensory ganglia (as well as the CNS) at different stages of the EAE model. We found that ATF3 is induced in peripheral sensory ganglia and brainstem well before the appearance of motor deficits. Unexpectedly, the ATF3 induction always preceded T cell infiltration, typically in adjacent, but non-overlapping regions. Surprisingly, control administration of the pertussis toxin and/or Complete Freund's adjuvants, without MOG, induced ATF3 in sensory neurons. In contrast, T cell infiltration only occurred with MOG. Taken together, our results suggest that the clinical manifestations in the EAE result not only from central demyelination but also from neuronal stress and subsequent pathophysiology of sensory neurons.

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Section: Discussionmentioning

confidence: 99%

Peripheral and central neuronal ATF3 precedes CD4+ T-cell infiltration in EAE

Frezel¹,

Sohet²,

Daneman³

et al. 2016

Experimental Neurology

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“…According to recent reports, in the MS murine model, a significant T cell mobilization was observed at 2 days post-immunization (DPI), thus an asymptomatic stage of the disease [13]. Furthermore, a transient vessel leak in the cortical gray matter has been described at the same time window [14]. Moreover, pain associated with microglia and astrocyte activation occurs in EAE prior to the onset of clinical signs [15, 16].…”

Section: Introductionmentioning

confidence: 99%

Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis

Borjini

Fernández

Giardino

et al. 2016

J Neuroinflammation

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BackgroundExperimental allergic encephalomyelitis (EAE) is the most commonly used experimental animal model for human multiple sclerosis (MS) that has been used so far to study the acute and remission-relapsing phases of the disease. Despite the vast literature on neuroinflammation onset and progression in EAE, important questions are still open regarding in particular the early asymptomatic phase between immunization and clinical onset.MethodsIn this study, we performed a time-course investigation of neuroinflammation and demyelination biomarkers in the spinal cord (SC), cerebrospinal fluid (CSF), and blood in EAE induced in dark agouti (DA) female rats compared to the controls and adjuvant-injected rats, using high-throughput technologies for gene expression and protein assays and focusing on the time-course between immunization, clinical onset (1, 5, 8 days post-immunization (DPI)), and progression (11 and 18 DPI). The expression profile of 84 genes related to T cell activation/signaling, adaptive immunity, cytokine/chemokine inflammation, demyelination, and cellular stress were analyzed in the tissue; 24 cytokines were measured in the CSF and plasma.ResultsThe macrophage colony-stimulating factor (CSF1) was the first up-regulated protein as far as 1 DPI, not only in blood but also in CSF and SC. A treatment with GW2580, a selective CSF1R inhibitor, slowed the disease progression, significantly reduced the severity, and prevented the relapse phase. Moreover, both pro-inflammatory (IL-1β, TNF-α) and anti-inflammatory cytokines (IL-5, IL-10, VEGF) were up-regulated starting from 8 DPI. Myelin genes were down-regulated starting from 8 DPI, especially MAL, MBP, and PMP22 while an opposite expression profile was observed for inflammation-related genes, such as CXCL11 and CXCL10.ConclusionsThis early cytokine and chemokine regulation indicates that novel biomarkers and therapeutic options could be explored in the asymptomatic phase of EAE. Overall, our findings provide clear evidence that CSF1R signaling regulates inflammation in EAE, supporting therapeutic targeting of CSF1R in MS.

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“…In addition to endothelial origin, the source of these markers in the blood could also be the CNS proper, due to an increased BBB permeability. PTX injection has been shown to induce a transient BBB opening, whereas an EAE-induced opening coincides with leukocyte entering the nervous tissue and initiation of the clinical phase thereafter ( 29 ). This is reflected in the CS response, where increased levels in the MOG-EAE animals were seen 2–3 days before clinical disease debut.…”

Section: Discussionmentioning

confidence: 99%

Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers?

et al. 2018

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IntroductionMultiple sclerosis (MS) is a devastating autoimmune disease, afflicting people in the prime of their lives. Presently, after initial clinical presentation, there are no reliable markers for whether a patient will develop MS, or whether their prognosis will be aggressive or relapsing–remitting. Furthermore, many MS patients do not respond to treatment. Thus, markers for diagnosis, prognosis, and treatment-responsiveness are lacking for a disease, where a precision medicine approach would be valuable. The glycocalyx (GLX) is the carbohydrate-rich outer surface of the blood vessel wall and is the first interaction between the blood and the vessel. We hypothesized that cleavage of the GLX may be an early stage predictor of immune attack, blood–brain barrier (BBB) breakdown, and disease severity in MS.MethodsTwo experimental models of MS, experimental autoimmune encephalitis (EAE), were included in this study. EAE was induced in C57BL/6J mice and Lewis rats, which were monitored for weight loss and clinical presentation in comparison to healthy controls. Plasma samples were obtained longitudinally from mice until peak disease severity and at peak disease severity in rats. Soluble GLX-associated glycosaminoglycans (GAG) and proteoglycans (PG) were detected in plasma samples.ResultsAll animals receiving EAE emulsion developed fulminant EAE (100% penetrance). Increased plasma levels of chondroitin sulfate were detected before the onset of clinical symptoms and remained elevated at peak disease severity. Hyaluronic acid was increased at the height of the disease, whereas heparan sulfate was transiently increased during early stages only. By contrast, syndecans 1, 3, and 4 were detected in EAE samples as well as healthy controls, with no significant differences between the two groups.DiscussionIn this study, we present data supporting the shedding of the GLX as a new class of biomarker for MS. In particular, soluble, sugar-based GLX components are associated with disease severity in two models of MS, molecules that would not be detected in proteomics-based screens of MS patient samples. Patient studies are presently underway.

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Focal transient CNS vessel leak provides a tissue niche for sequential immune cell accumulation during the asymptomatic phase of EAE induction

Cited by 33 publications

References 71 publications

Peripheral and central neuronal ATF3 precedes CD4+ T-cell infiltration in EAE

Peripheral and central neuronal ATF3 precedes CD4+ T-cell infiltration in EAE

Cytokine and chemokine alterations in tissue, CSF, and plasma in early presymptomatic phase of experimental allergic encephalomyelitis (EAE), in a rat model of multiple sclerosis

Detection of Glycan Shedding in the Blood: New Class of Multiple Sclerosis Biomarkers?

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