The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis

Mardiguian, Silvy; Ladds, Emma; Turner, Roberta; Shepherd, H. A.; Campbell, Sandra J.; Anthony, Daniel C.

doi:10.1186/s12974-017-0969-4

Cited by 15 publications

(8 citation statements)

References 60 publications

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“…SAA protein was found to be elevated in peripheral blood of patients with relapsing–remitting MS over a 3-month period [23]. In chronic-relapsing (CR) EAE models of MS, the contribution of the response in the acute phase was recently reported [33]. In CR-EAE, SAA1 mRNA was found to be significantly elevated in the liver in mice before the onset of clinical signs.…”

Section: Discussionmentioning

confidence: 99%

A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis

Contarini

Franceschini

Facci

et al. 2019

J Neuroinflammation

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Background Persistent and/or recurrent inflammatory processes are the main factor leading to multiple sclerosis (MS) lesions. The composite ultramicronized palmitoylethanolamide, an endogenous N-acylethanolamine, combined with the flavonoid luteolin, PEALut, have been found to exert neuroprotective activities in experimental models of spinal and brain injury and Alzheimer disease, as well as a clinical improvement in human stroke patients. Furthermore, PEALut enhances the expression of different myelin proteins in oligodendrocyte progenitor cells suggesting that this composite might have protective effects in MS experimental models. Methods The mouse model of experimental autoimmune encephalomyelitis (EAE) based on active immunization with a fragment of myelin oligodendrocyte glycoprotein (MOG 35-55 ) was used. The daily assessment of clinical score and the expression of serum amyloid A (SAA1), proinflammatory cytokines TNF-α, IL-1β, IFN-γ, and NLRP3 inflammasome, as well as TLR2, Fpr2, CD137, CD3-γ, and TCR-ζ chain, heterodimers that form T cell surface glycoprotein (TCR), and cannabinoid receptors CB 1 , CB 2 , and MBP, were evaluated in the brainstem and cerebellum at different postimmunization days (PIDs). Results Vehicle-MOG 35-55 -immunized (MOG 35-55 ) mice developed ascending paralysis which peaked several days later and persisted until the end of the experiment. PEALut, given intraperitoneally daily starting on day 11 post-immunization, dose-dependently improved clinical score over the range 0.1–5 mg/kg. The mRNA expression of SAA1, TNF-α, IL-1β, IFN-γ, and NLRP3 were significantly increased in MOG 35-55 mice at 14 PID. In MOG 35-55 mice treated with 5 mg /kg PEALut, the increase of SAA1, TNF- α, IL-1β, and IFN-γ transcripts at 14 PID was statistically downregulated as compared to vehicle-MOG 35-55 mice ( p < 0.05). The expression of TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB 2 receptors showed a significant upregulation in vehicle-MOG 35-55 mice at 14 PID. Instead, CB 1 and MBP transcripts have not changed in expression at any time. In MOG/PEALut-treated mice, TLR2, Fpr2, CD137, CD3-γ, TCR-ζ chain, and CB 2 mRNAs were significantly downregulated as compared to vehicle MOG 35-55 mice. Conclusions The present results demonstrate that the intraperitoneal administration of the composite PEALut significantly reduces the development of clinical signs in the MOG 35-55 model of EAE. The dose-dependent improvement of clinical score induced by PEALut was associated with a reduction in transcript e...

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Section: Discussionmentioning

confidence: 99%

A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis

Contarini

Franceschini

Facci

et al. 2019

J Neuroinflammation

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“…Additionally, to corroborate this notion are data indicating aging-related decrease of Thy-1 expression on the surface of rat DP TCRαβ lo thymocytes followed by a decline in the frequency of post-selected DP TCRαβ hi thymocytes [ 38 ]. Given that catecholamines were shown to downregulate Thy-1 mRNA expression [ 79 ], the decreased surface density of Thy-1 in immunized rats could be also related to data indicating an increase in the circulating levels of catecholamines during active EAE and MS [ 80 ].…”

Section: Discussionmentioning

confidence: 99%

Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization

Nacka-Aleksić¹,

Stojanović²,

Pilipović³

et al. 2018

PLoS ONE

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An accumulating body of evidence suggests that development of autoimmune pathologies leads to thymic dysfunction and changes in peripheral T-cell compartment, which, in turn, perpetuate their pathogenesis. To test this hypothesis, thymocyte differentiation/maturation in rats susceptible (Dark Agouti, DA) and relatively resistant (Albino Oxford, AO) to experimental autoimmune encephalomyelitis (EAE) induction was examined. Irrespective of strain, immunization for EAE (i) increased the circulating levels of IL-6, a cytokine causally linked with thymic atrophy, and (ii) led to thymic atrophy reflecting partly enhanced thymocyte apoptosis associated with downregulated thymic IL-7 expression. Additionally, immunization diminished the expression of Thy-1, a negative regulator of TCRαβ-mediated signaling and activation thresholds, on CD4+CD8+ TCRαβlo/hi thymocytes undergoing selection and thereby impaired thymocyte selection/survival. This diminished the generation of mature CD4+ and CD8+ single positive TCRαβhi thymocytes and, consequently, CD4+ and CD8+ recent thymic emigrants. In immunized rats, thymic differentiation of natural regulatory CD4+Foxp3+CD25+ T cells (nTregs) was particularly affected reflecting a diminished expression of IL-7, IL-2 and IL-15. The decline in the overall thymic T-cell output and nTreg generation was more pronounced in DA than AO rats. Additionally, differently from immunized AO rats, in DA ones the frequency of CD28- cells secreting cytolytic enzymes within peripheral blood CD4+ T lymphocytes increased, as a consequence of thymic atrophy-related replicative stress (mirrored in CD4+ cell memory pool expansion and p16INK4a accumulation). The higher circulating level of TNF-α in DA compared with AO rats could also contribute to this difference. Consistently, higher frequency of cytolytic CD4+ granzyme B+ cells (associated with greater tissue damage) was found in spinal cord of immunized DA rats compared with their AO counterparts. In conclusion, the study indicated that strain differences in immunization-induced changes in thymopoiesis and peripheral CD4+CD28- T-cell generation could contribute to rat strain-specific clinical outcomes of immunization for EAE.

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“…Intestinal barrier function in ocular BD patients has not yet been investigated and is indeed an interesting area for further research. LPS is one of the most potent gram-negative derived factors that can stimulate Th1 and Th17 cell differentiation and is able to exacerbate experimental autoimmune disease models such as EAU and EAE ( Fang et al, 2010 ; Klaska et al, 2017 ; Mardiguian et al, 2017 ). These findings are also consistent with previous studies in which LPS/TLR4 pathways are involved in the aberrant immune response observed in BD and our result showing a higher abundance of SRB (such as Bilophila species) in the BD-recipient mice ( Liang et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Changes in the Gut Microbiome Contribute to the Development of Behcet’s Disease via Adjuvant Effects

Wang

et al. 2021

Front. Cell Dev. Biol.

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Behcet’s disease (BD) is associated with considerable gut microbiome changes. However, it still remains unknown how the composition of the gut microbiome exactly affects the development of this disease. In this study, transplantation of stool samples from patients with active ocular BD to mice via oral gavage was performed. This resulted in decreases of three short chain fatty acids (SCFAs) including butyric acid, propionic acid and valeric acid in the feces of the BD-recipient group. Intestinal barrier integrity of mice receiving BD feces was damaged as shown by a decreased expression of tight junction proteins and was associated with the release of Lipopolysaccharides (LPS) in the circulation. The mice also showed a higher frequency of splenic neutrophils as well as an enrichment of genes associated with innate immune responses in the neutrophils and CD4 + T cells as identified by single cell RNA sequencing. Analysis of neutrophils and T cells functions in these mice showed an enhanced mesenteric lymph node and splenic Th1 and Th17 cell differentiation in association with activation of neutrophils. Transplantation of BD feces to mice and subsequent induction of experimental uveitis (EAU) or encephalomyelitis (EAE) led to an exacerbation of disease in both models, suggesting a microbial adjuvant effect. These findings suggest that the gut microbiome may regulate an autoimmune response via adjuvant effects including increased gut permeability and enhancement of innate immunity.

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The contribution of the acute phase response to the pathogenesis of relapse in chronic-relapsing experimental autoimmune encephalitis models of multiple sclerosis

Cited by 15 publications

References 60 publications

A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis

A co-ultramicronized palmitoylethanolamide/luteolin composite mitigates clinical score and disease-relevant molecular markers in a mouse model of experimental autoimmune encephalomyelitis

Strain differences in thymic atrophy in rats immunized for EAE correlate with the clinical outcome of immunization

Changes in the Gut Microbiome Contribute to the Development of Behcet’s Disease via Adjuvant Effects

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