Scoring disease in an animal model of multiple sclerosis using a novel infrared-based automated activity-monitoring system

Shahi, Shailesh K.; Freedman, Samantha N.; Dahl, Rachel; Karandikar, Nitin J.; Mangalam, Ashutosh K.

doi:10.1038/s41598-019-55713-7

Cited by 20 publications

(13 citation statements)

References 22 publications

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“…treatment with 90 mg/kg fedratinib or vehicle controls (Figure 7I). At this time point, the antigenspecific T cells are primed, proliferating, and infiltrating the CNS (Saligrama et al, 2019;Shahi et al, 2019). We observed that fedratinib significantly reduced EAE disease severity (n = 15 mice per group, Figure 7J).…”

Section: Mir-101-3p Is Necessary and Sufficient To Phenocopy Zeb1 Loss In Human Th17 Cellsmentioning

confidence: 83%

ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis

Yuan

Arellano²,

Ifergan³

et al. 2021

Cell Reports

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ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosisGraphical abstract Highlights d ZEB1 mutations modulate risk for multiple sclerosis (MS) in humans and in animal models d ZEB1 is required for Th1/Th17 and represses Th2 differentiation in both mice and humans d ZEB1 sustains JAK2 expression in Th1/Th17 cells by inhibiting JAK2-targeting miR-101-3p d Targeting ZEB1/JAK2 effectively reduces MS severity in in vitro and in vivo models Authors

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Section: Mir-101-3p Is Necessary and Sufficient To Phenocopy Zeb1 Loss In Human Th17 Cellsmentioning

confidence: 83%

ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis

Yuan

Arellano²,

Ifergan³

et al. 2021

Cell Reports

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“…Neurological disability was monitored using a standard EAE scoring system on a 0–5 disease severity scale. The clinical score was recorded as follows: 0, normal; 1, loss of tail tone; 2, hind limb weakness; 3, hind limb paralysis; 4, hind limb paralysis and forelimb paralysis or weakness; 5, moribund/death ( 36 ) ( Supplemental Figure 1B ).…”

Section: Methodsmentioning

confidence: 99%

Divergent complement system activation in two clinically distinct murine models of multiple sclerosis

Linzey

DiSano²,

Welsh³

et al. 2022

Front. Immunol.

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Multiple sclerosis (MS) is a neurological disease featuring neuroinflammation and neurodegeneration in young adults. So far, most research has focused on the peripheral immune system, which appears to be the driver of acute relapses. Concurrently, the mechanisms underlying neurodegeneration in the progressive forms of the disease remain unclear. The complement system, a molecular component of the innate immunity, has been recently implicated in several neurological disorders, including MS. However, it is still unknown if the complement proteins detected in the central nervous system (CNS) are actively involved in perpetuating chronic inflammation and neurodegeneration. To address this knowledge gap, we compared two clinically distinct mouse models of MS: 1) proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (rEAE) resembling a relapsing-remitting disease course, and 2) Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) resembling a progressive disease. Real-time PCR was performed in the spinal cord of rEAE mice, TMEV-IDD mice and age-matched sham controls to quantify gene expression for a broad range of complement components. In both experimental models, we found significantly increased expression of complement factors, such as C1q, C3, CfB, and C3aR. We showed that the complement system, specifically the classical complement pathway, was associated with TMEV-IDD pathogenesis, as the expression of C1q, C3 and C3aR1 were all significantly correlated to a worse disease outcome (all P≤0.0168). In line with this finding, C1q and C3 deposition was observed in the spinal cord of TMEV-IDD mice. Furthermore, C1q deposition was detected in spinal cord regions characterized by inflammation, demyelination, and axonal damage. Conversely, activation of the classical complement cascade seemed to result in protection from rEAE (C1q: P=0.0307). Interestingly, the alternative pathway related to a worse disease outcome in rEAE (CFb: P=0.0006). Overall, these results indicate potential divergent roles for the complement system in MS. The chronic-progressive disease form is more reliant on the activation of the classic complement pathway, while protecting from acute relapses. Conversely, relapsing MS appears more likely affected by the alternative pathway. Understanding the functions of the complement system in MS is critical and can lead to better, more targeted therapies in the future.

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“…Human leukocyte antigen (HLA)-DR3.DQ8 double transgenic [DQ8 (DQA1*0103, DQB1*0302)-DR3 (DRB1*0301)] mice used in this study has been previously characterized and validated by our group (3)(4)(5)(6)19). The HLA-DR3.DQ8 mouse expresses the human class II genes HLA-DR3 (DRB1*0301) and DQ8 (DQB1*0302), and lack endogenous murine major histocompatibility complex (MHC) class II genes I-A, I-E (AE −/− ).…”

Section: Micementioning

confidence: 99%

Human Commensal Prevotella histicola Ameliorates Disease as Effectively as Interferon-Beta in the Experimental Autoimmune Encephalomyelitis

et al. 2020

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Gut microbiota has emerged as an important environmental factor in the pathobiology of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS). Both genetic and environmental factors have been shown to play an important role in MS. Among genetic factors, the human leukocyte antigen (HLA) class II allele such as HLA-DR2, DR3, DR4, DQ6, and DQ8 show the association with the MS. We have previously used transgenic mice expressing MS susceptible HLA class II allele such as HLA-DR2, DR3, DQ6, and DQ8 to validate significance of HLA alleles in MS. Although environmental factors contribute to 2/3 of MS risk, less is known about them. Gut microbiota is emerging as an imporatnt environmental factor in MS pathogenesis. We and others have shown that MS patients have distinct gut microbiota compared to healthy control (HC) with a lower abundance of Prevotella. Additionally, the abundance of Prevotella increased in patients receiving disease-modifying therapies (DMTs) such as Copaxone and/or Interferon-beta (IFNβ). We have previously identified a specific strain of Prevotella (Prevotella histicola), which can suppress experimental autoimmune encephalomyelitis (EAE) disease in HLA-DR3.DQ8 transgenic mice. Since Interferon-β-1b [IFNβ (Betaseron)] is a major DMTs used in MS patients, we hypothesized that treatment with the combination of P. histicola and IFNβ would have an additive effect on the disease suppression. We observed that treatment with P. histicola suppressed disease as effectively as IFNβ. Surprisingly, the combination of P. histicola and IFNβ was not more effective than either treatment alone. P. histicola alone or in combination with IFNβ increased the frequency and number of CD4+FoxP3+ regulatory T cells in the gut-associated lymphoid tissue (GALT). Treatment with P. histicola alone, IFNβ alone, and in the combination decreased frequency of pro-inflammatory IFN-γ and IL17-producing CD4+ T cells in the CNS. Additionally, P. histicola alone or IFNβ alone or the combination treatments decreased CNS pathology, characterized by reduced microglia and astrocytic activation. In conclusion, our study indicates that the human gut commensal P. histicola can suppress disease as effectively as commonly used MS drug IFNβ and may provide an alternative treatment option for MS patients.

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Scoring disease in an animal model of multiple sclerosis using a novel infrared-based automated activity-monitoring system

Cited by 20 publications

References 22 publications

ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis

ZEB1 promotes pathogenic Th1 and Th17 cell differentiation in multiple sclerosis

Divergent complement system activation in two clinically distinct murine models of multiple sclerosis

Human Commensal Prevotella histicola Ameliorates Disease as Effectively as Interferon-Beta in the Experimental Autoimmune Encephalomyelitis

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