Sex differences in EAE reveal common and distinct cellular and molecular components

Wiedrick, Jack; Meza-Romero, Roberto; Gerstner, Grant; Seifert, Hilary; Chaudhary, Poras; Headrick, Ashley; Kent, Gail; Maestas, Ashley; Offner, Halina; Vandenbark, Arthur A.

doi:10.1016/j.cellimm.2020.104242

Cited by 34 publications

(25 citation statements)

References 51 publications

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“…The majority of our understanding of adaptive immunity in CNS malfunction comes from the prototypic inflammatory disease-MS and its animal model (experimental autoimmune encephalomyelitis) EAE (193)(194)(195)(196)(197)(198).…”

Section: An Adaptive Arm Of Immunity In Brain Diseasementioning

confidence: 99%

Cross-Talk of the CNS With Immune Cells and Functions in Health and Disease

Matejuk

Vandenbark²,

Offner³

2021

Front. Neurol.

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The immune system's role is much more than merely recognizing self vs. non-self and involves maintaining homeostasis and integrity of the organism starting from early development to ensure proper organ function later in life. Unlike other systems, the central nervous system (CNS) is separated from the peripheral immune machinery that, for decades, has been envisioned almost entirely as detrimental to the nervous system. New research changes this view and shows that blood-borne immune cells (both adaptive and innate) can provide homeostatic support to the CNS via neuroimmune communication. Neurodegeneration is mostly viewed through the lens of the resident brain immune populations with little attention to peripheral circulation. For example, cognition declines with impairment of peripheral adaptive immunity but not with the removal of microglia. Therapeutic failures of agents targeting the neuroinflammation framework (inhibiting immune response), especially in neurodegenerative disorders, call for a reconsideration of immune response contributions. It is crucial to understand cross-talk between the CNS and the immune system in health and disease to decipher neurodestructive and neuroprotective immune mechanisms for more efficient therapeutic strategies.

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Section: An Adaptive Arm Of Immunity In Brain Diseasementioning

confidence: 99%

Cross-Talk of the CNS With Immune Cells and Functions in Health and Disease

Matejuk

Vandenbark²,

Offner³

2021

Front. Neurol.

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“…However, recent data suggests that females experienced significantly greater spinal cord tissue damage than males in spite of essentially identical EAE disease severity. Pro‐inflammatory T cell responses appeared to be partially modulated by increased percentages of male‐specific anti‐inflammatory, regulatory, and checkpoint T cell, B cell, and monocyte/macrophage immune subsets (Wiedrick et al., 2021).…”

Section: Gender‐related Modulation Of Neuroinflammationmentioning

confidence: 99%

“…Overall, sex hormones can directly modulate effector lymphocyte responses, resulting in altered immune CNS infiltration, tissue damage, and altered balance of pro‐inflammatory versus regulatory cell types (Lasrado et al., 2020; Wiedrick et al., 2021).…”

Section: Gender‐related Modulation Of Neuroinflammationmentioning

confidence: 99%

Animal Models of Multiple Sclerosis

Smith

2021

Current Protocols

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Animal models with high translational validity are essential tools in understanding disease pathogenesis and in the development of therapeutic strategies. Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system characterized by progressive neurological deficits and socioeconomic burden. Experimental autoimmune encephalomyelitis (EAE) is the most extensively utilized animal model of MS, with well‐characterized rodent and non‐human primate variants. The EAE model is typically induced by either active immunization with myelin‐derived proteins or peptides in adjuvant or by passive transfer of activated myelin‐specific CD4+ T lymphocytes. To date, the EAE model has been an essential tool in the development of at least seven U.S. Food and Drug Administration (FDA)−approved immunomodulatory drugs for the treatment of MS, including glatiramer acetate, fingolimod, and natalizumab. However, the translational validity of the EAE model is frequently compromised due to poor study design, inconsistent clinical scoring endpoints, and inappropriate statistical calculations. No single animal model accurately reflects the complexity of human MS pathogenesis. Beyond EAE, multiple additional animal models are described, including Theiler's murine encephalomyelitis virus and cuprizone‐induced demyelination, which facilitate the study of pathogen‐induced CNS autoimmunity and remyelination, respectively. This overview summarizes several of the most frequently used animal models of MS and highlights key factors that significantly influence the experimental outcome and affect translational validity. © 2021 Wiley Periodicals LLC.

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“…Women develop MS 2– 3 times more commonly than men (Doss et al, 2021; Greer & McCombe, 2011; Voskuhl & Palaszynski, 2001). Heightened vulnerability among females has also been observed in preclinical rodent models of MS, such as experimental autoimmune encephalomyelitis (EAE) in mice (Cruz-Orengo et al, 2014; Doss et al, 2021; Hoghooghi et al, 2020; Wiedrick et al, 2021). EAE is a widely used animal model because it involves both the adaptive an innate immune responses (Berard, Wolak, Fournier, & David, 2010; Gerrard et al, 2017), and the formation of perivascular white-matter lesions that are characteristic for human MS (Wiedrick et al, 2021; Wuerch, Mishra, Melo, Ebacher, & Yong, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Heightened vulnerability among females has also been observed in preclinical rodent models of MS, such as experimental autoimmune encephalomyelitis (EAE) in mice (Cruz-Orengo et al, 2014; Doss et al, 2021; Hoghooghi et al, 2020; Wiedrick et al, 2021). EAE is a widely used animal model because it involves both the adaptive an innate immune responses (Berard, Wolak, Fournier, & David, 2010; Gerrard et al, 2017), and the formation of perivascular white-matter lesions that are characteristic for human MS (Wiedrick et al, 2021; Wuerch, Mishra, Melo, Ebacher, & Yong, 2022). Like MS, EAE also elicits acute, chronic, and progressive motor disabilities in rodents (Berard et al, 2010; Jensen et al, 2018; Reich, Lucchinetti, & Calabresi, 2018).…”

Section: Introductionmentioning

confidence: 99%

Thermoregulatory Dynamics Reveal Sex-Specific Inflammatory Responses to Experimental Autoimmune Encephalomyelitis in Mice: Implications for Multiple Sclerosis-Induced Fatigue in Females

Faraji

Bettenson

Babatunde

et al. 2022

Preprint

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The course of multiple sclerosis (MS) is characterized by striking sex differences in symptoms such as fatigue and impaired thermal regulation, which are associated with aggravated systemic pro-inflammatory processes. The purpose of this study was to replicate these symptoms in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice in the quest to advance the preclinical study of non-motor symptoms of MS. Male and female C57BL/6 mice exposed to a mild form of EAE were evaluated for the progression of clinical, behavioural, thermal, and inflammatory processes. We show higher susceptibility in females to EAE than males based on greater clinical score and cumulative disease index (CDI), fatigue-like and anxiety-like behaviours. Accordingly, infrared (IR) thermography indicated higher cutaneous temperature in females from post-induction days 12 to 23. Females also responded to EAE with greater splenic and adrenal gland weights than males as well as sex-specific changes in pro- and anti-inflammatory cytokines. These findings provide the first evidence of a sex-specific thermal response to immune-mediated demyelination, thus proposing a non-invasive assessment approach of the psychophysiological dynamics in EAE mice. The results are discussed in relation to the thermoregulatory correlates of fatigue and how endogenously elevated body temperature without direct heat exposure may be linked to psychomotor inhibition in patients with MS.

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Sex differences in EAE reveal common and distinct cellular and molecular components

Cited by 34 publications

References 51 publications

Cross-Talk of the CNS With Immune Cells and Functions in Health and Disease

Cross-Talk of the CNS With Immune Cells and Functions in Health and Disease

Animal Models of Multiple Sclerosis

Thermoregulatory Dynamics Reveal Sex-Specific Inflammatory Responses to Experimental Autoimmune Encephalomyelitis in Mice: Implications for Multiple Sclerosis-Induced Fatigue in Females

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