RESUMEN
Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.
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Envejecimiento , Vacuna BCG , Vaina de Mielina , Remielinización , Vacuna BCG/inmunología , Humanos , Envejecimiento/inmunología , Animales , Vaina de Mielina/inmunología , Vaina de Mielina/metabolismo , Microglía/inmunología , Enfermedades Desmielinizantes/inmunología , Epigénesis Genética , Ratones , VacunaciónRESUMEN
Multiple sclerosis (MS) is a devastating autoimmune disease that leads to profound disability. This disability arises from the stochastic, regional loss of myelin-the insulating sheath surrounding neurons-in the central nervous system (CNS). The demyelinated regions are dominated by the brain's resident macrophages: microglia. Microglia perform a variety of functions in MS and are thought to initiate and perpetuate demyelination through their interactions with peripheral immune cells that traffic into the brain. However, microglia are also likely essential for recruiting and promoting the differentiation of cells that can restore lost myelin in a process known as remyelination. Given these seemingly opposing functions, an overarching beneficial or detrimental role is yet to be ascribed to these immune cells. In this chapter, we will discuss microglia dynamics throughout the MS disease course and probe the apparent dichotomy of microglia as the drivers of both demyelination and remyelination.
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Microglía , Esclerosis Múltiple , Vaina de Mielina , Microglía/metabolismo , Microglía/patología , Humanos , Esclerosis Múltiple/patología , Esclerosis Múltiple/inmunología , Vaina de Mielina/patología , Vaina de Mielina/metabolismo , Remielinización/fisiología , Animales , Encéfalo/patología , Encéfalo/inmunología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/metabolismoRESUMEN
The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelination, we found that a substantial number of genes that were not effectively activated in aged myeloid cells displayed epigenetic modifications associated with restricted chromatin accessibility. Ablation of two class I histone deacetylases in microglia was sufficient to restore the capacity of aged mice to remyelinate lesioned tissue. We used Bacillus Calmette-Guerin (BCG), a live-attenuated vaccine, to train the innate immune system and detected epigenetic reprogramming of brain-resident myeloid cells and functional restoration of myelin debris clearance and lesion recovery. Our results provide insight into aging-associated decline in myeloid function and how this decay can be prevented by innate immune reprogramming.
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Envejecimiento , Sistema Nervioso Central , Inmunidad Innata , Ratones Endogámicos C57BL , Microglía , Células Mieloides , Remielinización , Animales , Ratones , Envejecimiento/inmunología , Microglía/inmunología , Microglía/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Sistema Nervioso Central/inmunología , Vaina de Mielina/metabolismo , Vaina de Mielina/inmunología , Epigénesis Genética , Enfermedades Desmielinizantes/inmunología , Modelos Animales de EnfermedadRESUMEN
Virus infections and autoimmune responses are implicated as primary triggers of demyelinating diseases. Specifically, the association of Epstein-Barr virus (EBV) infection with development of multiple sclerosis (MS) has re-ignited an interest in virus induced autoimmune responses to CNS antigens. Nevertheless, demyelination may also be caused by immune mediated bystander pathology in an attempt to control direct infection in the CNS. Tissue damage as a result of anti-viral responses or low level viral persistence may lead to immune activation manifesting in demyelinating lesions, axonal damage and clinical symptoms. This review focuses on the neurotropic mouse coronavirus induced demyelination model to highlight how immune responses activated during the acute phase pave the way to dampen pathology and promote repair. We specifically discuss the role of immune dampening factors programmed cell death ligand 1 (PD-L1) and interleukin (IL)-10, as well as microglia and triggering receptor expressed on myeloid cells 2 (Trem2), in limiting demyelination independent of viral persistence.
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Enfermedades Desmielinizantes , Virus de la Hepatitis Murina , Animales , Ratones , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/virología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/etiología , Virus de la Hepatitis Murina/patogenicidad , Virus de la Hepatitis Murina/inmunología , Humanos , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/complicaciones , Modelos Animales de EnfermedadRESUMEN
Emerging evidence underscores the importance of CD8+ T cells in the pathogenesis of multiple sclerosis (MS), but the precise mechanisms remain ambiguous. This study intends to elucidate the involvement of a novel subset of follicular CD8+ T cells (CD8+CXCR5+ T) in MS and an experimental autoimmune encephalomyelitis (EAE) murine model. The expansion of CD8+CXCR5+ T cells was observed in both MS patients and EAE mice during the acute phase. In relapsing MS patients, higher frequencies of circulating CD8+CXCR5+ T cells were positively correlated with new gadolinium-enhancement lesions in the central nervous system (CNS). In EAE mice, frequencies of CD8+CXCR5+ T cells were also positively correlated with clinical scores. These cells were found to infiltrate into ectopic lymphoid-like structures in the spinal cords during the peak of the disease. Furthermore, CD8+CXCR5+ T cells, exhibiting high expression levels of ICOS, CD40L, IL-21, and IL-6, were shown to facilitate B cell activation and differentiation through a synergistic interaction between CD40L and IL-21. Transferring CD8+CXCR5+ T cells into naïve mice confirmed their ability to enhance the production of anti-MOG35-55 antibodies and contribute to the disease progression. Consequently, CD8+CXCR5+ T cells may play a role in CNS demyelination through heightening humoral immune responses.
Asunto(s)
Linfocitos T CD8-positivos , Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Ratones , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Humanos , Femenino , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Receptores CXCR5/metabolismo , Masculino , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Adulto , Persona de Mediana Edad , Linfocitos B/inmunología , Linfocitos B/metabolismo , Inmunoglobulinas/metabolismo , Inmunoglobulinas/inmunología , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/patologíaRESUMEN
BACKGROUND: Vaccination constitutes a crucial preventive measure against COVID-19 infection. Concerns have been raised regarding the efficacy of vaccines in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) patients due to various immunomodulatory medications and potential adverse events that may impact neurological function. This study aimed to explore the implications of COVID-19 vaccination within MS and NMSOD patients and compare it with other neurological disorders (OND). METHOD: In this cross-sectional study conducted in Isfahan, Iran, baseline data and information on COVID-19 infections and vaccinations were collected from MS, NMOSD, and OND patients between September 2021 and September 2022. The predominant neurological disorders identified among OND patients encompassed headache, epilepsy, and Parkinson's disease. Logistic regression analysis was employed to compare COVID-19 vaccination outcomes among different patient groups, presenting odds ratios (OR) with 95% confidence intervals (CI). RESULTS: The study included 1,307 participants, with 738 having MS, 96 having NMOSD, 76 having clinically isolated syndrome (CIS), and 397 having OND. Significantly higher odds of post-vaccination COVID-19 infection were detected in MS (OR = 3.86, p < 0.001) NMOSD (OR = 2.77, p = 0.015) patients than OND patients. The prior history of COVID-19 infection and the type of vaccine administered did not demonstrate significant associations with the likelihood of post-vaccination COVID-19 infection in MS and NMOSD patients (p > 0.05 for all). There were no significant differences in the rates of adverse events in MS, NMOSD, and OND patients, except the second dose, where NMOSD patients had lower odds than OND patients (OR = 0.55, p = 0.019). CONCLUSION: Although the safety profile of COVID-19 vaccination in MS and NMOSD was similar to that in OND, the rates of post-vaccination COVID-19 infection in MS and NMOSD seem higher than OND. These findings highlight the importance of regular serological monitoring and the potential advantages of supplementary vaccine doses in MS and NMOSD patients.
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Vacunas contra la COVID-19 , COVID-19 , Esclerosis Múltiple , Vacunación , Humanos , COVID-19/prevención & control , Masculino , Vacunas contra la COVID-19/efectos adversos , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/inmunología , Femenino , Estudios Transversales , Adulto , Persona de Mediana Edad , Irán/epidemiología , Esclerosis Múltiple/inmunología , Vacunación/efectos adversos , Vacunación/métodos , SARS-CoV-2/inmunología , Anciano , Enfermedades del Sistema Nervioso/etiología , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/prevención & control , Adulto Joven , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/prevención & controlRESUMEN
BACKGROUND: Cystatin F is a secreted lysosomal cysteine protease inhibitor that has been implicated in affecting the severity of demyelination and enhancing remyelination in pre-clinical models of immune-mediated demyelination. How cystatin F impacts neurologic disease severity following viral infection of the central nervous system (CNS) has not been well characterized and was the focus of this study. We used cystatin F null-mutant mice (Cst7-/-) with a well-established model of murine coronavirus-induced neurologic disease to evaluate the contributions of cystatin F in host defense, demyelination and remyelination. METHODS: Wildtype controls and Cst7-/- mice were intracranially (i.c.) infected with a sublethal dose of the neurotropic JHM strain of mouse hepatitis virus (JHMV), with disease progression and survival monitored daily. Viral plaque assays and qPCR were used to assess viral levels in CNS. Immune cell infiltration into the CNS and immune cell activation were determined by flow cytometry and 10X genomics chromium 3' single cell RNA sequencing (scRNA-seq). Spinal cord demyelination was determined by luxol fast blue (LFB) and Hematoxylin/Eosin (H&E) staining and axonal damage assessed by immunohistochemical staining for SMI-32. Remyelination was evaluated by electron microscopy (EM) and calculation of g-ratios. RESULTS: JHMV-infected Cst7-/- mice were able to control viral replication within the CNS, indicating that cystatin F is not essential for an effective Th1 anti-viral immune response. Infiltration of T cells into the spinal cords of JHMV-infected Cst7-/- mice was increased compared to infected controls, and this correlated with increased axonal damage and demyelination associated with impaired remyelination. Single-cell RNA-seq of CD45 + cells enriched from spinal cords of infected Cst7-/- and control mice revealed enhanced expression of transcripts encoding T cell chemoattractants, Cxcl9 and Cxcl10, combined with elevated expression of interferon-g (Ifng) and perforin (Prf1) transcripts in CD8 + T cells from Cst7-/- mice compared to controls. CONCLUSIONS: Cystatin F is not required for immune-mediated control of JHMV replication within the CNS. However, JHMV-infected Cst7-/- mice exhibited more severe clinical disease associated with increased demyelination and impaired remyelination. The increase in disease severity was associated with elevated expression of T cell chemoattractant chemokines, concurrent with increased neuroinflammation. These findings support the idea that cystatin F influences expression of proinflammatory gene expression impacting neuroinflammation, T cell activation and/or glia cell responses ultimately impacting neuroinflammation and neurologic disease.
Asunto(s)
Infecciones por Coronavirus , Cistatinas , Enfermedades Desmielinizantes , Ratones Noqueados , Virus de la Hepatitis Murina , Animales , Ratones , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/virología , Enfermedades Desmielinizantes/inmunología , Virus de la Hepatitis Murina/patogenicidad , Cistatinas/genética , Cistatinas/metabolismo , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/metabolismoRESUMEN
Both Hedgehog and androgen signaling pathways are known to promote myelin regeneration in the central nervous system. Remarkably, the combined administration of agonists of each pathway revealed their functional cooperation towards higher regeneration in demyelination models in males. Since multiple sclerosis, the most common demyelinating disease, predominates in women, and androgen effects were reported to diverge according to sex, it seemed essential to assess the existence of such cooperation in females. Here, we developed an intranasal formulation containing the Hedgehog signaling agonist SAG, either alone or in combination with testosterone. We show that SAG promotes myelin regeneration and presumably a pro-regenerative phenotype of microglia, thus mimicking the effects previously observed in males. However, unlike in males, the combined molecules failed to cooperate in the demyelinated females, as shown by the level of functional improvement observed. Consistent with this observation, SAG administered in the absence of testosterone amplified peripheral inflammation by presumably activating NK cells and thus counteracting a testosterone-induced reduction in Th17 cells when the molecules were combined. Altogether, the data uncover a sex-dependent effect of the Hedgehog signaling agonist SAG on the peripheral innate immune system that conditions its ability to cooperate or not with androgens in the context of demyelination.
Asunto(s)
Enfermedades Desmielinizantes , Testosterona , Animales , Femenino , Masculino , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/tratamiento farmacológico , Ratones , Testosterona/farmacología , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/agonistas , Ratones Endogámicos C57BL , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Sistema Nervioso Central/metabolismo , Receptor Smoothened/metabolismo , Receptor Smoothened/agonistas , Vaina de Mielina/metabolismo , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Sistema Inmunológico/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/inmunología , Caracteres SexualesRESUMEN
Although Multiple Sclerosis (MS) is primarily thought to be an autoimmune condition, its possible viral etiology must be taken into consideration. When mice are administered neurotropic viruses like mouse hepatitis virus MHV-A59, a murine coronavirus, or its isogenic recombinant strain RSA59, neuroinflammation along with demyelination are observed, which are some of the significant manifestations of MS. MHV-A59/RSA59 induced neuroinflammation is one of the best-studied experimental animal models to understand the viral-induced demyelination concurrent with axonal loss. In this experimental animal model, one of the major immune checkpoint regulators is the CD40-CD40L dyad, which helps in mediating both acute-innate, innate-adaptive, and chronic-adaptive immune responses. Hence, they are essential in reducing acute neuroinflammation and chronic progressive adaptive demyelination. While CD40 is expressed on antigen-presenting cells and endothelial cells, CD40L is expressed primarily on activated T cells and during severe inflammation on NK cells and mast cells. Experimental evidences revealed that genetic deficiency of both these proteins can lead to deleterious effects in an individual. On the other hand, interferon-stimulated genes (ISGs) possess potent antiviral properties and directly or indirectly alter acute neuroinflammation. In this review, we will discuss the role of an ISG, ISG54, and its tetratricopeptide repeat protein Ifit2; the genetic and experimental studies on the role of CD40 and CD40L in a virus-induced neuroinflammatory demyelination model.
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Antígenos CD40 , Ligando de CD40 , Enfermedades Desmielinizantes , Virus de la Hepatitis Murina , Enfermedades Neuroinflamatorias , Animales , Ligando de CD40/metabolismo , Ligando de CD40/genética , Ligando de CD40/inmunología , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/virología , Enfermedades Desmielinizantes/virología , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/metabolismo , Humanos , Antígenos CD40/metabolismo , Antígenos CD40/genética , Antígenos CD40/inmunología , Virus de la Hepatitis Murina/patogenicidad , Virus de la Hepatitis Murina/inmunología , Ratones , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/virología , Esclerosis Múltiple/patología , Esclerosis Múltiple/genética , Esclerosis Múltiple/metabolismo , Modelos Animales de EnfermedadRESUMEN
Conflicting results on melatonin synthesis in multiple sclerosis (MS) have been reported due to variabilities in patient lifestyles, which are not considered when supplementing melatonin. Since melatonin acts through its receptors, we identified melatonin receptors in oligodendrocytes (OLs) in the corpus callosum, where demyelination occurs; the subventricular zone, where neural stem/progenitor cells (NSPCs) are located; and the choroid plexus, which functions as a blood-cerebrospinal fluid barrier. Moreover, using chimeric mice, resident macrophages were found to express melatonin receptors, whereas bone marrow-derived macrophages lost this expression in the demyelinated brain. Next, we showed that cuprizone-fed mice, which is an MS model, tended to have increased melatonin levels. While we used different approaches to alter the circadian rhythm of melatonin and cortisol, only the constant light approach increased NSPC proliferation and differentiation to oligodendrocyte precursor cells (OPCs), OPCs maturation to OLs and recruitment to the site of demyelination, the number of patrolling monocytes, and phagocytosis. In contrast, constant darkness and exogenous melatonin exacerbated these events and amplified monocyte infiltration. Therefore, melatonin should not be considered a universal remedy, as is currently claimed. Our data emphasize the importance of monitoring melatonin/cortisol oscillations in each MS patient by considering diet and lifestyle to avoid melatonin overdose.
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Enfermedades Desmielinizantes , Melatonina , Monocitos , Esclerosis Múltiple , Vaina de Mielina , Fagocitosis , Animales , Ratones , Diferenciación Celular , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/metabolismo , Modelos Animales de Enfermedad , Hidrocortisona , Melatonina/farmacología , Ratones Endogámicos C57BL , Monocitos/inmunología , Monocitos/metabolismo , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Fagocitosis/inmunología , Receptores de Melatonina , Vaina de Mielina/metabolismoRESUMEN
Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease of the central nervous system (CNS) with a high socioeconomic relevance. The pathophysiology of MS, which is both complex and incompletely understood, is believed to be influenced by various environmental determinants, including diet. Since the 1990s, a correlation between the consumption of bovine milk products and MS prevalence has been debated. Here, we show that C57BL/6 mice immunized with bovine casein developed severe spinal cord pathology, in particular, demyelination, which was associated with the deposition of immunoglobulin G. Furthermore, we observed binding of serum from casein-immunized mice to mouse oligodendrocytes in CNS tissue sections and in culture where casein-specific antibodies induced complement-dependent pathology. We subsequently identified myelin-associated glycoprotein (MAG) as a cross-reactive antigenic target. The results obtained from the mouse model were complemented by clinical data showing that serum samples from patients with MS contained significantly higher B cell and antibody reactivity to bovine casein than those from patients with other neurologic diseases. This reactivity correlated with the B cell response to a mixture of CNS antigens and could again be attributed to MAG reactivity. While we acknowledge disease heterogeneity among individuals with MS, we believe that consumption of cow's milk in a subset of patients with MS who have experienced a previous loss of tolerance to bovine casein may aggravate the disease. Our data suggest that patients with antibodies to bovine casein might benefit from restricting dairy products from their diet.
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Anticuerpos/inmunología , Caseínas/inmunología , Reacciones Cruzadas , Enfermedades Desmielinizantes/inmunología , Esclerosis Múltiple/inmunología , Glicoproteína Asociada a Mielina/inmunología , Animales , Especificidad de Anticuerpos , Humanos , Ratones , Ratones Endogámicos C57BL , Leche/inmunologíaRESUMEN
Manipulating lymphocyte functions with gene silencing approaches is promising for treating autoimmunity, inflammation, and cancer. Although oligonucleotide therapy has been proven to be successful in treating several conditions, efficient in vivo delivery of oligonucleotide to lymphocyte populations remains a challenge. Here, we demonstrate that intravenous injection of a heteroduplex oligonucleotide (HDO), comprised of an antisense oligonucleotide (ASO) and its complementary RNA conjugated to α-tocopherol, silences lymphocyte endogenous gene expression with higher potency, efficacy, and longer retention time than ASOs. Importantly, reduction of Itga4 by HDO ameliorates symptoms in both adoptive transfer and active experimental autoimmune encephalomyelitis models. Our findings reveal the advantages of HDO with enhanced gene knockdown effect and different delivery mechanisms compared with ASO. Thus, regulation of lymphocyte functions by HDO is a potential therapeutic option for immune-mediated diseases.
Asunto(s)
Linfocitos/metabolismo , Ácidos Nucleicos Heterodúplex/metabolismo , Oligonucleótidos/metabolismo , ARN/metabolismo , Administración Intravenosa , Traslado Adoptivo , Animales , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/patología , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Endocitosis/efectos de los fármacos , Femenino , Regulación de la Expresión Génica , Silenciador del Gen , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Humanos , Integrina alfa4/genética , Integrina alfa4/metabolismo , Células Jurkat , Masculino , Ratones Endogámicos C57BL , Ácidos Nucleicos Heterodúplex/administración & dosificación , Ácidos Nucleicos Heterodúplex/farmacocinética , Ácidos Nucleicos Heterodúplex/farmacología , Oligonucleótidos/administración & dosificación , Oligonucleótidos/farmacocinética , Oligonucleótidos/farmacología , ARN Largo no Codificante/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Médula Espinal/patología , Distribución Tisular/efectos de los fármacosRESUMEN
Demyelinating diseases of the central nervous system are characterized by recurrent demyelination and progressive neurodegeneration, but there are no clinical drugs targeting myelin regeneration or improving functional disability in the treatment of multiple sclerosis. Total flavone of Epimedium (TFE) is the main active components of Epimedium, which exhibits the beneficial biological activities in the treatment of diseases, but there is no report in the treatment of demyelinating disorder. The purpose of this study was to explore the therapeutic potential and possible mechanism of TFE in the treatment of demyelination. The results showed that TFE efficiently improved the behavioural performance and histological demyelination in cuprizone (CPZ)-induced demyelinating model. In terms of action, TFE increased astrocytes enrichment in corpus callosum, striatum and cortex, and promoted astrocytes to express neurotrophic factors. Furthermore, the expression of platelet-activating factor receptor (PAFR) in astrocytes was induced by CPZ feeding and LPS stimulation, accompanied by the increase of inflammatory cytokines TNF-α,IL-6 and IL-1ß. TFE declined the expression of PAFR, and inhibited inflammatory response. At the same time, TFE also antagonized PAFR activation and inflammatory response triggered by PAF, which further confirmed that TFE, as a new PAFR antagonist, inhibited the astrocyte-derived inflammatory response by antagonizing PAFR-neuroinflammation axis, thus contributing to myelin protection and regeneration.
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Enfermedades Desmielinizantes/tratamiento farmacológico , Epimedium/química , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Extractos Vegetales/farmacología , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Administración Oral , Animales , Astrocitos/efectos de los fármacos , Astrocitos/inmunología , Astrocitos/metabolismo , Cuprizona/administración & dosificación , Cuprizona/toxicidad , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/inmunología , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Flavonas/farmacología , Flavonas/uso terapéutico , Humanos , Masculino , Ratones , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/inmunología , Vaina de Mielina/patología , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/patología , Extractos Vegetales/uso terapéuticoRESUMEN
Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated diseases (MOGADs) account for a substantial proportion of pediatric and adult patients who present with acquired demyelinating disorders. Its pathogenesis and optimal therapy are incompletely understood. We profiled systemic complement activation in adult and pediatric patients with MOGAD compared with patients with relapse-onset multiple sclerosis, patients with neuromyelitis optica spectrum disorder, and pediatric control and adult healthy donors. Proteins indicative of systemic classical and alternative complement activation were substantially increased in patients with MOGAD compared to control groups. Elevated levels were detected in both adult and pediatric cases and across all clinical syndromes. Complement inhibition should be explored for its therapeutic merit in patients with MOGAD. ANN NEUROL 2021;90:976-982.
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Autoanticuerpos/inmunología , Activación de Complemento/fisiología , Enfermedades Desmielinizantes/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG)-IgG is increasingly detected in children with CNS demyelinating diseases. Due to the clinical overlap in children with CNS demyelination with and without MOG-IgG positivity, identifying distinct characteristics would help early diagnosis. OBJECTIVE: To compare the specific features that may help differentiate MOG-IgG positive from negative children with CNS demyelinating diseases. To compare characteristics of patients with high and low MOG-IgG titers. METHODS: Children with CNS demyelinating disorders with onset before 18 years of age who were tested for MOG-IgG at the University of California San Francisco were included. This retrospective study collected the following by chart review: demographic, clinical, MRI, CSF, and treatment data. Serum was tested for MOG-IgG at Mayo Clinic by live cell-based fluorescent activated cell sorting assay with titer ≥1:20 confirming positivity. RESULTS: We assessed 65 Mog-IgG positive and 65 MOG-IgG negative patients. Median (IQR) age of onset was 7.6 (6.6) years for MOG-IgG positive and 13.8 (5.8) years for MOG-IgG negative (p<0.001). The female to male ratio was approximately 1:1 for the MOG-IgG positive group and 3:1 for the negative group (p=0.042). The most common initial diagnosis was demyelinating disease not otherwise specified (52.3%) in the positive group, compared to relapsing-remitting multiple sclerosis (41.5%) in the negative group (p<0.01). Optic nerve involvement (52.3%) was the most common clinical localization at onset for the MOG-IgG positive group, while brainstem/cerebellar (49.2%) localization predominated in the MOG-IgG negative group. The positive group also presented more often with a severe event at disease onset than the negative group (81.5% vs 60.3%; p< 0.002). MOG-IgG positive children had a lower frequency of oligoclonal bands (15.8% vs 57.4%; p<0.001). The frequency of baseline brain and spinal cord MRI abnormalities were similar in both groups; however, MOG-IgG positive patients more often had T2 hyperintense lesions in the optic nerves (26/43 vs 10/41; p<0.001). Disease-modifying medications were used in 64.6% of MOG-IgG positive patients versus 80% of negative children. Of the 32 positive patients with follow-up titers, seven reverted to negative while two who tested negative initially converted to positive. Positive titers greater than 1:160 were only observed within four months of a clinical event (disease onset or relapse). Patients with high and low MOG-IgG titers were comparable in demographic and clinical characteristics. CONCLUSION: Despite some clinical overlap, we report notable demographic, MRI and CSF differences between MOG-IgG positive and negative children with CNS demyelinating disorders at disease onset. High MOG-IgG titers were only observed close to a clinical event.
Asunto(s)
Autoanticuerpos , Enfermedades Desmielinizantes/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Bandas Oligoclonales , Estudios RetrospectivosRESUMEN
After spinal cord injury, macrophages can exert either beneficial or detrimental effects depending on their phenotype. Aside from their critical role in inflammatory responses, macrophages are also specialized in the recognition, engulfment, and degradation of pathogens, apoptotic cells, and tissue debris. They promote remyelination and axonal regeneration by removing inhibitory myelin components and cellular debris. However, excessive intracellular presence of lipids and dysregulated intracellular lipid homeostasis result in the formation of foamy macrophages. These develop a pro-inflammatory phenotype that may contribute to further neurological decline. Additionally, myelin-activated macrophages play a crucial role in axonal dieback and retraction. Here, we review the opposing functional consequences of phagocytosis by macrophages in spinal cord injury, including remyelination and regeneration versus demyelination, degeneration, and axonal dieback. Furthermore, we discuss how targeting the phagocytic ability of macrophages may have therapeutic potential for the treatment of spinal cord injury.
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Enfermedades Desmielinizantes/metabolismo , Macrófagos/fisiología , Fagocitosis/fisiología , Remielinización/fisiología , Traumatismos de la Médula Espinal/metabolismo , Animales , Enfermedades Desmielinizantes/inmunología , Humanos , Traumatismos de la Médula Espinal/inmunologíaRESUMEN
OBJECTIVE: To analyze serum immunoglobulin G (IgG) antibodies to major isoforms of myelin oligodendrocyte glycoprotein (MOG-alpha 1-3 and beta 1-3) in patients with inflammatory demyelinating diseases. METHODS: Retrospective case-control study using 378 serum samples from patients with multiple sclerosis (MS), patients with non-MS demyelinating disease, and healthy controls with MOG alpha-1-IgG positive (n = 202) or negative serostatus (n = 176). Samples were analyzed for their reactivity to human, mouse, and rat MOG isoforms with and without mutations in the extracellular MOG Ig domain (MOG-ecIgD), soluble MOG-ecIgD, and myelin from multiple species using live cell-based, tissue immunofluorescence assays and ELISA. RESULTS: The strongest IgG reactivities were directed against the longest MOG isoforms alpha-1 (the currently used standard test for MOG-IgG) and beta-1, whereas the other isoforms were less frequently recognized. Using principal component analysis, we identified 3 different binding patterns associated with non-MS disease: (1) isolated reactivity to MOG-alpha-1/beta-1 (n = 73), (2) binding to MOG-alpha-1/beta-1 and at least one other alpha, but no beta isoform (n = 64), and (3) reactivity to all 6 MOG isoforms (n = 65). The remaining samples were negative (n = 176) for MOG-IgG. These MOG isoform binding patterns were associated with a non-MS demyelinating disease, but there were no differences in clinical phenotypes or disease course. The 3 MOG isoform patterns had distinct immunologic characteristics such as differential binding to soluble MOG-ecIgD, sensitivity to MOG mutations, and binding to human MOG in ELISA. CONCLUSIONS: The novel finding of differential MOG isoform binding patterns could inform future studies on the refinement of MOG-IgG assays and the pathophysiologic role of MOG-IgG.
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Autoanticuerpos/metabolismo , Enfermedades Desmielinizantes/metabolismo , Encefalitis/metabolismo , Glicoproteína Mielina-Oligodendrócito/metabolismo , Estudios de Casos y Controles , Enfermedades Desmielinizantes/inmunología , Encefalitis/inmunología , Femenino , Humanos , Masculino , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Glicoproteína Mielina-Oligodendrócito/inmunología , Unión Proteica , Isoformas de Proteínas/metabolismo , Estudios RetrospectivosRESUMEN
Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigen-presenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/ß plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1ß play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3+CD25- regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8+ T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses.
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Enfermedades Desmielinizantes/inmunología , Esclerosis Múltiple/inmunología , Theilovirus/fisiología , Inmunidad Adaptativa/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Astrocitos/metabolismo , Infecciones por Cardiovirus/inmunología , Infecciones por Cardiovirus/metabolismo , Infecciones por Cardiovirus/virología , Citocinas , Enfermedades Desmielinizantes/patología , Modelos Animales de Enfermedad , Humanos , Inmunidad Innata/inmunología , Ratones , Microglía/metabolismo , Esclerosis Múltiple/metabolismo , Oligodendroglía/metabolismo , Transducción de Señal/inmunología , Theilovirus/patogenicidadRESUMEN
OBJECTIVE: To study long-term outcomes in patients with CNS demyelinating events exposed to TNFa-inhibitors (TNFai), including subsequent clinical relapse, MRI lesions, and use of disease modifying therapy (DMT) for MS. METHODS: Adult patients evaluated for a CNS demyelinating disease during TNFai use were identified at Mass General Brigham [01/1998-08/2020] and analyzed in clinically-relevant subgroups. Inclusion criteria required a first neurological event while taking a TNFai, MRI lesions consistent with demyelination, and the absence of a more probable alternative diagnosis. RESULTS: 21 cases (mean age 44 years, 20 female, 14 ≥ 2 MS risk factors) had an index neurological event (INE) at a median of 12 months (range 1-176) from onset of TNFai use (adalimumab in 10, etanercept 6, infliximab 5). MRI lesions were most often present in periventricular (16/20, 80%) and spinal zones (10/20, 50%); 37% (7/19) met ≥ 2 Barkhof criteria at onset. CSF testing was abnormal in 64% (7/11). 67% (10/15) with available follow-up MRIs developed new lesions by a median of 29.5 months of MRI surveillance (median MRI surveillance 60 months); 55% (11/20) met ≥ 2 Barkhof criteria. 47% (8/17) suffered a clinical relapse by a median of 40.5 months of clinic follow-up (median clinic follow-up since INE: 26 months). In patients discontinuing TNFai (18/21, 86%) at INE onset, 56% (10/18) had further evidence of CNS demyelination. Six patients (6/21, 29%) started an MS disease modifying therapy (DMT) at INE of whom 50% (3/6) had subsequent disease activity. Continuing or restarting TNFai was followed by relapse in 75% (3/4). 65% (13/20) met 2017 McDonald criteria for MS at INE with another 10% (15/20, 75%) by study conclusion. CONCLUSIONS: With extended follow-up, a majority of patients had a relapsing CNS demyelinating disorder-as evidenced by new MRI lesions or clinical relapses-despite TNFai discontinuation.
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Antiinflamatorios/uso terapéutico , Enfermedades Desmielinizantes/diagnóstico por imagen , Enfermedades Desmielinizantes/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Antiinflamatorios/farmacología , Estudios de Cohortes , Enfermedades Desmielinizantes/inmunología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factor de Necrosis Tumoral alfa/inmunología , Adulto JovenRESUMEN
Angiostrongylus cantonensis infection is a typical cause of eosinophilic encephalitis (EM), which has been reported to induce serious damage in the central nervous system. Both parasite and host factors contribute to the onset of EM, but the related immune-inflammation pathogenesis remains poorly characterised. An A. cantonensis infection model was generated through the infection of mice by gavage. Transmission electron microscopy and immunohistochemistry were used to assess the pathologic changes in the brain. The mRNA expression of inflammatory factors was tested using qRT-PCR. A combination of flow cytometry and western blotting was used to evaluate the alteration of leukocytes and related cytokines. A critical role of IL-17 was found by injecting IL-17A monoclonal antibody into naïve and A. cantonensis-infected mice. A. cantonensis larvae altered the immune homeostasis in the brain, leading to the destruction of myelin sheaths and activation of microglia and macrophage. During this process, IL-17A accumulation was observed, and IL-17RA was expressed in oligodendrocytes and microglia during the infection. Notably, γδ T cell was the major origin of IL-17A production induced by the parasite. After an IL-17A-neutralising antibody was applied, alterations in myelination and the state of the microglia/macrophage were discovered; the neurobehavioural scores of the mice also improved. Our study reveals one unrecognised impact of the γδ T cells in parasitic encephalopathy and emphasises that blocking IL-17A signalling can attenuate microglia and macrophage activation, thus reducing CNS demyelination and ameliorating the neurobehavioural deficit in A. cantonensis-infected mice.