Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) with demyelination and axonal damage. MS is usually regarded as a young person's disease, diagnosing in patients between 20 and 40 years of age. However, the disability progression in old patient...
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) with demyelination and axonal damage. MS is usually regarded as a young person's disease, diagnosing in patients between 20 and 40 years of age. However, the disability progression in old patients was much faster with active inflammation than in young patients. To identify the age-related changes for MS, different age groups of experimental autoimmune encephalomyelitis (EAE; an animal model of MS) were used for approaching the age-related immunological and genetic changes. For immunological study, EAE was induced in various age groups for 60 days. In the groups for 6 weeks and 10 months mice, blood samples were collected at intervals of 10 days from day 0 to day 60 and the blood cell counts were promptly detected by using an automated hematological analyzer. In the groups for 6 weeks and 6 months mice, blood-brain barrier (BBB) disruption-related factors such as NADPH oxidase activity, MMP-9 activity, ICAM-1, VCAM-1, BBB permeability, and pro-inflammatory cytokines were measured. In addition, the correlations and interactions between NADPH oxidase, MMP-9, ICAM-1, and VCAM-1 were analyzed in mice tissue and plasma samples (in vivo), and MOG35–55 emulsion-exposed endothelial cell line (in vitro). In 6 weeks and 15 months groups for genetic study, differentially expressed-genes by EAE and/or age effects found with bio-functions and pathways of the genes. The genes for EAE susceptibility with aging effect were identified. EAE severity was higher in aged-group, showing the significantly changed body weight and clinical score. White blood cells, lymphocytes, and monocytes were rapidly elevated, whereas red blood cells, hemoglobin, and hematocrit were reduced before EAE onset. Interestingly, the changes were much higher in aged-EAE than in young-EAE. NADPH oxidase activity, MMP-9 activity, ICAM-1, and VCAM-1 (4 factors) were increased by age and EAE effects. BBB permeability was higher in aged-EAE and inflammatory cytokines were significantly altered with age or EAE effects. The 4 factors were positively correlated in EAE groups, and stronger correlations between NADPH oxidase and other factors were shown in CNS tissues, particularly in aged-EAE. In the in vitro study, NADPH oxidase directly influenced MMP-9, ICAM-1, and VCAM-1, but not vice versa.Inhibition of NADPH oxidase activity had greater effects on the decrease of BBB permeability than inhibition of other factors. In the genetic study, there were significantly regulated genes with aging (up: 4 genes, down: 19 genes; aging-related genes), EAE induction (up: 44, down: 4; EAE-related genes), and the interaction of aging and EAE (up: 13 genes, down: 24 genes, Aging × EAE-related genes). The Aging × EAE-related genes may aggravate EAE symptoms in aged mice and increase EAE susceptibility with aging, enhancing oxidative stress and DNA damage, and regulating the gene functions such as cell death, metal ion binding, and nucleotide binding. The Aging × EAE-related genes were verified by qRT-PCR to be increased in aged-EAE. The genes such as Actb, Bmi1, Sgk3, Trim35, Trim 23, and Sept7 are indicated to be novel biomarker candidates for EAE susceptibility with aging effect. In conclusion, the significantly changed hematological parameters for EAE induction with aging contribute to the T-cell infiltration and oxidative damages. In addition, NADPH oxidase-derived superoxide with aging upregulates MMP-9, ICAM-1, and VCAM-1 that ultimately lead to BBB disruption. Thus, the changes of these factors may result in the increase of EAE susceptibility in aged mice with severe inflammatory responses and demyelination. Furthermore, these results suggest that monitoring and regulation of these immunological and genetic factors can be possible approaches for EAE or MS susceptibility with aging.
Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) with demyelination and axonal damage. MS is usually regarded as a young person's disease, diagnosing in patients between 20 and 40 years of age. However, the disability progression in old patients was much faster with active inflammation than in young patients. To identify the age-related changes for MS, different age groups of experimental autoimmune encephalomyelitis (EAE; an animal model of MS) were used for approaching the age-related immunological and genetic changes. For immunological study, EAE was induced in various age groups for 60 days. In the groups for 6 weeks and 10 months mice, blood samples were collected at intervals of 10 days from day 0 to day 60 and the blood cell counts were promptly detected by using an automated hematological analyzer. In the groups for 6 weeks and 6 months mice, blood-brain barrier (BBB) disruption-related factors such as NADPH oxidase activity, MMP-9 activity, ICAM-1, VCAM-1, BBB permeability, and pro-inflammatory cytokines were measured. In addition, the correlations and interactions between NADPH oxidase, MMP-9, ICAM-1, and VCAM-1 were analyzed in mice tissue and plasma samples (in vivo), and MOG35–55 emulsion-exposed endothelial cell line (in vitro). In 6 weeks and 15 months groups for genetic study, differentially expressed-genes by EAE and/or age effects found with bio-functions and pathways of the genes. The genes for EAE susceptibility with aging effect were identified. EAE severity was higher in aged-group, showing the significantly changed body weight and clinical score. White blood cells, lymphocytes, and monocytes were rapidly elevated, whereas red blood cells, hemoglobin, and hematocrit were reduced before EAE onset. Interestingly, the changes were much higher in aged-EAE than in young-EAE. NADPH oxidase activity, MMP-9 activity, ICAM-1, and VCAM-1 (4 factors) were increased by age and EAE effects. BBB permeability was higher in aged-EAE and inflammatory cytokines were significantly altered with age or EAE effects. The 4 factors were positively correlated in EAE groups, and stronger correlations between NADPH oxidase and other factors were shown in CNS tissues, particularly in aged-EAE. In the in vitro study, NADPH oxidase directly influenced MMP-9, ICAM-1, and VCAM-1, but not vice versa.Inhibition of NADPH oxidase activity had greater effects on the decrease of BBB permeability than inhibition of other factors. In the genetic study, there were significantly regulated genes with aging (up: 4 genes, down: 19 genes; aging-related genes), EAE induction (up: 44, down: 4; EAE-related genes), and the interaction of aging and EAE (up: 13 genes, down: 24 genes, Aging × EAE-related genes). The Aging × EAE-related genes may aggravate EAE symptoms in aged mice and increase EAE susceptibility with aging, enhancing oxidative stress and DNA damage, and regulating the gene functions such as cell death, metal ion binding, and nucleotide binding. The Aging × EAE-related genes were verified by qRT-PCR to be increased in aged-EAE. The genes such as Actb, Bmi1, Sgk3, Trim35, Trim 23, and Sept7 are indicated to be novel biomarker candidates for EAE susceptibility with aging effect. In conclusion, the significantly changed hematological parameters for EAE induction with aging contribute to the T-cell infiltration and oxidative damages. In addition, NADPH oxidase-derived superoxide with aging upregulates MMP-9, ICAM-1, and VCAM-1 that ultimately lead to BBB disruption. Thus, the changes of these factors may result in the increase of EAE susceptibility in aged mice with severe inflammatory responses and demyelination. Furthermore, these results suggest that monitoring and regulation of these immunological and genetic factors can be possible approaches for EAE or MS susceptibility with aging.
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#Experimental Autoimmune Encephalomyelitis Age-related Changes
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