Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility

Science, Год журнала: 2019, Номер 365(6460)

Опубликована: Сен. 26, 2019

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects established a reference map the architecture MS that includes 200 autosomal susceptibility variants outside major histocompatibility complex (MHC), one chromosome X variant, 32 within extended MHC. used an ensemble methods to prioritize 551 putative genes implicate innate adaptive pathways distributed across cellular components immune system. Using expression profiles from purified human microglia, we observed enrichment for in these brain-resident cells, suggesting may have role targeting autoimmune process central nervous system, although is most likely initially triggered by perturbation peripheral responses.

Язык: Английский

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Astrocyte Reactivity and Reactive Astrogliosis: Costs and Benefits

Physiological Reviews, Год журнала: 2014, Номер 94(4), С. 1077 - 1098

Опубликована: Окт. 1, 2014

Astrocytes are the most abundant cells in central nervous system (CNS) that provide nutrients, recycle neurotransmitters, as well fulfill a wide range of other homeostasis maintaining functions. During past two decades, astrocytes emerged also increasingly important regulators neuronal functions including generation new nerve and structural functional synapse remodeling. Reactive gliosis or reactive astrogliosis is term coined for morphological changes seen astroglial cells/astrocytes responding to CNS injury neurological diseases. Whereas this defensive reaction conceivably aimed at handling acute stress, limiting tissue damage, restoring homeostasis, it may inhibit adaptive neural plasticity mechanisms underlying recovery function. Understanding multifaceted roles healthy diseased will undoubtedly contribute development treatment strategies will, context-dependent manner appropriate time points, modulate promote brain repair reduce impairment.

Язык: Английский

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Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque

Annals of Neurology, Год журнала: 2015, Номер 78(5), С. 710 - 721

Опубликована: Авг. 3, 2015

Objective An extensive analysis of white matter plaques in a large sample multiple sclerosis (MS) autopsies provides insights into the dynamic nature MS pathology. Methods One hundred twenty cases (1,220 tissue blocks) were included. Plaque types classified according to demyelinating activity based on stringent criteria. Early active, late smoldering, inactive, and shadow distinguished. A total 2,476 identified. type distribution was analyzed relation clinical data. Results Active most often found early disease, whereas at later stages, predominated. The presence active rapidly declined with disease duration. differed significantly by course. majority acute monophasic relapsing–remitting (RRMS) active. Among secondary progressive (SPMS) attacks, all plaque could be distinguished including plaques, contrast SPMS without which inactive Smoldering frequently almost exclusively MS. At 47 years age, an equilibrium observed between smoldering began peak. Men displayed higher proportion plaques. Interpretation Disease duration, course, gender contribute predominate RRMS are likely substrate attacks. Progressive transitions accumulation characterized microglial activation slow expansion pre‐existing Whether current therapeutics impact this pathological driver progression remains uncertain. Ann Neurol 2015;78:Ann 2015;78:679–696

Язык: Английский

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Sex and gender issues in multiple sclerosis

Therapeutic Advances in Neurological Disorders, Год журнала: 2013, Номер 6(4), С. 237 - 248

Опубликована: Май 13, 2013

Multiple sclerosis (MS) is universally found to be more prevalent in women than men. This has led extensive studies of differences the immune system or nervous between and men, which might caused by effects gonadal hormones, genetic differences, different environmental exposures modern lifestyle men women. We review sex gender from a genetic, immunological clinical point view. discuss on expression MS responses therapy, as well issues concerning pregnancy.

Язык: Английский

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Microglia express distinct M1 and M2 phenotypic markers in the postnatal and adult central nervous system in male and female mice

Journal of Neuroscience Research, Год журнала: 2013, Номер 91(9), С. 1143 - 1151

Опубликована: Май 17, 2013

Although microglial activation is associated with all CNS disorders, many of which are sexually dimorphic or age-dependent, little known about whether basal gene expression altered age in the healthy it sex dependent. Analysis microglia from brains 3-day (P3)- to 12-month-old male and female C57Bl/6 mice revealed distinct profiles during postnatal development that differ significantly those adulthood. Microglia at P3 characterized by relatively high iNOS, TNFα arginase-I mRNA levels, whereas P21 have increased CD11b, TLR4, FcRγI. Adult (2–4 months) low proinflammatory cytokine expression, increases 12 months age. Age-dependent differences suggest likely undergo phenotypic changes ontogenesis, although brain they did not express exclusively either M1 M2 markers any time. Interestingly, were only P3, when females had higher inflammatory cytokines than males, there no estrogen receptor this other time evaluated here. Compared vivo, primary prepared considerably levels TNFα, arginase-I, VEGF, suggesting culturing may alter properties. In conclusion, age- sex-specific variances allow differential responses same stimulus different ages, perhaps contributing vulnerabilities and/or disease courses. © 2013 Wiley Periodicals, Inc.

Язык: Английский

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Sex differences in neurodevelopmental and neurodegenerative disorders: Focus on microglial function and neuroinflammation during development

The Journal of Steroid Biochemistry and Molecular Biology, Год журнала: 2015, Номер 160, С. 127 - 133

Опубликована: Окт. 5, 2015

Язык: Английский

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Reactive gliosis in the pathogenesis of CNS diseases

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Год журнала: 2015, Номер 1862(3), С. 483 - 491

Опубликована: Дек. 3, 2015

Язык: Английский

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Sex differences in autoimmune diseases

Biology of Sex Differences, Год журнала: 2011, Номер 2(1), С. 1 - 1

Опубликована: Янв. 1, 2011

Women are more susceptible to a variety of autoimmune diseases including systemic lupus erythematosus (SLE), multiple sclerosis (MS), primary biliary cirrhosis, rheumatoid arthritis and Hashimoto's thyroiditis. This increased susceptibility in females compared males is also present animal models such as spontaneous SLE (NZBxNZW)F1 NZM.2328 mice, experimental encephalomyelitis (EAE) SJL thyroiditis, Sjogren's syndrome MRL/Mp-lpr/lpr mice diabetes non-obese diabetic mice. Indeed, being female confers greater risk developing these than any single genetic or environmental factor discovered date. Understanding how the state so profoundly affects disease would accomplish two major goals. First, it lead an insight into pathways pathogenesis and, secondly, likely novel treatments which disrupt pathways.

Язык: Английский

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Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes

Proceedings of the National Academy of Sciences, Год журнала: 2017, Номер 115(2)

Опубликована: Дек. 26, 2017

Significance Molecular mechanisms underlying distinct disabilities during neurological diseases may differ based on the pathway involved. Multiple sclerosis (MS) is multifocal, characterized by affecting walking, vision, cognition, and fatigue. Neuroprotective treatments tailored for each disability be more effective than nonspecific aiming to reduce a composite of in clinical trials. Here, we use MS model apply cell-specific region-specific gene expression approach discover targets neuroanatomic regions. Altered cholesterol synthesis astrocytes spinal cord optic nerve was identified as potential target walking visual disabilities, respectively. This disability-specific discovery represents strategy finding neuroprotective multifocal neurodegenerative diseases.

Язык: Английский

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Impact of sex hormones on immune function and multiple sclerosis development

Immunology, Год журнала: 2018, Номер 156(1), С. 9 - 22

Опубликована: Сен. 17, 2018

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting young people and leading to demyelination neurodegeneration. The clearly more common in women, whom incidence has been rising. Gender differences include: earlier onset frequent relapses women; faster progression worse outcomes men. Hormone-related physiological conditions women such as puberty, pregnancy, puerperium, menopause also exert significant influence both on prevalence well outcomes. Hormonal and/or genetic factors are therefore believed be involved regulating course disease. In this review, we discuss clinical evidence for impact sex hormones (estrogens, progesterone, prolactin, testosterone) MS attempt elucidate hormonal immunological mechanisms potentially underlying these changes. We review current knowledge relationship between resident CNS cells provide new insights context MS. Understanding molecular may contribute development safer treatments men women.

Язык: Английский

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