RESUMO
Multiple sclerosis (MS) is a chronic disease that is characterized by the inappropriate invasion of lymphocytes and monocytes into the central nervous system (CNS), where they orchestrate the demyelination of axons, leading to physical and cognitive disability. There are many reasons immunologists should be interested in MS. Aside from the fact that there is still significant unmet need for patients living with the progressive form of the disease, MS is a case study for how immune cells cross CNS barriers and subsequently interact with specialized tissue parenchymal cells. In this review, we describe the types of immune cells that infiltrate the CNS and then describe interactions between immune cells and glial cells in different types of lesions. Lastly, we provide evidence for CNS-compartmentalized immune cells and speculate on how this impacts disease progression for MS patients.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Sistema Nervoso Central , Humanos , Inflamação , MonócitosRESUMO
Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting the neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce the stimulator of interferon genes (STING). However, activation of neuronal STING requires its detachment from the stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to autophagic degradation of glutathione peroxidase 4 (GPX4), essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions that target STING in neurons protect against inflammation-induced neurodegeneration. Our findings position STING as a central regulator of the detrimental neuronal inflammatory stress response, integrating inflammation with glutamate signaling to cause neuronal cell death, and present it as a tractable target for treating neurodegeneration in MS.
Assuntos
Inflamação , Proteínas de Membrana , Esclerose Múltipla , Neurônios , Animais , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Camundongos , Humanos , Inflamação/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Transdução de Sinais , Autofagia , Camundongos Endogâmicos C57BL , Ácido Glutâmico/metabolismo , Ferroptose , Modelos Animais de Doenças , Feminino , MasculinoRESUMO
Multiple sclerosis (MS) is a neurological disease characterized by multifocal lesions and smoldering pathology. Although single-cell analyses provided insights into cytopathology, evolving cellular processes underlying MS remain poorly understood. We investigated the cellular dynamics of MS by modeling temporal and regional rates of disease progression in mouse experimental autoimmune encephalomyelitis (EAE). By performing single-cell spatial expression profiling using in situ sequencing (ISS), we annotated disease neighborhoods and found centrifugal evolution of active lesions. We demonstrated that disease-associated (DA)-glia arise independently of lesions and are dynamically induced and resolved over the disease course. Single-cell spatial mapping of human archival MS spinal cords confirmed the differential distribution of homeostatic and DA-glia, enabled deconvolution of active and inactive lesions into sub-compartments, and identified new lesion areas. By establishing a spatial resource of mouse and human MS neuropathology at a single-cell resolution, our study unveils the intricate cellular dynamics underlying MS.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Medula Espinal , Animais , Humanos , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Medula Espinal/metabolismo , Medula Espinal/patologia , Camundongos , Análise da Expressão Gênica de Célula Única , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Neuroglia/metabolismo , Neuroglia/patologiaRESUMO
Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.
Assuntos
Epigênese Genética , Bainha de Mielina , Oligodendroglia , Remielinização , Animais , Bainha de Mielina/metabolismo , Humanos , Camundongos , Remielinização/efeitos dos fármacos , Oligodendroglia/metabolismo , Sistema Nervoso Central/metabolismo , Camundongos Endogâmicos C57BL , Rejuvenescimento , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Organoides/metabolismo , Organoides/efeitos dos fármacos , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/genética , Diferenciação Celular/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Masculino , Regeneração/efeitos dos fármacos , Esclerose Múltipla/metabolismo , Esclerose Múltipla/genética , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologiaRESUMO
Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system afflicting nearly three million individuals worldwide. Neuroimmune interactions between glial, neural, and immune cells play important roles in MS pathology and offer potential targets for therapeutic intervention. Here, we review underlying risk factors, mechanisms of MS pathogenesis, available disease modifying therapies, and examine the value of emerging technologies, which may address unmet clinical needs and identify novel therapeutic targets.
Assuntos
Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Sistema Nervoso Central , Neuroglia , Fenômenos Fisiológicos Celulares , Inflamação/patologiaRESUMO
Autoimmune cross-reaction of specific antibodies to Epstein-Barr virus (EBV) has been associated with development of multiple sclerosis (MS). In this issue of Cell, Vietzen et al. identify additional immunological regulatory mechanisms that protect against autoimmunity in healthy people but are reduced in MS cases. The results confirm the link between EBV and MS.
Assuntos
Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Humanos , Herpesvirus Humano 4 , Infecções por Vírus Epstein-Barr/complicaçõesRESUMO
Multiple sclerosis (MS) is a demyelinating disease of the CNS. Epstein-Barr virus (EBV) contributes to the MS pathogenesis because high levels of EBV EBNA386-405-specific antibodies cross react with the CNS-derived GlialCAM370-389. However, it is unclear why only some individuals with such high autoreactive antibody titers develop MS. Here, we show that autoreactive cells are eliminated by distinct immune responses, which are determined by genetic variations of the host, as well as of the infecting EBV and human cytomegalovirus (HCMV). We demonstrate that potent cytotoxic NKG2C+ and NKG2D+ natural killer (NK) cells and distinct EBV-specific T cell responses kill autoreactive GlialCAM370-389-specific cells. Furthermore, immune evasion of these autoreactive cells was induced by EBV-variant-specific upregulation of the immunomodulatory HLA-E. These defined virus and host genetic pre-dispositions are associated with an up to 260-fold increased risk of MS. Our findings thus allow the early identification of patients at risk for MS and suggest additional therapeutic options against MS.
Assuntos
Autoimunidade , Infecções por Vírus Epstein-Barr , Esclerose Múltipla , Humanos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/genética , Antígenos de Histocompatibilidade Classe I , Esclerose Múltipla/imunologia , Células Matadoras Naturais/imunologiaRESUMO
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system (CNS). Bone marrow hematopoietic stem and progenitor cells (HSPCs) rapidly sense immune activation, yet their potential interplay with autoreactive T cells in MS is unknown. Here, we report that bone marrow HSPCs are skewed toward myeloid lineage concomitant with the clonal expansion of T cells in MS patients. Lineage tracing in experimental autoimmune encephalomyelitis, a mouse model of MS, reveals remarkable bone marrow myelopoiesis with an augmented output of neutrophils and Ly6Chigh monocytes that invade the CNS. We found that myelin-reactive T cells preferentially migrate into the bone marrow compartment in a CXCR4-dependent manner. This aberrant bone marrow myelopoiesis involves the CCL5-CCR5 axis and augments CNS inflammation and demyelination. Our study suggests that targeting the bone marrow niche presents an avenue to treat MS and other autoimmune disorders.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Medula Óssea , Hematopoese , Humanos , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Changes in the gut microbiota are associated with the etiopathogenesis of complex diseases, such as multiple sclerosis. In this issue of Cell, the international Multiple Sclerosis Microbiome Study consortium deployed a multi-omics approach to profile the composition and function of the gut microbiome in an extensive cohort of MS patients.
Assuntos
Microbioma Gastrointestinal , Microbiota , Esclerose Múltipla , Dispositivos de Proteção da Cabeça , Humanos , Estrutura Secundária de ProteínaRESUMO
Changes in gut microbiota have been associated with several diseases. Here, the International Multiple Sclerosis Microbiome Study (iMSMS) studied the gut microbiome of 576 MS patients (36% untreated) and genetically unrelated household healthy controls (1,152 total subjects). We observed a significantly increased proportion of Akkermansia muciniphila, Ruthenibacterium lactatiformans, Hungatella hathewayi, and Eisenbergiella tayi and decreased Faecalibacterium prausnitzii and Blautia species. The phytate degradation pathway was over-represented in untreated MS, while pyruvate-producing carbohydrate metabolism pathways were significantly reduced. Microbiome composition, function, and derived metabolites also differed in response to disease-modifying treatments. The therapeutic activity of interferon-ß may in part be associated with upregulation of short-chain fatty acid transporters. Distinct microbial networks were observed in untreated MS and healthy controls. These results strongly support specific gut microbiome associations with MS risk, course and progression, and functional changes in response to treatment.
Assuntos
Microbioma Gastrointestinal , Esclerose Múltipla , Ácidos Graxos Voláteis , Humanos , Interferon beta , Ácido Fítico , PiruvatosRESUMO
Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS.
Assuntos
Astrócitos , Esclerose Múltipla , Animais , Humanos , Camundongos , Anti-Inflamatórios , Modelos Animais de Doenças , Epigênese Genética , Fator de Crescimento Semelhante a EGF de Ligação à Heparina/genética , Inflamação , ProteômicaRESUMO
Interleukin-17 (IL-17)-producing helper T (TH17) cells are heterogenous and consist of nonpathogenic TH17 (npTH17) cells that contribute to tissue homeostasis and pathogenic TH17 (pTH17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying TH17 heterogeneity and discover substantial differences in the chromatin landscape of npTH17 and pTH17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTH17 cells share accessible chromatin configurations with regulatory T cells, whereas pTH17 cells exhibit features of both npTH17 cells and type 1 helper T (TH1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating TH17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npTH17 programs and restrains proinflammatory TH1-like programs in TH17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of TH17 heterogeneity as potential targets to mitigate autoimmunity.
Assuntos
Fatores de Transcrição de Zíper de Leucina Básica , Cromatina , Células Th17 , Animais , Feminino , Humanos , Camundongos , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Cromatina/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/genética , Inflamação/imunologia , Inflamação/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esclerose Múltipla/imunologia , Esclerose Múltipla/genética , Análise de Célula Única , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th17/imunologia , Células Th17/metabolismoRESUMO
Eighty percent of individuals with multiple sclerosis (MS) initially develop a clinical pattern with periodic relapses followed by remissions, called relapsing-remitting MS (RRMS). This period of fluctuating disease may last for a decade or more. Clinical relapses reflect acute inflammation in the central nervous system (CNS), composed of the brain and spinal cord. Often, different anatomic areas in the CNS are involved each time a relapse occurs, resulting in varied clinical manifestations in each instance. Relapses are nearly always followed by some degree of remission, though recovery to baseline status before the flare is often incomplete. There are nine approved drugs for treatment of RRMS. The most potent drug for inhibiting relapses, the humanized anti-α4 integrin antibody known as Natalizumab, blocks homing of mononuclear cells to the CNS. The mechanisms of action of the approved drugs for RRMS provide a strong foundation for understanding the pathobiology of the relapse. Despite substantial progress in controlling relapses with the current armamentarium of medications, there is much to learn and ever more effective and safe therapies to develop.
Assuntos
Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla/imunologia , Animais , Progressão da Doença , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/metabolismo , RecidivaRESUMO
Successful therapeutic options directly targeting disability progression in patients with multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system, are lacking. Now, a study published in Nature by Absinta and colleagues profiles a lymphocyte-glia connection at the edge of chronic active lesions that continuously drives neurodegenerative pathways.
Assuntos
Esclerose Múltipla , Sistema Nervoso Central , Humanos , Inflamação , Linfócitos , NeurogliaRESUMO
Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.
Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Esclerose Múltipla , Humanos , Estudo de Associação Genômica Ampla , Doenças Inflamatórias Intestinais/genética , Locos de Características Quantitativas , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Inflamação/genética , Esclerose Múltipla/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
CD4+ T helper 17 (TH17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic TH17 cells in the central nervous system (CNS) but not that of protective TH17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4+ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the TH17 cell transcriptional regulatory network and showed high interconnectivity with core TH17 cell-specific transcription factors. Mechanistically, EGR2 enhanced TH17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host's ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic TH17 cells in the CNS.
Assuntos
Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Camundongos , Diferenciação Celular , Sistema Nervoso Central , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Células Th1 , Células Th17 , Fatores de Transcrição , Virulência , HumanosRESUMO
Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development. VIDEO ABSTRACT.
Assuntos
Comunicação Celular/genética , Doença/genética , Oligodendroglia/metabolismo , Animais , Encéfalo/metabolismo , Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes/metabolismo , Doenças Desmielinizantes/patologia , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/metabolismo , Esclerose Múltipla/fisiopatologia , Bainha de Mielina/metabolismo , Neurônios/metabolismo , Oligodendroglia/fisiologia , Fatores de RiscoRESUMO
Short-chain fatty acids are processed from indigestible dietary fibers by gut bacteria and have immunomodulatory properties. Here, we investigate propionic acid (PA) in multiple sclerosis (MS), an autoimmune and neurodegenerative disease. Serum and feces of subjects with MS exhibited significantly reduced PA amounts compared with controls, particularly after the first relapse. In a proof-of-concept study, we supplemented PA to therapy-naive MS patients and as an add-on to MS immunotherapy. After 2 weeks of PA intake, we observed a significant and sustained increase of functionally competent regulatory T (Treg) cells, whereas Th1 and Th17 cells decreased significantly. Post-hoc analyses revealed a reduced annual relapse rate, disability stabilization, and reduced brain atrophy after 3 years of PA intake. Functional microbiome analysis revealed increased expression of Treg-cell-inducing genes in the intestine after PA intake. Furthermore, PA normalized Treg cell mitochondrial function and morphology in MS. Our findings suggest that PA can serve as a potent immunomodulatory supplement to MS drugs.
Assuntos
Esclerose Múltipla/metabolismo , Propionatos/imunologia , Propionatos/metabolismo , Adulto , Idoso , Progressão da Doença , Fezes/química , Fezes/microbiologia , Feminino , Humanos , Imunomodulação/fisiologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/imunologia , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/terapia , Propionatos/uso terapêutico , Linfócitos T Reguladores/imunologia , Células Th17/imunologiaRESUMO
The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4+ T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4+ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4+ T cells in MS.
Assuntos
Subtipos Sorológicos de HLA-DR/imunologia , Esclerose Múltipla/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Alelos , Antígenos/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Células Cultivadas , Reações Cruzadas/imunologia , Feminino , Humanos , Memória Imunológica , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Peptídeos/imunologia , Proteoma/metabolismo , Adulto JovemRESUMO
Progressive multiple sclerosis (PMS) causes slow accumulation of neurologic disability and has been refractory to treatment with the immunomodulatory medications that effectively control relapsing MS. Siponimod modestly slowed the rate of disability progression among PMS patients who had inflammatory disease activity, evidenced by new or gadolinium-enhancing MRI lesions. To view this Bench to Bedside, open or download the PDF.