RESUMO
Long-term therapeutic outcomes of multiple sclerosis (MS) remain hindered by the chronic nature of immune cell stimulation toward self-antigens. Development of novel methods to target and deplete autoreactive T lymphocytes remains an attractive target for therapeutics for MS. We developed a programmed cell death 1 (PD-1)-targeted radiolabeled mAb and assessed its ability to deplete activated PD-1+ T lymphocytes in vitro and its ability to reduce disease burden of the myelin oligodendrocyte glycoprotein 35-55 experimental autoimmune encephalomyelitis (EAE) model in C57BL/6 mice. We also investigated the upregulation of PD-1 on infiltrating lymphocytes in an animal model of MS. Finally, we demonstrate the (to our knowledge) first reported positron-emission tomography/computed tomography imaging of activated PD-1+ cells in the EAE animal model of MS. We found that the 177Lu radioisotope-labeled anti-PD-1 mAb demonstrated significant in vitro cytotoxicity toward activated CD4+PD-1+ T lymphocytes and led to significant reduction in overall disease progression in the EAE animal model. Our results show high expression of PD-1 on infiltrating lymphocytes in the spinal cords of EAE diseased animals. Positron-emission tomography/computed tomography imaging of the anti-PD-1 mAb demonstrated significant uptake in the cervical draining lymph nodes highlighting accumulation of activated lymphocytes. Targeted depletion of T lymphocytes using T cell activation markers such as PD-1 may present a novel method to reduce autoimmune attack and inflammation in autoimmune diseases such as MS. Development of multimodal nuclear theranostic agents may present the opportunity to monitor T cell activation via imaging radioisotopes and simultaneously treat MS using therapeutic radioisotopes.
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Encefalomielite Autoimune Experimental , Ativação Linfocitária , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1 , Animais , Encefalomielite Autoimune Experimental/imunologia , Receptor de Morte Celular Programada 1/imunologia , Camundongos , Ativação Linfocitária/imunologia , Anticorpos Monoclonais , Linfócitos T/imunologia , Feminino , Modelos Animais de Doenças , Esclerose Múltipla/imunologia , Esclerose Múltipla/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , HumanosRESUMO
Oligodendrocyte (OL) damage and death are prominent features of multiple sclerosis (MS) pathology, yet mechanisms contributing to OL loss are incompletely understood. Dysfunctional RNA binding proteins (RBPs), hallmarked by nucleocytoplasmic mislocalization and altered expression, have been shown to result in cell loss in neurologic diseases, including in MS. Since we previously observed that the RBP heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) was dysfunctional in neurons in MS, we hypothesized that it might also contribute to OL pathology in MS and relevant models. We discovered that hnRNP A1 dysfunction is characteristic of OLs in MS brains. These findings were recapitulated in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, where hnRNP A1 dysfunction was characteristic of OLs, including oligodendrocyte precursor cells and mature OLs in which hnRNP A1 dysfunction correlated with demyelination. We also found that hnRNP A1 dysfunction was induced by IFNγ, indicating that inflammation influences hnRNP A1 function. To fully understand the effects of hnRNP A1 dysfunction on OLs, we performed siRNA knockdown of hnRNP A1, followed by RNA sequencing. RNA sequencing detected over 4000 differentially expressed transcripts revealing alterations to RNA metabolism, cell morphology, and programmed cell death pathways. We confirmed that hnRNP A1 knockdown was detrimental to OLs and induced apoptosis and necroptosis. Together, these data demonstrate a critical role for hnRNP A1 in proper OL functioning and survival and suggest a potential mechanism of OL damage and death in MS that involves hnRNP A1 dysfunction.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Camundongos , Ribonucleoproteína Nuclear Heterogênea A1/genética , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Esclerose Múltipla/patologia , Proteínas de Ligação a RNA/metabolismo , RNA Interferente PequenoRESUMO
Remyelination and neurodegeneration prevention mitigate disability in Multiple Sclerosis (MS). We have shown acute intermittent hypoxia (AIH) is a novel, non-invasive and effective therapy for peripheral nerve repair, including remyelination. Thus, we posited AIH would improve repair following CNS demyelination and address the paucity of MS repair treatments. AIH's capacity to enhance intrinsic repair, functional recovery and alter disease course in the experimental autoimmune encephalomyelitis (EAE) model of MS was assessed. EAE was induced by MOG35-55 immunization in C57BL/6 female mice. EAE mice received either AIH (10 cycles-5 min 11% oxygen alternating with 5 min 21% oxygen) or Normoxia (control; 21% oxygen for same duration) once daily for 7d beginning at near peak EAE disease score of 2.5. Mice were followed post-treatment for an additional 7d before assessing histopathology or 14d to examine maintenance of AIH effects. Alterations in histopathological correlates of multiple repair indices were analyzed quantitatively in focally demyelinated ventral lumbar spinal cord areas to assess AIH impacts. AIH begun at near peak disease significantly improved daily clinical scores/functional recovery and associated histopathology relative to Normoxia controls and the former were maintained for at least 14d post-treatment. AIH enhanced correlates of myelination, axon protection and oligodendrocyte precursor cell recruitment to demyelinated areas. AIH also effected a dramatic reduction in inflammation, while polarizing remaining macrophages/microglia toward a pro-repair state. Collectively, this supports a role for AIH as a novel non-invasive therapy to enhance CNS repair and alter disease course following demyelination and holds promise as a neuroregenerative MS strategy.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Remielinização , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Anaerobiose , Oxigênio , FemininoRESUMO
Neurodegeneration, the progressive loss or damage to neurons and axons, underlies permanent disability in multiple sclerosis (MS); yet its mechanisms are incompletely understood. Recent data indicates autoimmunity to several intraneuronal antigens, including the RNA binding protein (RBP) heterogenous nuclear ribonucleoprotein A1 (hnRNP A1), as contributors to neurodegeneration. We previously showed that addition of anti-hnRNP A1 antibodies, which target the same immunodominant domain of MS IgG, to mice with experimental autoimmune encephalomyelitis (EAE) worsened disease and resulted in an exacerbation of hnRNP A1 dysfunction including cytoplasmic mislocalization of hnRNP A1, stress granule (SG) formation and neurodegeneration in the chronic stages of disease. Because this previous study focused on a singular timepoint during EAE, it is unclear whether anti-hnRNP A1 antibody induced hnRNP A1 dysfunction caused neurodegeneration or was result of it. In the present study, we analyzed in vivo and in vitro models of anti-hnRNP A1 antibody-mediated autoimmunity for markers of hnRNP A1 dysfunction and neurodegeneration over a time course to gain a better understanding of the connection between hnRNP A1 dysfunction and neurodegeneration. Anti-hnRNP A1 antibody treatment resulted in increased neuronal hnRNP A1 mislocalization and nuclear depletion temporally followed by altered RNA expression and SG formation, and lastly an increase in necroptotic signalling and neuronal cell death. Treatment with necrostatin-1s inhibited necroptosis and partially rescued anti-hnRNP A1 antibody-mediated neurodegeneration while clathrin knockdown specifically inhibited anti-hnRNP A1 antibody uptake into neurons. This data identifies a novel antibody-mediated mechanism of neurodegeneration, which may be targeted to inhibit neurodegeneration and prevent permanent neurological decline in persons living with MS.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Animais , Autoimunidade , Ribonucleoproteína Nuclear Heterogênea A1/genética , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Camundongos , Esclerose Múltipla/metabolismo , Degeneração Neural , Neurônios/metabolismo , RibonucleoproteínasRESUMO
Evidence indicates that dysfunctional heterogeneous ribonucleoprotein A1 (hnRNPA1; A1) contributes to the pathogenesis of neurodegeneration in multiple sclerosis. Understanding molecular mechanisms of neurodegeneration in multiple sclerosis may result in novel therapies that attenuate neurodegeneration, thereby improving the lives of MS patients with multiple sclerosis. Using an in vitro, blue light induced, optogenetic protein expression system containing the optogene Cryptochrome 2 and a fluorescent mCherry reporter, we examined the effects of multiple sclerosis-associated somatic A1 mutations (P275S and F281L) in A1 localization, cluster kinetics and stress granule formation in real-time. We show that A1 mutations caused cytoplasmic mislocalization, and significantly altered the kinetics of A1 cluster formation/dissociation, and the quantity and size of clusters. A1 mutations also caused stress granule formation to occur more quickly and frequently in response to blue light stimulation. This study establishes a live cell optogenetics imaging system to probe localization and association characteristics of A1. It also demonstrates that somatic mutations in A1 alter its function and promote stress granule formation, which supports the hypothesis that A1 dysfunction may exacerbate neurodegeneration in multiple sclerosis.
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Esclerose Lateral Amiotrófica/genética , Ribonucleoproteína Nuclear Heterogênea A1/genética , Esclerose Múltipla/genética , Degeneração Neural/genética , Esclerose Lateral Amiotrófica/patologia , Citoplasma/genética , Citoplasma/metabolismo , Humanos , Esclerose Múltipla/patologia , Mutação/genéticaRESUMO
Altered stress granule (SG) and RNA-binding protein (RBP) biology have been shown to contribute to the pathogenesis of several neurodegenerative diseases, yet little is known about their role in multiple sclerosis (MS). Pathological features associated with dysfunctional RBPs include RBP mislocalization from its normal nuclear location to the cytoplasm and the formation of chronic SGs. We tested the hypothesis that altered SG and RBP biology might contribute to the neurodegeneration in experimental autoimmune encephalomyelitis (EAE). C57BL/6 female mice were actively immunized with MOG35-55 to induce EAE. Spinal cords were examined for mislocalization of the RBPs, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and TAR-DNA binding protein-43 (TDP-43), SGs, neurodegeneration (SMI-32), T cells (CD3), and macrophages (CD68). In contrast to naive mice, mice with EAE showed SG formation (p < 0.0001) and mislocalization of hnRNP A1 (p < 0.05) in neurons of the ventral spinal cord gray matter, which correlated with clinical score (R = 0.8104, p = 0.0253). In these same areas, there was a neuronal loss (p < 0.0001) and increased SMI-32 immunoreactivity (both markers of neurodegeneration) and increased staining for CD3+ T cells and IFN-gamma. These findings recapitulate the SG and RBP biology and markers of neurodegeneration in MS tissues and suggest that altered SG and RBP biology contribute to the neurodegeneration in EAE, which might also apply to the pathogenesis of MS.
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Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Proteínas de Ligação a RNA/metabolismo , Medula Espinal/metabolismo , Medula Espinal/patologia , Animais , Proteínas de Ligação a DNA/metabolismo , Feminino , Substância Cinzenta/metabolismo , Substância Cinzenta/patologia , Ribonucleoproteína Nuclear Heterogênea A1/metabolismo , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Neurônios/metabolismo , Neurônios/patologia , Estresse FisiológicoRESUMO
The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and modifying or switching therapies to optimize disease control. The current TORs also address the treatment of pediatric MS, progressive MS and the identification and treatment of aggressive forms of the disease. Newer therapies offer improved efficacy, but also have potential safety concerns that must be adequately balanced, notably when treatment sequencing is considered. There are added discussions regarding the management of pregnancy, the future potential of biomarkers and consideration as to when it may be prudent to stop therapy. These TORs are meant to be used and interpreted by all neurologists with a special interest in the management of MS.
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Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Guias de Prática Clínica como Assunto/normas , Canadá/epidemiologia , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/normas , Esclerose Múltipla/diagnóstico por imagem , Resultado do TratamentoRESUMO
Neurodegeneration in multiple sclerosis (MS) is believed to underlie disease progression and permanent disability. Many mechanisms of neurodegeneration in MS have been proposed, such as mitochondrial dysfunction, oxidative stress, neuroinflammation, and RNA-binding protein dysfunction. The purpose of this review is to highlight mechanisms of neurodegeneration in MS and its models, with a focus on RNA-binding protein dysfunction. Studying RNA-binding protein dysfunction addresses a gap in our understanding of the pathogenesis of MS, which will allow for novel therapies to be generated to attenuate neurodegeneration before irreversible central nervous system damage occurs.
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Esclerose Múltipla/complicações , Doenças Neurodegenerativas/patologia , Proteínas de Ligação a RNA/metabolismo , Animais , Progressão da Doença , Humanos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Estresse OxidativoRESUMO
BACKGROUND: Neurodegeneration is believed to be the primary cause of permanent, long-term disability in patients with multiple sclerosis. The cause of neurodegeneration in multiple sclerosis appears to be multifactorial. One mechanism that has been implicated in the pathogenesis of neurodegeneration in multiple sclerosis is the targeting of neuronal and axonal antigens by autoantibodies. Multiple sclerosis patients develop antibodies to the RNA-binding protein, heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), which is enriched in neurons. We hypothesized that anti-hnRNP A1 antibodies would contribute to neurodegeneration in an animal model of multiple sclerosis. METHODS: Following induction of experimental autoimmune encephalomyelitis (EAE) by direct immunization with myelin oligodendrocyte glycoprotein, mice were injected with anti-hnRNP A1 or control antibodies. Animals were examined clinically, and the central nervous system (CNS) tissues were tested for neurodegeneration with Fluoro-Jade C, a marker of degenerating neural elements. RESULTS: Injection of anti-hnRNP A1 antibodies in mice with EAE worsened clinical disease, altered the clinical disease phenotype, and caused neurodegeneration preferentially in the ventral spinocerebellar tract and deep white matter of the cerebellum in the CNS. Neurodegeneration in mice injected with hnRNP A1-M9 antibodies compared to control groups was consistent with "dying back" axonal degeneration. CONCLUSIONS: These data suggest that antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in immune-mediated disease of the CNS.
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Autoanticorpos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/imunologia , Doenças Neurodegenerativas/imunologia , Doenças Neurodegenerativas/patologia , Animais , Autoanticorpos/metabolismo , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Ribonucleoproteína Nuclear Heterogênea A1 , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Doenças Neurodegenerativas/metabolismoRESUMO
Neurodegeneration is the primary driver of disease progression in multiple sclerosis (MS) resulting in permanent disability, creating an urgent need to discover its underlying mechanisms. Herein, we establish that dysfunction of the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) results in differential of binding to RNA targets causing alternative RNA splicing, which contributes to neurodegeneration in MS and its models. Using RNAseq of MS brains, we discovered differential expression and aberrant splicing of hnRNP A1 target RNAs involved in neuronal function and RNA homeostasis. We confirmed this in vivo in experimental autoimmune encephalomyelitis employing CLIPseq specific for hnRNP A1, where hnRNP A1 differentially binds and regulates RNA, including aberrantly spliced targets identified in human samples. Additionally, dysfunctional hnRNP A1 expression in neurons caused neurite loss and identical changes in splicing, corroborating hnRNP A1 dysfunction as a cause of neurodegeneration. Collectively, these data indicate hnRNP A1 dysfunction causes altered neuronal RNA splicing, resulting in neurodegeneration in MS.
Assuntos
Ribonucleoproteína Nuclear Heterogênea A1 , Esclerose Múltipla , Humanos , Processamento Alternativo , Ribonucleoproteína Nuclear Heterogênea A1/genética , Esclerose Múltipla/genética , RNA , Splicing de RNA/genéticaRESUMO
Oligodendrocyte (OL) injury and subsequent loss is a pathologic hallmark of multiple sclerosis (MS). Stress granules (SGs) are membrane-less organelles containing mRNAs stalled in translation and considered as participants of the cellular response to stress. Here we show SGs in OLs in active and inactive areas of MS lesions as well as in normal-appearing white matter. In cultures of primary human adult brain derived OLs, metabolic stress conditions induce transient SG formation in these cells. Combining pro-inflammatory cytokines, which alone do not induce SG formation, with metabolic stress results in persistence of SGs. Unlike sodium arsenite, metabolic stress induced SG formation is not blocked by the integrated stress response inhibitor. Glycolytic inhibition also induces persistent SGs indicating the dependence of SG formation and disassembly on the energetic glycolytic properties of human OLs. We conclude that SG persistence in OLs in MS reflects their response to a combination of metabolic stress and pro-inflammatory conditions.
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Grânulos Citoplasmáticos , Esclerose Múltipla , Humanos , Grânulos Citoplasmáticos/metabolismo , Grânulos de Estresse , Oligodendroglia , Citocinas/metabolismo , Estresse Fisiológico , Esclerose Múltipla/metabolismoRESUMO
The one-carbon cycle is composed of four major biologically important molecules: methionine (L-Met), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), and homocysteine (Hcy). In addition to these key metabolites, there are multiple enzymes, vitamins, and cofactors that play essential roles in the cascade of the biochemical reactions that convert one metabolite into another in the cycle. Simultaneous quantitative measurement of four major metabolites can be used to detect possible aberrations in this vital cycle. Abnormalities in the one-carbon cycle might lead to hyper- or hypomethylation, homocystinemia, liver dysfunction, and accumulation of white-matter hyperintensities in the human brain. Previously published methods describe evaluation of several components of the one-carbon cycle, but none to our knowledge demonstrated simultaneous measurement of all four key molecules (L-Met, SAM, SAH, and Hcy). We describe a novel analytical method suitable for simultaneous identification and quantification of L-Met, SAM, SAH, and Hcy with LC-MS/MS. Moreover, we tested this method to identify these metabolites in human plasma collected from patients with multiple sclerosis and healthy individuals. In a pilot feasibility study, our results indicate that patients with multiple sclerosis showed abnormalities in the one-carbon cycle.
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Homocisteína/sangue , Metionina/sangue , Esclerose Múltipla/sangue , S-Adenosil-Homocisteína/sangue , S-Adenosilmetionina/sangue , Espectrometria de Massas em Tandem/métodos , Adulto , Cromatografia Líquida/métodos , Feminino , Homocisteína/metabolismo , Humanos , Masculino , Metionina/metabolismo , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismoRESUMO
The RNA binding protein heterogeneous nuclear ribonucleoprotein A1 (A1) regulates RNA metabolism, which is crucial to maintaining cellular homeostasis. A1 dysfunction mechanistically contributes to reduced cell viability and loss, but molecular mechanisms of how A1 dysfunction affects cell viability and loss, and methodologies to attenuate its dysfunction, are lacking. Utilizing in silico molecular modeling and an in vitro optogenetic system, this study examined the consequences of RNA oligonucleotide (RNAO) treatment on attenuating A1 dysfunction and its downstream cellular effects. In silico and thermal shift experiments revealed that binding of RNAOs to the RNA Recognition Motif 1 of A1 is stabilized by sequence- and structure-specific RNAO-A1 interactions. Using optogenetics to model A1 cellular dysfunction, we show that sequence- and structure-specific RNAOs significantly attenuated abnormal cytoplasmic A1 self-association kinetics and A1 cytoplasmic clustering. Downstream of A1 dysfunction, we demonstrate that A1 clustering affects the formation of stress granules, activates cell stress, and inhibits protein translation. With RNAO treatment, we show that stress granule formation is attenuated, cell stress is inhibited, and protein translation is restored. This study provides evidence that sequence- and structure-specific RNAO treatment attenuates A1 dysfunction and its downstream effects, thus allowing for the development of A1-specific therapies that attenuate A1 dysfunction and restore cellular homeostasis.
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BACKGROUND: Multiple sclerosis (MS) is a degenerative disease of the central nervous system (CNS) that disrupts walking function and results in other debilitating symptoms. This study compares the effects of 'task-oriented exercise' against 'generalized resistance and aerobic exercise' and a 'stretching control' on walking and CNS function in people with MS (PwMS). We hypothesize that task-oriented exercise will enhance walking speed and related neural changes to a greater extent than other exercise approaches. METHODS: This study is a single-blinded, three-arm randomized controlled trial conducted in Saskatchewan, Canada. Eligible participants are those older than 18 years of age with a diagnosis of MS and an expanded Patient-Determined Disease Steps (PDDS) score between 3 ('gait disability') and 6 ('bilateral support'). Exercise interventions are delivered for 12 weeks (3 × 60-min per week) in-person under the supervision of a qualified exercise professional. Interventions differ in exercise approach, such that task-oriented exercise involves weight-bearing, walking-specific activities, while generalized resistance and aerobic exercise uses seated machine-based resistance training of major upper and lower body muscle groups and recumbent cycling, and the stretching control exercise involves seated flexibility and relaxation activities. Participants are allocated to interventions using blocked randomization that stratifies by PDDS (mild: 3-4; moderate: 5-6). Assessments are conducted at baseline, post-intervention, and at a six-week retention time point. The primary and secondary outcome measures are the Timed 25-Foot Walk Test and corticospinal excitability for the tibialis anterior muscles determined using transcranial magnetic stimulation (TMS), respectively. Tertiary outcomes include assessments of balance, additional TMS measures, blood biomarkers of neural health and inflammation, and measures of cardiorespiratory and musculoskeletal fitness. DISCUSSION: A paradigm shift in MS healthcare towards the use of "exercise as medicine" was recently proposed to improve outcomes and alleviate the economic burden of MS. Findings will support this shift by informing the development of specialized exercise programming that targets walking and changes in corticospinal excitability in PwMS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05496881, Registered August 11, 2022. https://classic. CLINICALTRIALS: gov/ct2/show/NCT05496881 . Protocol amendment number: 01; Issue date: August 1, 2023; Primary reason for amendment: Expand eligibility to include people with all forms of MS rather than progressive forms of MS only.
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Our lab recently identified a cross-reactive antibody response between human T-lymphotropic virus type-1-p24-(gag) (HTLV-1-p24-(gag)) and peroxiredoxin-1 (PrX-1) as potentially contributing to the pathogenesis of HTLV-1 associated neurological disease via molecular mimicry. These targets proteins were glycosylated, yet the glycan side chains immunoreactive with the immunoglobulins were unknown. Using a combination of lectin isolation and serial enzymatic deglycosylation of glycoproteins, we determined that the immunoreactive epitopes contained branched oligomannose side chains. These data suggest that post-translational glycosylation specifically related to oligomannose immunoreactivity to both the infecting and host antigens may contribute to molecular mimicry and be important in the pathogenesis of HTLV-1 associated neurological disease.
Assuntos
Vírus Linfotrópico T Tipo 1 Humano/imunologia , Doenças do Sistema Nervoso/imunologia , Oligossacarídeos/imunologia , Paraparesia Espástica Tropical/imunologia , Peroxirredoxinas/imunologia , Proteínas Oncogênicas de Retroviridae/imunologia , Linhagem Celular , Reações Cruzadas , Epitopos/imunologia , Glicosilação , Vírus Linfotrópico T Tipo 1 Humano/patogenicidade , Humanos , Mimetismo Molecular , Doenças do Sistema Nervoso/virologia , Processamento de Proteína Pós-TraducionalRESUMO
One hypothesis that couples infection with autoimmune disease is molecular mimicry. Molecular mimicry is characterized by an immune response to an environmental agent that cross-reacts with a host antigen, resulting in disease. This hypothesis has been implicated in the pathogenesis of diabetes, lupus and multiple sclerosis (MS). There is limited direct evidence linking causative agents with pathogenic immune reactions in these diseases. Our study establishes a clear link between viral infection, autoimmunity and neurological disease in humans. As a model for molecular mimicry, we studied patients with human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), a disease that can be indistinguishable from MS (refs. 5,6,7). HAM/TSP patients develop antibodies to neurons. We hypothesized these antibodies would identify a central nervous system (CNS) autoantigen. Immunoglobulin G isolated from HAM/TSP patients identified heterogeneous nuclear ribonuclear protein-A1 (hnRNP-A1) as the autoantigen. Antibodies to hnRNP-A1 cross-reacted with HTLV-1-tax, the immune response to which is associated with HAM/TSP (refs. 5,9). Immunoglobulin G specifically stained human Betz cells, whose axons are preferentially damaged. Infusion of autoantibodies in brain sections inhibited neuronal firing, indicative of their pathogenic nature. These data demonstrate the importance of molecular mimicry between an infecting agent and hnRNP-A1 in autoimmune disease of the CNS.
Assuntos
Autoimunidade/fisiologia , Infecções por HTLV-I/imunologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Imunoglobulina G/análise , Mimetismo Molecular/imunologia , Doenças do Sistema Nervoso/imunologia , Anticorpos Monoclonais , Encéfalo/metabolismo , Reações Cruzadas , DNA Complementar , Infecções por HTLV-I/patologia , Infecções por HTLV-I/fisiopatologia , Ribonucleoproteína Nuclear Heterogênea A1 , Ribonucleoproteínas Nucleares Heterogêneas , Humanos , Imunoglobulina G/sangue , Doenças do Sistema Nervoso/patologia , Doenças do Sistema Nervoso/fisiopatologia , Especificidade de Órgãos , Técnicas de Patch-Clamp , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonucleoproteínas/genéticaRESUMO
Distinguishing between tumefactive demyelinating lesions (TDLs) and brain tumors in multiple sclerosis (MS) can be challenging. A progressive course is highly common with brain tumors in MS and no single neuroimaging technique is foolproof when distinguishing between the two. We report a case of a 41-year-old female with relapsing-remitting multiple sclerosis, who had a suspicious lesion within the left frontal hemisphere, without a progressive course. The patient experienced paresthesias primarily to her right hand but remained stable without any functional decline and new neurological symptoms over the four years she was followed. The lesion was followed with brain magnetic resonance imaging (MRI) scans, positron emission tomography-computed tomography scans, and magnetic resonance spectroscopy. Together, these scans favored the diagnosis of a TDL, but a low-grade tumor was difficult to rule out. Examination of serial brain MRI scans showed an enlarging lesion in the left middle frontal gyrus involving the deep white matter. Neurosurgery was consulted and an elective left frontal awake craniotomy was performed. Histopathology revealed a grade II astrocytoma. This case emphasizes the importance of thorough and continuous evaluation of atypical MRI lesions in MS and contributes important features to the literature for timely diagnosis and treatment of similar cases.
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Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a significant neurodegenerative component. Dysfunctional RNA-binding proteins (RBPs) are causally linked to neuronal damage and are a feature of MS, including the mislocalization of the RBP heterogeneous nuclear ribonucleoprotein A1 (A1). Here, we show that primary neurons exposed to pro-inflammatory cytokines and anti-A1 antibodies, both characteristic of an MS autoimmune response, displayed increased A1 mislocalization, stress granule formation, and decreased neurite length, a marker of neurodegeneration. These findings illustrate a significant relationship between secreted immune factors, A1 dysfunction, and neuronal damage in a disease-relevant model system.
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Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a member of the hnRNP family of conserved proteins that is involved in RNA transcription, pre-mRNA splicing, mRNA transport, protein translation, microRNA processing, telomere maintenance and the regulation of transcription factor activity. HnRNP A1 is ubiquitously, yet differentially, expressed in many cell types, and due to post-translational modifications, can vary in its molecular function. While a plethora of knowledge is known about the function and dysfunction of hnRNP A1 in diseases other than neurodegenerative disease (e.g., cancer), numerous studies in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, multiple sclerosis, spinal muscular atrophy, Alzheimer's disease, and Huntington's disease have found that the dysregulation of hnRNP A1 may contribute to disease pathogenesis. How hnRNP A1 mechanistically contributes to these diseases, and whether mutations and/or altered post-translational modifications contribute to pathogenesis, however, is currently under investigation. The aim of this comprehensive review is to first describe the background of hnRNP A1, including its structure, biological functions in RNA metabolism and the post-translational modifications known to modify its function. With this knowledge, the review then describes the influence of hnRNP A1 in neurodegenerative disease, and how its dysfunction may contribute the pathogenesis.
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BACKGROUND: Spinal cord lesions (SCLs) contribute to disability in multiple sclerosis (MS). Data in Saskatchewan, Canada, concerning SCLs and their association with disability levels in patients with MS are lacking. The study objectives were to identify clinicodemographic profiles of patients with MS with respect to spinal cord magnetic resonance imaging (MRI) involvement; determine the frequency of individuals with MRI SCLs; and explore differences between patients with MS with and without SCLs with respect to disability and disease-modifying therapy status. METHODS: A monocentric, cross-sectional, retrospective review of prospectively collected data from 532 research-consented patients seen at Saskatoon MS Clinic was performed. Data were collected from a database and electronic medical records. RESULTS: Of the 356 patients (66.9%) with an SCL, 180 (50.6%) had only cervical cord lesions. Median Expanded Disability Status Scale (EDSS), ambulation, and pyramidal scores of patients with SCLs were higher than those of patients without SCLs. Of patients with EDSS scores of at least 6, those with SCLs were younger than those without SCLs (P = .01). Patients with SCLs were 55% less likely to have been on continuous disease-modifying therapy since diagnosis than patients without SCLs (adjusted odds ratio, 0.45; 95% CI, 0.25-0.81; P = .008). CONCLUSIONS: Prevalence and association with disability of SCLs in patients with MS are comparable with existing literature. Patients with MS with SCLs have higher levels of disability and attain EDSS scores of at least 6 at a younger age.