RESUMEN
Neurological disorders, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), may be associated with alterations in blood cell composition and phenotype. Here, we focused our attention on circulating mucosal-associated invariant T (MAIT) cells, a CD8+ T cell memory population expressing the invariant Vα7.2 region in the T cell receptor and high surface levels of the CD161 marker. Transcriptomics data relative to peripheral blood mononuclear cells (PBMC) highlighted downregulation of CD161 and other MAIT-associated markers in progressive MS and not relapsing remitting (RR)-MS when gene expressions relative to each disease course were compared to those from healthy controls. Multiparametric flow cytometry of freshly isolated PBMC samples from untreated RR-MS, primary or secondary progressive MS (PP- or SP-MS), ALS and age- and sex-matched healthy controls revealed specific loss of circulating CD8+ MAIT cells in PP-MS and no other MS courses or another neurological disorder such as ALS. Overall, these observations point to the existence of immunological changes in blood specific for the primary progressive course of MS that may support clinical definition of disease.
Asunto(s)
Esclerosis Amiotrófica Lateral , Células T Invariantes Asociadas a Mucosa , Humanos , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/sangre , Células T Invariantes Asociadas a Mucosa/inmunología , Células T Invariantes Asociadas a Mucosa/metabolismo , Masculino , Persona de Mediana Edad , Femenino , Adulto , Anciano , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/sangre , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Biomarcadores , Citometría de FlujoRESUMEN
Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease. Immune system dysregulation plays an essential role in ALS onset and progression. Our preclinical studies have shown that the administration of exogenous allogeneic B cells improves outcomes in murine models of skin and brain injury through a process termed pligodraxis, in which B cells adopt an immunoregulatory and neuroprotective phenotype in an injured environment. Here, we investigated the effects of B-cell therapy in the SOD1G93A mouse preclinical model of ALS and in a person living with ALS. Purified splenic mature naïve B cells from haploidentical donor mice were administered intravenously in SOD1G93A mice for a total of 10 weekly doses. For the clinical study in a person with advanced ALS, IgA gammopathy of unclear significance, and B lymphopenia, CD19+ B cells were positively selected from a healthy haploidentical donor and infused intravenously twice, at a 60-day interval. Repeated intravenous B-cell administration was safe and significantly delayed disease onset, extended survival, reduced cellular apoptosis, and decreased astrogliosis in SOD1G93A mice. Repeated B-cell infusion in a person with ALS was safe and did not appear to generate a clinically evident inflammatory response. An improvement of 5 points on the ALSFRS-R scale was observed after the first infusion. Levels of inflammatory markers showed persistent reduction post-infusion. This represents a first demonstration of the efficacy of haploidentical B-cell infusion in the SOD1G93A mouse and the safety and feasibility of using purified haploidentical B lymphocytes as a cell-based therapeutic strategy for a person with ALS.
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Esclerosis Amiotrófica Lateral , Linfocitos B , Esclerosis Amiotrófica Lateral/terapia , Esclerosis Amiotrófica Lateral/inmunología , Animales , Ratones , Humanos , Linfocitos B/inmunología , Modelos Animales de Enfermedad , Ratones Transgénicos , Masculino , Femenino , Ratones Endogámicos C57BL , Inmunomodulación , Persona de Mediana EdadRESUMEN
Inflammation is a hallmark of amyotrophic lateral sclerosis (ALS) and is often assessed through biological samples. Due to the easier access, peripheral blood is more commonly phenotyped instead of cerebrospinal fluid (CSF) or affected tissues in ALS. Here, using flow cytometry, we compared the composition of T cell subsets in blood and CSF in ALS patients. We found consistent but weak correlations between blood and CSF for all T cell subsets examined. This finding implies that blood and CSF offer complementary information when characterizing T cell immunity in ALS and blood may not be used as a surrogate for CSF.
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Esclerosis Amiotrófica Lateral , Citometría de Flujo , Subgrupos de Linfocitos T , Humanos , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/sangre , Masculino , Femenino , Persona de Mediana Edad , Anciano , Subgrupos de Linfocitos T/inmunología , AdultoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.
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Esclerosis Amiotrófica Lateral , Autoanticuerpos , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/sangre , Humanos , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Relevancia ClínicaRESUMEN
Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in patients with CNS diseases, including MS and ALS. In total, 771 serum samples from the John L. Trotter MS Center and the Northeast ALS Consortium were examined using a live cell-based assay for detection of anti-MOG IgG1. Samples from three cohorts were tested in blinded fashion: healthy control (HC) subjects, patients with clinically diagnosed MOGAD, and an experimental group of ALS and MS patients. All samples from established MOGAD cases were positive for anti-MOG antibodies, while all HC samples were negative. Anti-MOG IgG1 was detected in 65 of 658 samples (9.9%) from MS subjects and 4 of 108 (3.7%) samples from ALS subjects. The presence of serum anti-MOG IgG1 in MS and ALS patients raises questions about the contribution of these antibodies to disease pathophysiology as well as accuracy of diagnostic approaches for CNS inflammatory diseases.
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Esclerosis Amiotrófica Lateral , Autoanticuerpos , Inmunoglobulina G , Glicoproteína Mielina-Oligodendrócito , Glicoproteína Mielina-Oligodendrócito/inmunología , Humanos , Autoanticuerpos/sangre , Femenino , Masculino , Persona de Mediana Edad , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/diagnóstico , Inmunoglobulina G/sangre , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/sangre , Enfermedades Neurodegenerativas/diagnóstico , Anciano , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/sangre , Adulto , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/sangre , AnimalesRESUMEN
Amyotrophic lateral sclerosis (ALS) is an untreatable and clinically heterogeneous condition primarily affecting motor neurons. The ongoing quest for reliable biomarkers that mirror the disease status and progression has led to investigations that extend beyond motor neurons' pathology, encompassing broader systemic factors such as metabolism, immunity, and the microbiome. Our study contributes to this effort by examining the potential role of microbiome-related components, including viral elements, such as torque tenovirus (TTV), and various inflammatory factors, in ALS. In our analysis of serum samples from 100 ALS patients and 34 healthy controls (HC), we evaluated 14 cytokines, TTV DNA load, and 18 free fatty acids (FFA). We found that the evaluated variables are effective in differentiating ALS patients from healthy controls. In addition, our research identifies four unique patient clusters, each characterized by distinct biological profiles. Intriguingly, no correlations were found with site of onset, sex, progression rate, phenotype, or C9ORF72 expansion. A remarkable aspect of our findings is the discovery of a gender-specific relationship between levels of 2-ethylhexanoic acid and patient survival. In addition to contributing to the growing body of evidence suggesting altered peripheral immune responses in ALS, our exploratory research underscores metabolic diversity challenging conventional clinical classifications. If our exploratory findings are validated by further research, they could significantly impact disease understanding and patient care customization. Identifying groups based on biological profiles might aid in clustering patients with varying responses to treatments.
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Esclerosis Amiotrófica Lateral , Inflamación , Viroma , Humanos , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/inmunología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Inflamación/sangre , Citocinas/sangre , Torque teno virus/genética , Ácidos Grasos no Esterificados/sangre , Adulto , Biomarcadores/sangre , ADN Viral/sangreRESUMEN
Neuroinflammation and chronic activation of microglial cells are the prominent features of amyotrophic lateral sclerosis (ALS) pathology. While alterations in the mRNA profile of diseased microglia have been well documented, the actual microglia proteome remains poorly characterized. Here we performed a functional characterization together with proteome analyses of microglial cells at different stages of disease in the SOD1-G93A model of ALS. Functional analyses of microglia derived from the lumbar spinal cord of symptomatic mice revealed: (i) remarkably high mitotic index (close to 100% cells are Ki67+) (ii) significant decrease in phagocytic capacity when compared to age-matched control microglia, and (iii) diminished response to innate immune challenges in vitro and in vivo. Proteome analysis revealed a development of two distinct molecular signatures at early and advanced stages of disease. While at early stages of disease, we identified several proteins implicated in microglia immune functions such as GPNMB, HMBOX1, at advanced stages of disease microglia signature at protein level was characterized with a robust upregulation of several unconventional proteins including rootletin, major vaults proteins and STK38. Upregulation of GPNMB and rootletin has been also found in the spinal cord samples of sporadic ALS. Remarkably, the top biological functions of microglia, in particular in the advanced disease, were not related to immunity/immune response, but were highly enriched in terms linked to RNA metabolism. Together, our results suggest that, over the course of disease, chronically activated microglia develop unconventional protein signatures and gradually lose their immune identity ultimately turning into functionally inefficient immune cells.
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Esclerosis Amiotrófica Lateral , Ratones Transgénicos , Microglía , Proteoma , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/patología , Esclerosis Amiotrófica Lateral/genética , Microglía/metabolismo , Microglía/inmunología , Animales , Proteoma/metabolismo , Ratones , Médula Espinal/metabolismo , Médula Espinal/patología , Médula Espinal/inmunología , Modelos Animales de Enfermedad , Fagocitosis/fisiología , Humanos , Femenino , Ratones Endogámicos C57BL , MasculinoRESUMEN
Eomesodermin-expressing (Eomes+) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes+ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes+ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes+ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes+ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093-1098.
Asunto(s)
Enfermedades Neurodegenerativas , Proteínas de Dominio T Box , Linfocitos T Colaboradores-Inductores , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Esclerosis Amiotrófica Lateral/inmunología , Granzimas/metabolismo , Enfermedades Neurodegenerativas/inmunología , Proteínas de Dominio T Box/metabolismo , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Amyotrophic lateral sclerosis (ALS) is a progressive neurogenerative disorder with uncertain origins. Emerging evidence implicates N6-methyladenosine (m6A) modification in ALS pathogenesis. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and liquid chromatography-mass spectrometry were utilized for m6A profiling in peripheral immune cells and serum proteome analysis, respectively, in patients with ALS (n = 16) and controls (n = 6). The single-cell transcriptomic dataset (GSE174332) of primary motor cortex was further analyzed to illuminate the biological implications of differentially methylated genes and cell communication changes. Analysis of peripheral immune cells revealed extensive RNA hypermethylation, highlighting candidate genes with differential m6A modification and expression, including C-X3-C motif chemokine receptor 1 (CX3CR1). In RAW264.7 macrophages, disrupted CX3CR1 signaling affected chemotaxis, potentially influencing immune cell migration in ALS. Serum proteome analysis demonstrated the role of dysregulated immune cell migration in ALS. Cell type-specific expression variations of these genes in the central nervous system (CNS), particularly microglia, were observed. Intercellular communication between neurons and glial cells was selectively altered in ALS CNS. This integrated approach underscores m6A dysregulation in immune cells as a potential ALS contributor.
Asunto(s)
Adenosina , Esclerosis Amiotrófica Lateral , Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/inmunología , Adenosina/análogos & derivados , Adenosina/metabolismo , Humanos , Animales , Femenino , Ratones , Masculino , Persona de Mediana Edad , Anciano , Estudios de Casos y Controles , Células RAW 264.7RESUMEN
BACKGROUND: Recent studies have revealed the link between immune activation and neurodegenerative diseases. METHODS: By employing meta-analysis, we estimated the standardized mean difference (SMD) and their corresponding 95% confidence intervals (CIs) between the groups. RESULTS: According to the pre-set criteria, a total of 21 published articles including 2377 ALS patients and 1244 HCs, as well as 60 articles including 5111 PD patients and 4237 HCs, were identified. This study provided evidence of peripheral immune activation in the pathogenesis of ALS and PD. CONCLUSION: Our results suggested monitoring changes in peripheral blood immune cell populations, particularly lymphocyte subsets, will benefit understanding the developments and exploring reliable and specific biomarkers of these two diseases.
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Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Enfermedad de Parkinson , Humanos , Esclerosis Amiotrófica Lateral/inmunología , Biomarcadores , Enfermedades Neurodegenerativas/inmunología , Enfermedad de Parkinson/inmunologíaRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Abnormalities in the peripheral immune system in ALS have been paid attention; however, the results of changes in peripheral immune parameters were inconsistent. METHODS: A total of 1109 ALS patients were enrolled in the study. All patients received clinical evaluation and peripheral immune parameters measurement. The outcomes were analyzed by correlation analysis, multiple linear regression and cox survival analysis. RESULTS: We found that ALS patients had significantly higher percentage of CD4+ T cells (39.3 vs. 37.1%, p < 0.001) and CD4+/CD8+ ratio (1.88 vs. 1.72, p = 0.011), significantly lower IgG (11.73 vs.12.82, p < 0.001) and IgA (2130.70 vs. 2284.8, p = 0.013) compared with the health controls. In the multivariate linear model, we found that each increase of 1.262, 0.278, and 4.44E-4 in ALSFRS-R scores were significantly associated with each increment of lymphocyte count, IgG, and IgA, respectively. However, each decrease of 0.341, 0.068, and 0.682 in ALSFRS-R score was associated with each increment in neutrophils, CD4+ T cells, and CD4+/CD8+ ratio, respectively. Cox survival regression analysis showed that the death risk of ALS patients was related to the levels of C3 (HR 0.592, 95% CI 0.361-0.973). CONCLUSION: We found that there were differences in peripheral immune parameters of ALS patients with the severity of the disease, especially neutrophil, lymphocyte, CD4+ T, and IgG; C3 is an independent predictor of survival in ALS patients. More studies are needed to elucidate the mechanisms associated with altered immune parameters in ALS.
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Esclerosis Amiotrófica Lateral , Progresión de la Enfermedad , Humanos , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/mortalidad , Masculino , Femenino , Persona de Mediana Edad , Anciano , Pronóstico , Adulto , Linfocitos T CD4-Positivos/inmunología , Inmunoglobulina G/sangreRESUMEN
The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.
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Esclerosis Amiotrófica Lateral , Ubiquitina-Proteína Ligasas , Animales , Ratones , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/inmunología , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Inmunidad Innata/genética , Nucleotidiltransferasas/metabolismo , Proteolisis , Transducción de Señal/fisiología , Modelos Animales de Enfermedad , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/inmunología , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Amyotrophic lateral sclerosis (ALS) is an auto-immune neurodegenerative disorder affecting the motor-neuron system. The causes of ALS are heterogeneous, and are only partially understood. We studied different aspects of immune pathogenesis in ALS and found several basic mechanisms which are potentially involved in the disease. Our findings demonstrated that ALS patients' peripheral blood contains higher proportions of NK and B cells in comparison to healthy individuals. Significantly increased IFN-γ secretion by anti-CD3/28 mAbs-treated peripheral blood mononuclear cells (PBMCs) were observed in ALS patients, suggesting that hyper-responsiveness of T cell compartment could be a potential mechanism for ALS progression. In addition, elevated granzyme B and perforin secretion at a single cell level, and increased cytotoxicity and secretion of IFN-γ by patients' NK cells under specific treatment conditions were also observed. Increased IFN-γ secretion by ALS patients' CD8+ T cells in the absence of IFN-γ receptor expression, and increased CD8+ T cell effector/memory phenotype as well as increased granzyme B at the single cell level points to the CD8+ T cells as potential cells in targeting motor neurons. Along with the hyper-responsiveness of cytotoxic immune cells, significantly higher levels of inflammatory cytokines including IFN-γ was observed in peripheral blood-derived serum of ALS patients. Supernatants obtained from ALS patients' CD8+ T cells induced augmented cell death and differentiation of the epithelial cells. Weekly N-acetyl cysteine (NAC) infusion in patients decreased the levels of many inflammatory cytokines in peripheral blood of ALS patient except IFN-γ, TNF-α, IL-17a and GMCSF which remained elevated. Findings of this study indicated that CD8+ T cells and NK cells are likely culprits in targeting motor neurons and therefore, strategies should be designed to decrease their function, and eliminate the aggressive nature of these cells. Analysis of genetic mutations in ALS patient in comparison to identical twin revealed a number of differences and similarities which may be important in the pathogenesis of the disease.
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Esclerosis Amiotrófica Lateral , Linfocitos T CD8-positivos , Linfocitos T Citotóxicos , Humanos , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/metabolismo , Esclerosis Amiotrófica Lateral/patología , Linfocitos T CD8-positivos/metabolismo , Citocinas/metabolismo , Granzimas/metabolismo , Leucocitos Mononucleares/metabolismo , Linfocitos T Citotóxicos/metabolismoRESUMEN
Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.
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Esclerosis Amiotrófica Lateral , Linfocitos T CD8-positivos , Células Clonales , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/patología , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Células Clonales/patología , ADN Helicasas/genética , ADN Helicasas/metabolismo , Técnicas de Sustitución del Gen , Ratones , Neuronas Motoras/patología , Enzimas Multifuncionales/genética , Enzimas Multifuncionales/metabolismo , Mutación , ARN Helicasas/genética , ARN Helicasas/metabolismoRESUMEN
Neurodegenerative diseases are a group of disorders characterized by progressive loss of certain populations of neurons, which eventually lead to dysfunction. These diseases include Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Immune pathway dysregulation is one of the common features of neurodegeneration. Recently, there is growing interest in the specific role of T helper Th 17 cells and Interleukin-17A (IL-17A), the most important cytokine of Th 17 cells, in the pathogenesis of the central nervous system (CNS) of neurodegenerative diseases. In the present study, we summarized current knowledge about the function of Th17/IL-17A, the physiology of Th17/IL-17A in diseases, and the contribution of Th17/IL-17A in AD, PD, and ALS. We also update the findings on IL-17A-targeting drugs as potentially immunomodulatory therapeutic agents for neurodegenerative diseases. Although the specific mechanism of Th17/IL-17A in this group of diseases is still controversial, uncovering the molecular pathways of Th17/IL-17A in neurodegeneration allows the identification of suitable targets to modulate these cellular processes. Therapeutics targeting IL-17A might represent potentially novel anti-neurodegeneration drugs.
Asunto(s)
Enfermedad de Alzheimer , Esclerosis Amiotrófica Lateral , Interleucina-17 , Enfermedad de Parkinson , Células Th17 , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/metabolismo , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/patología , Humanos , Interleucina-17/inmunología , Enfermedades Neurodegenerativas/inmunología , Enfermedades Neurodegenerativas/patología , Enfermedad de Parkinson/inmunología , Células Th17/inmunologíaRESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease with few therapeutic options. However, the immune system, including natural killer (NK) cells, is linked to ALS progression and may constitute a viable therapeutic ALS target. Tofacitinib is an FDA-approved immunomodulating small molecule which suppresses immune cell function by blocking proinflammatory cytokine signaling. This includes the cytokine IL-15 which is the primary cytokine associated with NK cell function and proliferation. However, the impact of tofacitinib on NK activation and cytotoxicity has not been thoroughly investigated, particularly in ALS. We therefore tested the ability of tofacitinib to suppress cytotoxicity and cytokine production in an NK cell line and in primary NK cells derived from control and ALS participants. We also investigated whether tofacitinib protected ALS neurons from NK cell cytotoxicity. Finally, we conducted a comprehensive pharmacokinetic study of tofacitinib in mice and tested the feasibility of administration formulated in chow. Success was assessed through the impact of tofacitinib on peripheral NK cell levels in mice. We found tofacitinib suppressed IL-15-induced activation as measured by STAT1 phosphorylation, cytotoxicity, pro-inflammatory gene expression, and pro-inflammatory cytokine secretion in both an NK cell line and primary NK cells. Furthermore, tofacitinib protected ALS neurons from NK cell-mediated cytotoxicity. In mice, we found tofacitinib bioavailability was 37% in both male and female mice; using these data we formulated mouse containing low and high doses of tofacitinib and found that the drug suppressed peripheral NK cell levels in a dose-dependent manner. These results demonstrate that tofacitinib can suppress NK cell function and may be a viable therapeutic strategy for ALS.
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Esclerosis Amiotrófica Lateral/inmunología , Animales , Apoptosis , Citocinas/metabolismo , Femenino , Humanos , Células Asesinas Naturales/inmunología , Masculino , Ratones , Enfermedades Neurodegenerativas/metabolismo , Piperidinas , Pirimidinas , Transducción de SeñalRESUMEN
Up to 50% of amyotrophic lateral sclerosis patients present with cognitive deficits in addition to motor dysfunction, but the molecular mechanisms underlying diverse clinical and pathological presentations remain poorly understood. There is therefore an unmet need to identify molecular drivers of cognitive dysfunction to enable better therapeutic targeting and prognostication. To address this, we employed a non-biased approach to identify molecular targets using a deeply phenotyped, clinically stratified cohort of cognitively affected and unaffected brain regions from three brain regions of 13 amyotrophic lateral sclerosis patients with the same cognitive screening test performed during life. Using NanoString molecular barcoding as a sensitive mRNA sequencing technique on post-mortem tissue, we profiled a data-driven panel of 770 genes using the Neuropathology Panel, followed by region and cell type-specific validation using BaseScope in situ hybridisation and immunohistochemistry. We identified 50 significantly dysregulated genes that are distinct between cognitively affected and unaffected brain regions. Using BaseScope in situ hybridisation, we also demonstrate that macromolecular complex regulation, notably NLRP3 inflammasome modulation, is a potential, therapeutically targetable, pathological correlate of cognitive resilience in ALS. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Esclerosis Amiotrófica Lateral/genética , Encéfalo/inmunología , Cognición , Disfunción Cognitiva/genética , Inflamasomas/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Resiliencia Psicológica , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/fisiopatología , Esclerosis Amiotrófica Lateral/radioterapia , Encéfalo/fisiopatología , Disfunción Cognitiva/inmunología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Perfilación de la Expresión Génica , Humanos , Inflamasomas/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , TranscriptomaRESUMEN
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disorder of motor neurons in adults, with a median survival of 3-5 years after appearance of symptoms, and with no curative treatment currently available. Frontotemporal dementia (FTD) is also an adult-onset neurodegenerative disease, displaying not only clinical overlap with ALS, but also significant similarities at genetic and pathologic levels. Apart from the progressive loss of neurons and the accumulation of protein inclusions in certain cells and tissues, both disorders are characterized by chronic inflammation mediated by activated microglia and astrocytes, with an early and critical impact of neurodegeneration along the disease course. Despite the progress made in the last two decades in our knowledge around these disorders, the underlying molecular mechanisms of such non-cell autonomous neuronal loss still need to be clarified. In particular, immune signaling kinases are currently thought to have a key role in determining the neuroprotective or neurodegenerative nature of the central and peripheral immune states in health and disease. This review provides a comprehensive and updated view of the proposed mechanisms, therapeutic potential, and ongoing clinical trials of immune-related kinases that have been linked to ALS and/or FTD, by covering the more established TBK1, RIPK1/3, RACK I, and EPHA4 kinases, as well as other emerging players in ALS and FTD immune signaling.
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Esclerosis Amiotrófica Lateral/enzimología , Demencia Frontotemporal/enzimología , Sistema Inmunológico/enzimología , Inflamación , Fosfotransferasas/metabolismo , Transducción de Señal , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/metabolismo , Demencia Frontotemporal/tratamiento farmacológico , Demencia Frontotemporal/inmunología , Demencia Frontotemporal/metabolismo , Humanos , Sistema Inmunológico/metabolismo , Fosfotransferasas/antagonistas & inhibidoresRESUMEN
Neurodegenerative diseases (NDD) are disorders characterized by the progressive loss of neurons affecting motor, sensory, and/or cognitive functions. The incidence of these diseases is increasing and has a great impact due to their high morbidity and mortality. Unfortunately, current therapeutic strategies only temporarily improve the patients' quality of life but are insufficient for completely alleviating the symptoms. An interaction between the immune system and the central nervous system (CNS) is widely associated with neuronal damage in NDD. Usually, immune cell infiltration has been identified with inflammation and is considered harmful to the injured CNS. However, the immune system has a crucial role in the protection and regeneration of the injured CNS. Nowadays, there is a consensus that deregulation of immune homeostasis may represent one of the key initial steps in NDD. Dr. Michal Schwartz originally conceived the concept of "protective autoimmunity" (PA) as a well-controlled peripheral inflammatory reaction after injury, essential for neuroprotection and regeneration. Several studies suggested that immunizing with a weaker version of the neural self-antigen would generate PA without degenerative autoimmunity. The development of CNS-related peptides with immunomodulatory neuroprotective effect led to important research to evaluate their use in chronic and acute NDD. In this review, we refer to the role of PA and the potential applications of active immunization as a therapeutic option for NDD treatment. In particular, we focus on the experimental and clinical promissory findings for CNS-related peptides with beneficial immunomodulatory effects.
Asunto(s)
Autoantígenos/uso terapéutico , Autoinmunidad/inmunología , Factores Inmunológicos/uso terapéutico , Regeneración Nerviosa/inmunología , Enfermedades Neurodegenerativas/terapia , Neuroprotección/inmunología , Péptidos/uso terapéutico , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/terapia , Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/terapia , Animales , Acetato de Glatiramer/uso terapéutico , Humanos , Inmunización Pasiva , Inmunomodulación , Proteína Básica de Mielina/uso terapéutico , Enfermedades Neurodegenerativas/inmunología , Enfermedad de Parkinson/inmunología , Enfermedad de Parkinson/terapia , Fragmentos de Péptidos/uso terapéutico , Deficiencias en la Proteostasis , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/terapia , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/terapiaRESUMEN
Accumulating evidence show that the gut microbiota is deeply involved not only in host nutrient metabolism but also in immune function, endocrine regulation, and chronic disease. In neurodegenerative conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis, the gut-brain axis, the bidirectional interaction between the brain and the gut, provides new route of pathological spread and potential therapeutic targets. Although studies of gut microbiota have been conducted mainly in mice, mammalian gut microbiota is highly diverse, complex, and sensitive to environmental changes. Drosophila melanogaster, a fruit fly, has many advantages as a laboratory animal: short life cycle, numerous and genetically homogenous offspring, less ethical concerns, availability of many genetic models, and low maintenance costs. Drosophila has a simpler gut microbiota than mammals and can be made to remain sterile or to have standardized gut microbiota by simple established methods. Research on the microbiota of Drosophila has revealed new molecules that regulate the brain-gut axis, and it has been shown that dysbiosis of the fly microbiota worsens lifespan, motor function, and neurodegeneration in AD and PD models. The results shown in fly studies represents a fundamental part of the immune and proteomic process involving gut-microbiota interactions that are highly conserved. Even though the fly's gut microbiota are not simple mimics of humans, flies are a valuable system to learn the molecular mechanisms of how the gut microbiota affect host health and behavior.