RESUMEN
Amyloidosis is a collection of diseases caused by the misfolding of proteins that aggregate into insoluble amyloid fibrils and deposit in tissues. While these fibrils may aggregate to form insignificant localised deposits, they can also accumulate in multiple organs to the extent that amyloidosis can be an immediately life-threatening disease, requiring urgent treatment. Recent advances in diagnostic techniques and therapies are dramatically changing the disease landscape and patient prognosis. Delays in diagnosis and treatment remain the greatest challenge, necessitating physician awareness of the common clinical presentations that suggest amyloidosis. The most common types are transthyretin (ATTR) amyloidosis followed by immunoglobulin light-chain (AL) amyloidosis. While systemic AL amyloidosis was previously considered a death sentence with no effective therapies, significant improvement in patient survival has occurred over the past 2 decades, driven by greater understanding of the disease process, risk-adapted adoption of myeloma therapies such as proteosome inhibitors (bortezomib) and monoclonal antibodies (daratumumab) and improved supportive care. ATTR amyloidosis is an underdiagnosed cause of heart failure. Technetium scintigraphy has made noninvasive diagnosis much easier, and ATTR is now recognised as the most common type of amyloidosis because of the increased identification of age-related ATTR. There are emerging ATTR treatments that slow disease progression, decrease patient hospitalisations and improve patient quality of life and survival. This review aims to update physicians on recent developments in amyloidosis diagnosis and management and to provide a diagnostic and treatment framework to improve the management of patients with all forms of amyloidosis.
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Amiloidosis , Cardiomiopatías , Insuficiencia Cardíaca , Humanos , Calidad de Vida , Amiloidosis/diagnóstico , Amiloidosis/terapia , Amiloidosis/complicaciones , Insuficiencia Cardíaca/diagnóstico , Pronóstico , Bortezomib/uso terapéutico , Cardiomiopatías/diagnósticoRESUMEN
BACKGROUND: Cardiac involvement in AL amyloidosis portends a poor prognosis. 2D-speckle tracking echocardiography (2D-STE) strain can identify subclinical cardiac involvement. This study performed multilayer and multiplanar 2D-STE myocardial strain analysis. METHODS: We compared 75 AL amyloidosis patients to 49 hypertensive patients and 49 healthy controls. Longitudinal strain was obtained from epicardial, mid-myocardial and endocardial layers; segmental strain was measured from mid-myocardial basal, mid and apical segments. RESULTS: Global longitudinal strain was reduced in epicardial (-14.3 ± -4.0% vs. -17.4 ± 2.2% vs. -17.5 ± -2.0%, p < .001), mid-myocardial (-16.3 ± -4.5% vs. -19.7 ± 2.5% vs. -19.7 ± -2.2%, p < .001) and endocardial layers (-18.7 ± -4.9% vs. -22.2 ± 3.0% vs. -22.3 ± -2.6%, p < .001) in amyloid patients compared to hypertensive and healthy controls. Segmental strain confirmed significant reduction in basal (-11.2 ± -3.9% vs. -17.6 ± 2.7% vs. -20.9 ± -3.4%, p < .001) and mid (-14.8 ± -4.3% vs. -19.2 ± 2.5% vs. -19.6 ± -2.2%, p < .001) LV segments in the AL amyloid group. Receiver operating curve analysis demonstrated that an optimal cut-off of -16% for basal segmental strain better differentiated AL amyloid from hypertensive group (sensitivity 96%, specificity 70%, AUC 0.93), compared to relative apical sparing (AUC of 0.85). CONCLUSION: Strain demonstrated myocardial involvement in all layers in AL amyloidosis, with reduced basal segmental longitudinal strain a likely marker of early disease.
Asunto(s)
Amiloidosis , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Amiloidosis/diagnóstico por imagen , Ecocardiografía , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico por imagen , Miocardio , Función Ventricular IzquierdaRESUMEN
AIM: Cardiac transthyretin amyloidosis (ATTR) patients have high rates of atrial arrhythmias. We evaluated echocardiographic structural and functional left atrial (LA) parameters and correlated these with technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphy tracer uptake within the LA in ATTR patients. METHODS: ATTR patients (wild-type, hereditary and asymptomatic transthyretin [TTR] variant carriers) who had undergone 99mTc-DPD and transthoracic echocardiogram (TTE) were selected. Quantitative 99mTc-DPD uptake analysis and echocardiographic evaluation of LA structural and functional parameters was performed. RESULTS: Forty (40) ATTR patients (wild-type n=17; hereditary ATTR and TTR variant carriers n=23; median age 68.8±22 years) were included. TTE parameters including indexed LA minimum (LAVmin) (r=0.66), and LA maximum volumes (LAVmax) (r=0.64), LA emptying fraction (LAEF) (r=-0.68), LA function index (LAFI) (r=-0.70) and reservoir strain (ÆR) (r=-0.70) (p<0.001 for all) demonstrated good correlation to LA tracer uptake. Normal LA volume (LAVmin and LAVmax) and function (LAEF, LAFI and ÆR) was observed in hereditary ATTR and TTR variant carriers without cardiac tracer uptake. The subgroup of ATTR patients with atrial fibrillation/flutter demonstrated increased LAVmin and LAVmax with further reduction in LA function (LAEF, LAFI and ÆR). Receiver operating characteristic curves demonstrated strong diagnostic accuracies for LA structural (LAVmin and LAVmax; area under the curve [AUC] of 0.83 and 0.84 respectively) and functional (LAEF, LAFI and ÆR; AUC 0.81, 0.88 and 0.85, respectively) parameters. CONCLUSION: Left atrial structural and functional parameters demonstrated good correlations with quantitative 99mTc-DPD tracer LA uptake. Echocardiography and 99mTc-DPD scintigraphy may have significant roles in identification and surveillance of ATTR patients likely to develop atrial arrhythmias.
Asunto(s)
Neuropatías Amiloides Familiares , Cardiomiopatías , Anciano , Anciano de 80 o más Años , Neuropatías Amiloides Familiares/diagnóstico por imagen , Ecocardiografía , Humanos , Persona de Mediana Edad , Cintigrafía , Tomografía Computarizada por Rayos XRESUMEN
PURPOSE: Critical illness is a transformative experience for both patients and their family members. For COVID-19 patients admitted to the intensive care unit (ICU), survival may be the start of a long road to recovery. Our knowledge of the post-ICU long-term sequelae of acute respiratory distress syndrome (ARDS) and severe acute respiratory syndrome (SARS) may inform our understanding and management of the long-term effects of COVID-19. SOURCE: We identified international and Canadian epidemiologic data on ICU admissions for COVID-19, COVID-19 pathophysiology, emerging ICU practice patterns, early reports of long-term outcomes, and federal support programs for survivors and their families. Centred around an illustrating case study, we applied relevant literature from ARDS and SARS to contextualize knowledge within emerging COVID-19 research and extrapolate findings to future long-term outcomes. PRINCIPAL FINDINGS: COVID-19 is a multisystem disease with unknown long-term morbidity and mortality. Its pathophysiology is distinct and unique from ARDS, SARS, and critical illness. Nevertheless, based on initial reports of critical care management for COVID-19 and the varied injurious supportive practices employed in the ICU, patients and families are at risk for post-intensive care syndrome. The distinct incremental risk of COVID-19 multiple organ dysfunction is unknown. The risk of mood disorders in family members may be further exacerbated by imposed isolation and stigma. CONCLUSION: Emerging literature on COVID-19 outcomes suggests some similarities with those of ARDS/SARS and prolonged mechanical ventilation. The pathophysiology of COVID-19 is presented here in the context of early outcome data and to inform an agenda for longitudinal research for patients and families.
RéSUMé: OBJECTIF: Les maladies au stade critique constituent une expérience bouleversante tant pour les patients que pour leurs proches. Pour les patients atteints de la COVID-19 admis aux soins intensifs (USI), la survie peut être le début d'un long parcours vers la guérison. Notre connaissance des séquelles à long terme post-USI d'un syndrome de détresse respiratoire aiguë (SDRA) ou d'un syndrome respiratoire aigu sévère (SRAS) pourrait éclairer notre compréhension et notre prise en charge des effets à long terme de la COVID-19. SOURCES: Nous avons identifié des données épidémiologiques internationales et canadiennes sur les admissions aux soins intensifs pour la COVID-19, la physiopathologie de la COVID-19, les schémas de pratique émergents en soins intensifs, les premiers rapports sur les issues à long terme et les programmes de soutien fédéraux pour les survivants et leurs familles. En nous centrant autour d'une étude de cas pour illustrer notre propos, nous avons appliqué la littérature pertinente à propos du SDRA et du SRAS afin de contextualiser les connaissances de la recherche émergente sur la COVID-19 et extrapoler les conclusions aux futures issues à long terme. CONSTATATIONS PRINCIPALES: La COVID-19 est une maladie multisystémique dont la morbidité et la mortalité à long terme sont inconnues. Sa physiopathologie est unique et distincte du SDRA, du SRAS et des maladies graves. Néanmoins, en nous fondant sur les rapports initiaux de prise en charge aux soins intensifs de la COVID-19 et sur les diverses pratiques de support préjudiciables utilisées aux soins intensifs, les patients et les familles sont à risque de syndrome post-soins intensifs. Le risque distinct supplémentaire de dysfonctionnement multiviscéral de la COVID-19 est inconnu. Le risque de troubles de l'humeur chez les proches peut être encore exacerbé par l'isolement imposé et la stigmatisation. CONCLUSION: La littérature émergente sur les issues de la COVID-19 suggère certaines similitudes avec celles du SDRA/SRAS et de la ventilation mécanique prolongée. La physiopathologie de la COVID-19 est présentée ici dans le contexte des premières données sur les issues et pour éclairer un programme de recherche longitudinale pour les patients et leurs familles.
Asunto(s)
COVID-19 , Síndrome de Dificultad Respiratoria , COVID-19/terapia , Canadá/epidemiología , Cuidadores , Enfermedad Crítica/terapia , Humanos , Unidades de Cuidados Intensivos , Respiración Artificial , Síndrome de Dificultad Respiratoria/epidemiología , Síndrome de Dificultad Respiratoria/terapia , SARS-CoV-2 , SobrevivientesRESUMEN
Aims: There has been a paradigm shift in diagnosis of cardiac transthyretin amyloidosis (ATTR) with non-invasive techniques including technetium-99m 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphy. We evaluated structural and functional biventricular alterations by transthoracic echocardiography (TTE) and determined the correlation with 99mTc-DPD tracer uptake in ATTR. Materials and Methods: ATTR patients (wild-type, hereditary or asymptomatic transthyretin [TTR] variant carriers) with 99mTc-DPD and TTE were selected; 99mTc-DPD uptake was analyzed quantitatively. TTE assessment of left ventricle (LV) and right ventricle (RV) parameters was performed. Results: Forty ATTR patients (wild-type n = 17; hereditary ATTR and TTR variant carriers n = 23; median age 68.8 ± 22 years) were included. TTE parameters displaying good correlation with 99mTc-DPD tracer uptake included LV average wall thickness (r = 0.837), LV indexed mass (LVMI; r = 0.802), RV wall thickness (r = 0.610), average e' (r = -0.830), E/e' ratio (r = 0.786), LV global longitudinal strain (GLS; r = 0.714) and RV GLS (r = 0.632; p < 0.001 for all). Hereditary ATTR and TTR variant carriers without cardiac tracer uptake had normal echocardiographic parameters. Receiver operating characteristic curves demonstrated strong diagnostic accuracies for structural (LV wall thickness, LVMI and RV wall thickness; area under the curve (AUC) of 0.96 for all) and functional (LV and RV GLS; AUC of 0.86 and 0.88, respectively) parameters. Conclusion: Good correlations between TTE biventricular structural and functional parameters were demonstrated with quantitative 99mTc-DPD uptake. Echocardiography may potentially assume a significant role in longitudinal follow-up for monitoring disease progression and for evaluating treatment response.
RESUMEN
The long-term sustainability of the high-energy physics (HEP) research software ecosystem is essential to the field. With new facilities and upgrades coming online throughout the 2020s, this will only become increasingly important. Meeting the sustainability challenge requires a workforce with a combination of HEP domain knowledge and advanced software skills. The required software skills fall into three broad groups. The first is fundamental and generic software engineering (e.g., Unix, version control, C++, and continuous integration). The second is knowledge of domain-specific HEP packages and practices (e.g., the ROOT data format and analysis framework). The third is more advanced knowledge involving specialized techniques, including parallel programming, machine learning and data science tools, and techniques to maintain software projects at all scales. This paper discusses the collective software training program in HEP led by the HEP Software Foundation (HSF) and the Institute for Research and Innovation in Software in HEP (IRIS-HEP). The program equips participants with an array of software skills that serve as ingredients for the solution of HEP computing challenges. Beyond serving the community by ensuring that members are able to pursue research goals, the program serves individuals by providing intellectual capital and transferable skills important to careers in the realm of software and computing, inside or outside HEP.
RESUMEN
Although genetic and epidemiological evidence indicates vitamin D insufficiency contributes to multiple sclerosis (MS), and serum levels of vitamin D increase on treatment with cholecalciferol, recent metanalyses indicate that this vitamin D form does not ameliorate disease. Genetic variation in genes regulating vitamin D, and regulated by vitamin D, affect MS risk. We evaluated if the expression of vitamin D responsive MS risk genes could be used to assess vitamin D response in immune cells. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls and people with MS treated with dimethyl fumarate. We assayed changes in expression of vitamin D responsive MS risk (VDRMS) genes in response to treatment with 25 hydroxy vitamin D in the presence or absence of inflammatory stimuli. Expression of CYP24A1 and other VDRMS genes was significantly altered in PBMCs treated with vitamin D in the homeostatic and inflammatory models. Gene expression in MS samples had similar responses to controls, but lower initial expression of the risk genes. Vitamin D treatment abrogated these differences. Expression of CYP24A1 and other MS risk genes in blood immune cells indicate vitamin D response and could enable assessment of immunological response to vitamin D in clinical trials and on therapy.
Asunto(s)
Esclerosis Múltiple , Humanos , Leucocitos Mononucleares , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Vitamina D , Vitamina D3 24-Hidroxilasa/genéticaRESUMEN
Multiple lines of evidence indicate Multiple Sclerosis (MS) is affected by vitamin D. This effect may be mediated by methylation in immune cell progenitors. We aimed to determine (1) if haematopoietic stem cell methylation constrains methylation in daughter cells and is variable between individuals, and (2) the interaction of methylation with the vitamin D receptor binding sites. We interrogated genomic methylation levels from matching purified CD34+ haematopoietic stem cells and progeny CD14+ monocytes and CD56+ NK cells from 11 individuals using modified reduced representation bisulfite sequencing. Differential methylation of Vitamin D Receptor binding sites and MS risk genes was assessed from this and using pyrosequencing for the vitamin D regulated MS risk gene ZMIZ1. Although DNA methylation states at CpG islands and other sites are almost entirely recapitulated between progenitor and progeny immune cells, significant variation was detected at some regions between cell subsets and individuals; including around the MS risk genes HLA DRB1 and the vitamin D repressor NCOR2. Methylation of the vitamin D responsive MS risk gene ZMIZ1 was associated with risk SNP and disease. We conclude that DNA methylation settings in adult haematopoietic stem cells may contribute to individual variation in vitamin D responses in immune cells.
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Metilación de ADN , Epigenoma , Células Madre Hematopoyéticas/metabolismo , Esclerosis Múltiple/genética , Vitamina D/metabolismo , Adulto , Islas de CpG , Femenino , Cadenas HLA-DRB1/genética , Hematopoyesis , Células Madre Hematopoyéticas/citología , Humanos , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/citología , Monocitos/metabolismo , Esclerosis Múltiple/metabolismo , Co-Represor 2 de Receptor Nuclear/genética , Unión Proteica , Receptores de Calcitriol/metabolismo , Factores de Transcripción/genéticaRESUMEN
Amyloid cardiomyopathy is emerging as an important and under-recognised cause of heart failure and cardiac arrhythmias, especially in older adults. This disorder is characterised by extracellular deposition of amyloid fibrils that form due to misfolding of secreted light chains (AL) or transthyretin protein (ATTR). In ATTR, amyloid aggregates typically result from excessive accumulation of wild-type transthyretin (ATTRwt) or from protein structural defects caused by TTR gene variants (ATTRv). Amyloid fibril deposition may predominantly affect the heart or show multi-system involvement. Previously considered to be rare and inexorably progressive with no specific therapy, there has been enormous recent interest in ATTR cardiomyopathy due to upwardly-revised estimates of disease prevalence together with development of disease-modifying interventions. Because of this, there is a clinical imperative to have a high index of suspicion to identify potential cases and to be aware of contemporary diagnostic methods and treatment options. Genetic testing should be offered to all patients with proven ATTR to access the benefits of new therapies specific to ATTRv and allow predictive testing of family members. With heightened awareness of amyloid cardiomyopathy and expanded use of genetic testing, a substantial rise in the numbers of asymptomatic individuals who are carriers of pathogenic variants is expected, and optimal strategies for monitoring and treatment of these individuals at risk need to be determined. Pre-emptive administration of fibril-modifying therapies provides an unprecedented opportunity for disease prevention and promises to change amyloid cardiomyopathy from being a fatal to a treatable disorder.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Neuropatías Amiloides Familiares/complicaciones , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/terapia , Cardiomiopatías/etiología , Cardiomiopatías/genética , Cardiomiopatías/terapia , Humanos , Prealbúmina/genéticaRESUMEN
Translating the findings of genome wide association studies (GWAS) to new therapies requires identification of the relevant immunological contexts to interrogate for genetic effects. In one of the largest GWAS, more than 200 risk loci have been identified for Multiple Sclerosis (MS) susceptibility. Infection with Epstein-Barr virus (EBV) appears to be necessary for the development of Multiple Sclerosis (MS). Many MS risk loci are associated with altered gene expression in EBV infected B cells (LCLs). We have interrogated this immunological context to identify interaction between MS risk loci and EBV DNA copy number, intrinsic growth rate and EBV encoded miRNA expression. The EBV DNA copy number was associated with significantly more risk alleles for MS than for other diseases or traits. EBV miRNAs BART4-3p and BART3-5p were highly associated with EBV DNA copy number and MS risk loci. The poliovirus receptor (PVR) risk SNP was associated with EBV DNA copy number, PVR and miRNA expression. Targeting EBV miRNAs BART4-3p and BART3-5p, and the gene PVR, may provide therapeutic benefit in MS. This study also indicates how immunological context and risk loci interactions can be exploited to validate and develop novel therapeutic approaches.
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Variaciones en el Número de Copia de ADN , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4/genética , Interacciones Huésped-Patógeno/genética , Esclerosis Múltiple/patología , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Estudios de Cohortes , ADN Viral/análisis , ADN Viral/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/virología , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Herpesvirus Humano 4/aislamiento & purificación , Humanos , MicroARNs/genética , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/virología , FenotipoRESUMEN
Epstein-Barr Virus (EBV) infection appears to be necessary for the development of Multiple Sclerosis (MS), although the specific mechanisms are unknown. More than 200 single-nucleotide polymorphisms (SNPs) are known to be associated with the risk of developing MS. About a quarter of these are also highly associated with proximal gene expression in B cells infected with EBV (lymphoblastoid cell lines-LCLs). The DNA of LCLs is hypomethylated compared with both uninfected and activated B cells. Since methylation can affect gene expression, and so cell differentiation and immune evasion, we hypothesised that EBV-driven hypomethylation may affect the interaction between EBV infection and MS. We interrogated an existing dataset comprising three individuals with whole-genome bisulfite sequencing data from EBV transformed B cells and CD40L-activated B cells. DNA methylation surrounding MS risk SNPs associated with gene expression in LCLs (LCLeQTL) was less likely to be hypomethylated than randomly selected chromosomal regions. Differential methylation was independent of genomic features such as promoter regions, but genes preferentially expressed in EBV-infected B cells, including the LCLeQTL genes, were underrepresented in the hypomethylated regions. Our data does not indicate MS genetic risk is affected by EBV hypomethylation.
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Linfocitos B/metabolismo , Herpesvirus Humano 4/genética , Esclerosis Múltiple/genética , Linfocitos B/fisiología , Metilación de ADN/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/metabolismo , Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/metabolismo , Humanos , Regiones Promotoras Genéticas/genéticaRESUMEN
BACKGROUND: Genome wide association studies have identified > 200 susceptibility loci accounting for much of the heritability of multiple sclerosis (MS). Epstein-Barr virus (EBV), a memory B cell tropic virus, has been identified as necessary but not sufficient for development of MS. The molecular and immunological basis for this has not been established. Infected B cell proliferation is driven by signalling through the EBV produced cell surface protein LMP1, a homologue of the MS risk gene CD40. METHODS: We have investigated transcriptomes of B cells and EBV-infected B cells at Latency III (LCLs) and identified MS risk genes with altered expression on infection and with expression levels associated with the MS risk genotype (LCLeQTLs). The association of LCLeQTL genomic burden with EBV phenotypes in vitro and in vivo was examined. The risk genotype effect on LCL proliferation with CD40 stimulation was assessed. RESULTS: These LCLeQTL MS risk SNP:gene pairs (47 identified) were over-represented in genes dysregulated between B and LCLs (p < 1.53 × 10-4), and as target loci of the EBV transcription factor EBNA2 (p < 3.17 × 10-16). Overall genetic burden of LCLeQTLs was associated with some EBV phenotypes but not others. Stimulation of the CD40 pathway by CD40L reduced LCL proliferation (p < 0.001), dependent on CD40 and TRAF3 MS risk genotypes. Both CD40 and TRAF3 risk SNPs are in binding sites for the EBV transcription factor EBNA2, with expression of each correlated with EBNA2 expression dependent on genotype. CONCLUSIONS: These data indicate targeting EBV may be of therapeutic benefit in MS.
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Linfocitos B/metabolismo , Antígenos CD4/genética , Herpesvirus Humano 4/fisiología , Esclerosis Múltiple/genética , Polimorfismo de Nucleótido Simple , Factor 3 Asociado a Receptor de TNF/genética , Linfocitos B/virología , Células Cultivadas , Endonucleasas/genética , Herpesvirus Humano 4/patogenicidad , Humanos , Sitios de Carácter Cuantitativo , Transcriptoma , Latencia del Virus , Replicación ViralAsunto(s)
Neuropatías Amiloides Familiares/complicaciones , Diarrea/complicaciones , Enfermedades Gastrointestinales/complicaciones , Prealbúmina/genética , Anciano de 80 o más Años , Sustitución de Aminoácidos , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/genética , Neuropatías Amiloides Familiares/patología , Diarrea/diagnóstico por imagen , Diarrea/genética , Diarrea/patología , Femenino , Enfermedades Gastrointestinales/diagnóstico por imagen , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/patología , Humanos , Población BlancaRESUMEN
Epidemiological, molecular and genetic studies have indicated that high serum vitamin D levels are associated with lower risk of several autoimmune diseases. The vitamin D receptor (VDR) binding sites in monocytes and dendritic cells (DCs) are more common in risk genes for diseases with latitude dependence than in risk genes for other diseases. The transcription factor genes Zinc finger MIZ domain-containing protein 1 (ZMIZ1) and interferon regulatory factor 8 (IRF8)-risk genes for many of these diseases-have VDR binding peaks co-incident with the risk single nucleotide polymorphisms (SNPs). We show these genes are responsive to vitamin D: ZMIZ1 expression increased and IRF8 expression decreased, and this response was affected by genotype in different cell subsets. The IL10/IL12 ratio in tolerogenic DCs increased with vitamin D. These data indicate that vitamin D regulation of ZMIZ1 and IRF8 in DCs and monocytes contribute to latitude-dependent autoimmune disease risk.
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Enfermedades Autoinmunes/genética , Diferenciación Celular/genética , Factores Reguladores del Interferón/genética , Monocitos/citología , Factores de Transcripción/genética , Vitamina D/farmacología , Vitaminas/farmacología , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Células Dendríticas/citología , Geografía Médica , HumanosRESUMEN
Importance: Neuroinflammation appears to be a key modulator of disease progression in amyotrophic lateral sclerosis (ALS) and thereby a promising therapeutic target. The CD4+Foxp3+ regulatory T-cells (Tregs) infiltrating into the central nervous system suppress neuroinflammation and promote the activation of neuroprotective microglia in mouse models of ALS. To our knowledge, the therapeutic association of host Treg expansion with ALS progression has not been studied in vivo. Objective: To assess the role of Tregs in regulating the pathophysiology of ALS in humans and the therapeutic outcome of increasing Treg activity in a mouse model of the disease. Design, Setting, and Participants: This prospective multicenter human and animal study was performed in hospitals, outpatient clinics, and research institutes. Clinical and function assessment, as well as immunological studies, were undertaken in 33 patients with sporadic ALS, and results were compared with 38 healthy control participants who were consecutively recruited from the multidisciplinary ALS clinic at Westmead Hospital between February 1, 2013, and December 31, 2014. All data analysis on patients with ALS was undertaken between January 2015 and December 2016. Subsequently, we implemented a novel approach to amplify the endogenous Treg population using peripheral injections of interleukin 2/interleukin 2 monoclonal antibody complexes (IL-2c) in transgenic mice that expressed mutant superoxide dismutase 1 (SOD1), a gene associated with motor neuron degeneration. Main Outcomes and Measures: In patients with ALS, Treg levels were determined and then correlated with disease progression. Circulating T-cell populations, motor neuron size, glial cell activation, and T-cell and microglial gene expression in spinal cords were determined in SOD1G93A mice, as well as the association of Treg amplification with disease onset and survival time in mice. Results: The cohort of patients with ALS included 24 male patients and 9 female patients (mean [SD] age at assessment, 58.9 [10.9] years). There was an inverse correlation between total Treg levels (including the effector CD45RO+ subset) and rate of disease progression (R = -0.40, P = .002). Expansion of the effector Treg population in the SOD1G93A mice was associated with a significant slowing of disease progression, which was accompanied by an increase in survival time (IL-2c-treated mice: mean [SD], 160.6 [10.8] days; control mice: mean [SD], 144.9 [10.6] days; P = .003). Importantly, Treg expansion was associated with preserved motor neuron soma size and marked suppression of astrocytic and microglial immunoreactivity in the spinal cords of SOD1G93A mice, as well as elevated neurotrophic factor gene expression in spinal cord and peripheral nerves. Conclusions and Relevance: These findings establish a neuroprotective effect of Tregs, possibly mediated by suppression of toxic neuroinflammation in the central nervous system. Strategies aimed at enhancing the Treg population and neuroprotective activity from the periphery may prove therapeutically useful for patients with ALS.
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Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Linfocitos T Reguladores/metabolismo , Anciano , Esclerosis Amiotrófica Lateral/diagnóstico , Animales , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Persona de Mediana Edad , Estudios Prospectivos , Superóxido Dismutasa/genéticaRESUMEN
The G protein-coupled receptor 65 (GPR65) gene has been genetically associated with several autoimmune diseases, including multiple sclerosis (MS). GPR65 is predominantly expressed in lymphoid organs and is activated by extracellular protons. In this study, we tested whether GPR65 plays a functional role in demyelinating autoimmune disease. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we found that Gpr65-deficient mice develop exacerbated disease. CD4+ helper T cells are key drivers of EAE pathogenesis, however, Gpr65 deficiency in these cells did not contribute to the observed exacerbated disease. Instead, Gpr65 expression levels were found to be highest on invariant natural killer T (iNKT) cells. EAE severity in Gpr65-deficient mice was normalized in the absence of iNKT cells (CD1d-deficient mice), suggesting that GPR65 signals in iNKT cells are important for suppressing autoimmune disease. These findings provide functional support for the genetic association of GPR65 with MS and demonstrate GPR65 signals suppress autoimmune activity in EAE.
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Linfocitos T CD4-Positivos/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Células T Asesinas Naturales/inmunología , Traslado Adoptivo , Animales , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/inmunología , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/metabolismoRESUMEN
Multiple Sclerosis (MS) is an autoimmune disease treated by therapies targeting peripheral blood cells. We previously identified that expression of two MS-risk genes, the transcription factors EOMES and TBX21 (ET), was low in blood from MS and stable over time. Here we replicated the low ET expression in a new MS cohort (p<0.0007 for EOMES, p<0.028 for TBX21) and demonstrate longitudinal stability (p<10(-4)) and high heritability (h(2)=0.48 for EOMES) for this molecular phenotype. Genes whose expression correlated with ET, especially those controlling cell migration, further defined the phenotype. CD56+ cells and other subsets expressed lower levels of Eomes or T-bet protein and/or were under-represented in MS. EOMES and TBX21 risk SNP genotypes, and serum EBNA-1 titres were not correlated with ET expression, but HLA-DRB1*1501 genotype was. ET expression was normalised to healthy control levels with natalizumab, and was highly variable for glatiramer acetate, fingolimod, interferon-beta, dimethyl fumarate.
Asunto(s)
Esclerosis Múltiple/genética , Proteínas de Dominio T Box/genética , Adulto , Anciano , Antígeno CD56 , Estudios de Casos y Controles , Movimiento Celular , Dimetilfumarato/uso terapéutico , Antígenos Nucleares del Virus de Epstein-Barr/sangre , Femenino , Clorhidrato de Fingolimod/uso terapéutico , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Acetato de Glatiramer/uso terapéutico , Cadenas HLA-DRB1/genética , Humanos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Interferón beta/uso terapéutico , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/uso terapéutico , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
A promising new avenue of MS research that may lead to a better understanding of pathogenesis, progression and therapeutic response, and to development of new therapies, comes from the recent identification of defined immune cell populations that are highly heritable. Such stable populations have been identified in three recent papers using extensive flow cytometric panels to investigate twin and family cohorts. They showed that while most of the variation in immune cell populations between individuals was not heritable, some was. This heritability was sometimes very high, and the authors concluded that it likely contributes to variability in response among individuals for disease and drug response traits.