RESUMO
Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disorder characterized by the loss of upper and lower motor neurons in the brain and spinal cord. Accumulating evidence suggests that ALS is not solely a neuronal cell- or brain tissue-autonomous disease and that neuroinflammation plays a key role in disease progression. Furthermore, whereas both CD4 and CD8 T cells were observed in spinal cords of ALS patients and in mouse models of the disease, their role in the neuroinflammatory process, especially considering their functional changes with age, is not fully explored. In this study, we revealed the structure of the CD4 T-cell compartment during disease progression of early-onset SOD1G93A and late-onset SOD1G37R mouse models of ALS. We show age-related changes in the CD4 T-cell subset organization between these mutant SOD1 mouse models towards increased frequency of effector T cells in spleens of SOD1G37R mice and robust infiltration of CD4 T cells expressing activation markers and the checkpoint molecule PD1 into the spinal cord. The frequency of infiltrating CD4 T cells correlated with the frequency of infiltrating CD8 T cells which displayed a more exhausted phenotype. Moreover, RNA-Seq and immunohistochemistry analyses of spinal cords from SOD1G37R mice with early clinical symptoms demonstrated immunological trajectories reminiscent of a neurotoxic inflammatory response which involved proinflammatory T cells and antigen presentation related pathways. Overall, our findings suggest that age-related changes of the CD4 T cell landscape is indicative of a chronic inflammatory response, which aggravates the disease process and can be therapeutically targeted.
Assuntos
Esclerose Lateral Amiotrófica , Humanos , Camundongos , Animais , Esclerose Lateral Amiotrófica/metabolismo , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Camundongos Transgênicos , Doenças Neuroinflamatórias , Senescência de Células T , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Medula Espinal/metabolismo , Progressão da Doença , Modelos Animais de DoençasRESUMO
Alzheimer's disease (AD) is the primary cause of age-related dementia. Pathologically, AD is characterized by synaptic loss, the accumulation of ß-amyloid peptides and neurofibrillary tangles, glial activation, and neuroinflammation. Whereas extensive studies focused on neurons and activation of microglia in AD, the role of astrocytes has not been well-characterized. Protein kinase C (PKC) was also implicated in AD; however, its role in astrocyte activation was not elucidated. Using the 5XFAD mouse model of AD, we show that PKC-eta (PKCη), an astrocyte-specific stress-activated and anti-apoptotic kinase, plays a role in reactive astrocytes. We demonstrate that PKCη staining is highly enriched in cortical astrocytes in a disease-dependent manner and in the vicinity of amyloid-ß peptides plaques. Moreover, activation of PKCη, as indicated by its increased phosphorylation levels, is exhibited mainly in cortical astrocytes derived from adult 5XFAD mice. PKCη activation was associated with elevated levels of reactive astrocytic markers and upregulation of the pro-inflammatory cytokine interleukin 6 (IL-6) compared to littermate controls. Notably, inhibiting the kinase activity of PKCη in 5XFAD astrocyte cultures markedly increased the levels of secreted IL-6-a phenomenon that was also observed in wild-type astrocytes stimulated by inflammatory cytokines (e.g., TNFα, IL-1). Similar increase in the release of IL-6 was also observed upon inhibition of either the mammalian target of rapamycin (mTOR) or the protein phosphatase 2A (PP2A). Our findings suggest that the mTOR-PKCη-PP2A signaling cascade functions as a negative feedback loop of NF-κB-induced IL-6 release in astrocytes. Thus, we identify PKCη as a regulator of neuroinflammation in AD.
Assuntos
Doença de Alzheimer , Astrócitos , Peptídeos beta-Amiloides , Animais , Citocinas , Interleucina-6 , Camundongos , Doenças Neuroinflamatórias , Proteína Quinase C , Serina-Treonina Quinases TORRESUMO
TGF-ß1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-ß1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-ß signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6 -: treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-ß1 -: induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-ß signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte -: neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-ß1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.
Assuntos
Epilepsia/metabolismo , Interleucina-6/metabolismo , Neuroglia/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/genética , Epilepsia/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/genética , Camundongos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Especificidade de Órgãos/genética , Fosforilação/efeitos dos fármacos , Transporte Proteico , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/administração & dosagem , Fator de Crescimento Transformador beta/farmacologiaRESUMO
Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview of physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia and astrocyte cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article. Neuroinflammation is critically involved in numerous neurodegenerative diseases, and key signaling steps of innate immune activation hence represent promising therapeutic targets. This mini review series originated from the 4th Venusberg Meeting on Neuroinflammation held in Bonn, Germany, 7-9th May 2015, presenting updates on innate immunity in acute brain injury and chronic neurodegenerative disorders, such as traumatic brain injury and Alzheimer's disease, on the role of astrocytes and microglia, as well as technical developments that may help elucidate neuroinflammatory mechanisms and establish clinical relevance. In this meeting report, a brief overview on physiological and pathological microglia morphology is followed by a synopsis on PGE2 receptors, insights into the role of arginine metabolism and further relevant aspects of neuroinflammation in various clinical settings, and concluded by a presentation of technical challenges and solutions when working with microglia cultures. Microglial ontogeny and induced pluripotent stem cell-derived microglia, advances of TREM2 signaling, and the cytokine paradox in Alzheimer's disease are further contributions to this article.
Assuntos
Astrócitos/metabolismo , Sistema Nervoso Central/metabolismo , Imunidade Inata/imunologia , Microglia/metabolismo , Doenças Neurodegenerativas/metabolismo , Animais , Sistema Nervoso Central/imunologia , Humanos , Inflamação/imunologia , Inflamação/patologia , Doenças Neurodegenerativas/imunologiaRESUMO
Although CD4 T cells reside within the cerebrospinal fluid, it is yet unclear whether and how they enter the brain parenchyma and migrate to target specific Ags. We examined the ability of Th1, Th2, and Th17 CD4 T cells injected intracerebroventricularly to migrate from the lateral ventricles into the brain parenchyma in mice. We show that primarily Th1 cells cross the ependymal layer of the ventricle and migrate within the brain parenchyma by stimulating an IFN-γ-dependent dialogue with neural cells, which maintains the effector function of the T cells. When injected into a mouse model of Alzheimer's disease, amyloid-ß (Aß)-specific Th1 cells target Aß plaques, increase Aß uptake, and promote neurogenesis with no evidence of pathogenic autoimmunity or neuronal loss. Overall, we provide a mechanistic insight to the migration of cerebrospinal fluid CD4 T cells into the brain parenchyma and highlight implications on brain immunity and repair.
Assuntos
Doença de Alzheimer/imunologia , Encéfalo/imunologia , Líquido Cefalorraquidiano/imunologia , Monitorização Imunológica , Células Th1/imunologia , Transferência Adotiva , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/imunologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Movimento Celular/imunologia , Líquido Cefalorraquidiano/citologia , Quimiocinas/genética , Quimiocinas/metabolismo , Modelos Animais de Doenças , Ativação Linfocitária/imunologia , Camundongos , Camundongos Transgênicos , Placa Amiloide , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Th1/citologia , Células Th1/metabolismo , Células Th17/imunologia , Células Th17/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
Stress activates the hypothalamic-pituitary-adrenocortical axis to promote the release of corticosterone (CORT), which consequently suppresses pathogenic stimulation of the immune system. Paradoxically, however, stress often promotes autoimmunity through yet unknown mechanisms. Here we investigated how chronic variable stress (CVS), and the associated alterations in CORT levels, affect the susceptibility to experimental autoimmune encephalomyelitis (EAE) in female and male C57BL/6 mice. Under baseline (nonstressed) conditions, females exhibited substantially higher CORT levels and an attenuated EAE with less mortality than males. However, CVS induced a significantly worsened EAE in females, which was prevented if CORT signaling was blocked. In addition, females under CVS conditions showed a shift toward proinflammatory Th1/Th17 versus Th2 responses and a decreased proportion of CD4(+) CD25(+) Treg cells. This demonstrates that whereas C57BL/6 female mice generally exhibit higher CORT levels and an attenuated form of EAE than males, they become less responsive to the immunosuppressive effects of CORT under chronic stress and thereby prone to a higher risk of destructive autoimmunity.
Assuntos
Autoimunidade , Suscetibilidade a Doenças/imunologia , Glucocorticoides/fisiologia , Estresse Fisiológico/imunologia , Animais , Ansiedade , Corticosterona/imunologia , Corticosterona/farmacologia , Encefalomielite Autoimune Experimental/etiologia , Feminino , Glucocorticoides/farmacologia , Sistema Hipotálamo-Hipofisário/fisiologia , Terapia de Imunossupressão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sistema Hipófise-Suprarrenal/fisiologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologiaRESUMO
Alzheimer's disease (AD) is the most common form of dementia, with prevalence progressively increasing with aging. Pathological hallmarks of the disease include accumulation of amyloid ß-protein (Aß) peptides and neurofibrillary tangles in the brain associated with glial activation and synaptotoxicity. In addition, AD involves peripheral and brain endogenous inflammatory processes that appear to enhance disease progression. More than a decade ago a new therapeutic paradigm emerged for AD, namely the activation of the adaptive immune system directly against the self-peptide Aß, aimed at lowering its accumulation in the brain. This was the first time that a brain peptide was used to vaccinate human subjects in a manner similar to classic viral or bacterial vaccines. The vaccination approach has taken several forms, from initially active to passive and then back to modified active vaccines. As the first two approaches to date failed to show sufficient efficacy, the last is presently being evaluated in ongoing clinical trials. The present review summarizes the immunogenic characteristics of Aß in humans and mice and discusses past, present and future Aß-based immunotherapeutic approaches for AD. We emphasize potential pathogenic and beneficial roles of CD4 T cells in light of the pathogenesis and the general decline in T-cell responsiveness evident in the disease.
Assuntos
Doença de Alzheimer/terapia , Vacinas contra Alzheimer/uso terapêutico , Peptídeos beta-Amiloides/imunologia , Linfócitos T CD4-Positivos/imunologia , Imunoterapia/métodos , Imunidade Adaptativa , Doença de Alzheimer/imunologia , Animais , Autoimunidade , HumanosRESUMO
Correlation between objects is prone to occur coincidentally, and exploring correlation or association in most situations does not answer scientific questions rich in causality. Causal discovery (also called causal inference) infers causal interactions between objects from observational data. Reported causal discovery methods and single-cell datasets make applying causal discovery to single cells a promising direction. However, evaluating and choosing causal discovery methods and developing and performing proper workflow remain challenges. We report the workflow and platform CausalCell (http://www.gaemons.net/causalcell/causalDiscovery/) for performing single-cell causal discovery. The workflow/platform is developed upon benchmarking four kinds of causal discovery methods and is examined by analyzing multiple single-cell RNA-sequencing (scRNA-seq) datasets. Our results suggest that different situations need different methods and the constraint-based PC algorithm with kernel-based conditional independence tests work best in most situations. Related issues are discussed and tips for best practices are given. Inferred causal interactions in single cells provide valuable clues for investigating molecular interactions and gene regulations, identifying critical diagnostic and therapeutic targets, and designing experimental and clinical interventions.
Assuntos
Algoritmos , Análise de Célula Única , Causalidade , Perfilação da Expressão Gênica , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodosRESUMO
BACKGROUND: Chronic abdominal pain and fatigue are characteristics of Crohn's disease (CD) and contribute to functional impairments. AIMS: To examine whether CD-tailored cognitive-behavioural and mindfulness intervention (COBMINDEX) is effective in reducing abdominal pain and fatigue in patients with CD and whether changes in abdominal pain and fatigue mediate any beneficial effects of COBMINDEX on impairments in work productivity and daily activities. METHODS: This is a secondary analysis of a parallel-group multicentre randomised controlled trial. Patients with mild-to-moderate CD (n = 142) were randomised into either intervention group receiving COBMINDEX, or control group receiving treatment-as-usual for 3 months followed by COBMINDEX. Complete data were collected from 120 patients (34.0 ± 10.7 years, 62.5% female, intervention = 60, control = 60). Analysis of covariance assessed group differences in 3-month follow-up scores, controlling for baseline scores. Multiple parallel mediation analysis assessed the proposed mechanisms for the entire sample. RESULTS: The intervention group demonstrated significantly lower levels of abdominal pain (F = 17.46, p < 0.001, η2 p = 0.13), fatigue (F = 7.26, p = 0.008, η2 p = 0.06) and impairments at work (F = 4.82, p = 0.032, η2 p = 0.07) and daily activities (F = 6.26, p = 0.014, η2 p = 0.05), compared with treatment-as-usual. Moreover, changes in abdominal pain and fatigue significantly mediated the beneficial effects of COBMINDEX on patients' work productivity (b = -9.90, SE = 2.86, 95% CI: -16.11 to -4.94) and daily activities (b = -9.65, SE = 1.91, 95% CI: -13.77 to 6.35), independent of changes in disease activity. CONCLUSIONS: COBMINDEX is effective at reducing abdominal pain and fatigue in patients with CD, which in turn leads to improvement in functioning. Clinicians should incorporate screening for severe abdominal pain and fatigue and consider offering cognitive-behavioural and mindfulness training. CLINICALTRIALS: gov, Number: NCT05085925. Ministry of Health in Israel (https://my.health.gov.il/CliniTrials/Pages/MOH_2020-02-24_008721.aspx).
Assuntos
Doença de Crohn , Humanos , Feminino , Masculino , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Intervenção Psicossocial , Dor Abdominal/tratamento farmacológico , Dor Abdominal/etiologia , Fadiga/etiologia , Fadiga/terapia , Israel , Qualidade de VidaRESUMO
Microglia are myeloid-derived cells that colonize the central nervous system (CNS) at early stages of development and constitute up to 20% of the glial populations throughout life. While extensive progress has been recently made in identifying the cellular origin of microglia, the mechanism whereby the cells acquire the unique ramified and quiescent phenotype within the CNS milieu remains unknown. Here, we show that upon co-culturing of either CD117(+) /Lin(-) hematopoietic progenitors or CD11c(+) bone marrow derived cells with organotypic hippocampal slices or primary glia, the cells acquire a ramified morphology concomitant with reduced levels of CD86, MHCII, and CD11c and up-regulation of the microglial cell-surface proteins CX(3) CR1 and Iba-1. We further demonstrate that the transforming growth factor beta (TGF-ß) signaling pathway via SMAD2/3 phosphorylation is essential for both primary microglia and myeloid-derived cells in order to acquire their quiescent phenotype. Our study suggests that the abundant expression of TGF-ß within the CNS during development and various inflammatory processes plays a key role in promoting the quiescent phenotype of microglia and may thus serve as a target for therapeutic strategies aimed at modulating the function of microglia in neurodegenerative diseases such as Alzheimer's and prion.
Assuntos
Células da Medula Óssea/metabolismo , Microglia/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Receptor 1 de Quimiocina CX3C , Células Cultivadas , Técnicas de Cocultura , Camundongos , Microglia/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Receptores de Quimiocinas/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Proper function of the neurovasculature is required for optimal brain function and preventing neuroinflammation and neurodegeneration. Within this review, we discuss alterations of the function of the blood-brain barrier in neurologic disorders such as multiple sclerosis, epilepsy, and Alzheimer's disease and address potential underlying mechanisms.
Assuntos
Barreira Hematoencefálica/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Animais , HumanosRESUMO
BACKGROUND AND AIMS: Crohn's disease (CD) is a chronic inflammatory bowel disease associated with psychological stress that is regulated primarily by the hypothalamus-pituitary-adrenal (HPA) axis. Here, we determined whether the psychological characteristics of CD patients associate with their inflammatory state, and whether a 3-month trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) impacts their inflammatory process. METHODS: Circulating inflammatory markers and a wide range of psychological parameters related to stress and well-being were measured in CD patients before and after COBMINDEX. Inflammatory markers in CD patients were also compared to age- and sex-matched healthy controls (HCs). RESULTS: CD patients exhibited increased peripheral low-grade inflammation compared with HCs, demonstrated by interconnected inflammatory modules represented by IL-6, TNFα, IL-17, MCP-1 and IL-18. Notably, higher IL-18 levels correlated with higher score of stress and a lower score of wellbeing in CD patients. COBMINDEX was accompanied by changes in inflammatory markers that coincided with changes in cortisol: changes in serum levels of cortisol correlated positively with those of IL-10 and IFNα and negatively with those of MCP-1. Furthermore, inflammatory markers of CD patients at baseline predicted COBMINDEX efficacy, as higher levels of distinct cytokines and cortisol at baseline, correlated negatively with changes in disease activity (by Harvey-Bradshaw Index) and psychological distress (global severity index measure) following COBMINDEX. CONCLUSION: CD patients have a characteristic immunological profile that correlates with psychological stress, and disease severity. We suggest that COBMINDEX induces stress resilience in CD patients, which impacts their well-being, and their disease-associated inflammatory process.
RESUMO
BACKGROUND: Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca2+ homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction. METHODS: To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests. RESULTS: In neuronal cultures, amyloid-beta (Aß)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aß plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aß-plaque load. CONCLUSIONS: The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment.
Assuntos
Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Proteínas Mitocondriais , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Mitocôndrias/metabolismoRESUMO
BACKGROUND: Patients with Crohn disease have debilitating psychological symptoms, mental fatigue, and poor quality of life. Psychological intervention may improve these symptoms. METHODS: We performed a randomized parallel-group physician-blinded trial of cognitive-behavioral and mindfulness-based stress reduction (COBMINDEX) on quality of life and psychological symptoms in adults with mild-moderate Crohn disease. COBMINDEX was taught by social workers in one-on-one video conferences over 3 months; quotidian home practice was mandated. RESULTS: Fifty-five COBMINDEX and 61 waitlist control patients completed the study; mean age was 33 years and 65% of participants were women. At 3 months, COBMINDEX patients had significantly reduced disease activity (per Harvey-Bradshaw Index score, C-reactive protein level, and calprotectin level), increased quality of life (Short Inflammatory Bowel Disease Questionnaire [SIBDQ] score increased from baseline 41 to 50; Pâ <â 0.001), decreased psychological symptoms (Global Severity Index [GSI], 0.98-0.70; Pâ <â 0.001), reduced fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue, 26-33; Pâ <â 0.001), and increased mindfulness disposition (Freiburg Mindfulness Inventory, 33-38; Pâ <â 0.001). Waitlist patients had a significant but small change in Harvey-Bradshaw Index, SIBDQ, and GSI scores, without improvement in fatigue or mindfulness. There were significant correlations (0.02â >â Pâ <â 0.002) in COBMINDEX patients between baseline SIBDQ, GSI, Freiburg Mindfulness Inventory, and Functional Assessment of Chronic Illness Therapy-Fatigue scores with a relative change (baseline to 3 months) of the SIBDQ score, but none among waitlist patients. Predictors of relative change of the SIBDQ score in COBMINDEX patients included the GSI score (90% quantile; coefficient 0.52; Pâ <â 0.001), somatization (90%; 0.20; Pâ =â 0.001), depression (75%; 0.16; Pâ =â 0.03), and phobic anxiety (75%; 0.31; Pâ =â 0.008). CONCLUSIONS: COBMINDEX was effective in increasing patients' quality of life and reducing psychological symptoms and fatigue. Patients with severe baseline psychological symptoms benefited the most from COBMINDEX.
Assuntos
Doença de Crohn , Atenção Plena , Adulto , Cognição , Doença de Crohn/diagnóstico , Depressão/psicologia , Feminino , Humanos , Qualidade de Vida , Estresse Psicológico/psicologiaRESUMO
BACKGROUND: Immunosenescence (ISC) describes age-related changes in immune-system composition and function. Multiple sclerosis (MS) is a lifelong inflammatory condition involving effector and regulatory T-cell imbalance, yet little is known about T-cell ISC in MS. We examined age-associated changes in circulating T cells in MS compared to normal controls (NC). METHODS: Forty untreated MS (Mean Age 43·3, Range 18-72) and 49 NC (Mean Age 48·6, Range 20-84) without inflammatory conditions were included in cross-sectional design. T-cell subsets were phenotypically and functionally characterized using validated multiparametric flow cytometry. Their aging trajectories, and differences between MS and NC, were determined using linear mixed-effects models. FINDINGS: MS patients demonstrated early and persistent redistribution of naïve and memory CD4 T-cell compartments. While most CD4 and CD8 T-cell aging trajectories were similar between groups, MS patients exhibited abnormal age-associated increases of activated (HLA-DR+CD38+; (P = 0·013) and cytotoxic CD4 T cells, particularly in patients >60 (EOMES: P < 0·001). Aging MS patients also failed to upregulate CTLA-4 expression on both CD4 (P = 0·014) and CD8 (P = 0·009) T cells, coupled with abnormal age-associated increases in frequencies of B cells expressing costimulatory molecules. INTERPRETATION: While many aspects of T-cell aging in MS are conserved, the older MS patients harbour abnormally increased frequencies of CD4 T cells with activated and cytotoxic effector profiles. Age-related decreased expression of T-cell co-inhibitory receptor CTLA-4, and increased B-cell costimulatory molecule expression, may provide a mechanism that drives aberrant activation of effector CD4 T cells that have been implicated in progressive disease. FUNDING: Stated in Acknowledgements section of manuscript.
Assuntos
Linfócitos T CD4-Positivos , Esclerose Múltipla , Adulto , Envelhecimento , Linfócitos T CD8-Positivos , Antígeno CTLA-4 , Estudos Transversais , Humanos , Ativação Linfocitária , Pessoa de Meia-IdadeRESUMO
Axonal degeneration is an important determinant of progressive neurological disability in multiple sclerosis (MS). Thus, therapeutic approaches promoting neuroprotection could aid the treatment of progressive MS. Here, we used what we believe is a novel water-soluble fullerene derivative (ABS-75) attached to an NMDA receptor antagonist, which combines antioxidant and anti-excitotoxic properties, to block axonal damage and reduce disease progression in a chronic progressive EAE model. Fullerene ABS-75 treatment initiated after disease onset reduced the clinical progression of chronic EAE in NOD mice immunized with myelin-oligodendrocyte glycoprotein (MOG). Reduced disease progression in ABS-75-treated mice was associated with reduced axonal loss and demyelination in the spinal cord. Fullerene ABS-75 halted oxidative injury, CD11b+ infiltration, and CCL2 expression in the spinal cord of mice without interfering with antigen-specific T cell responses. In vitro, fullerene ABS-75 protected neurons from oxidative and glutamate-induced injury and restored glutamine synthetase and glutamate transporter expression in astrocytes under inflammatory insult. Glutamine synthetase expression was also increased in the white matter of fullerene ABS-75-treated animals. Our data demonstrate the neuroprotective effect of treatment with a fullerene compound combined with a NMDA receptor antagonist, which may be useful in the treatment of progressive MS and other neurodegenerative diseases.
Assuntos
Axônios/patologia , Esclerose Múltipla/patologia , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Axônios/efeitos dos fármacos , Axônios/metabolismo , Linfócitos B/efeitos dos fármacos , Antígeno CD11b/metabolismo , Quimiocina CCL2/metabolismo , Doença Crônica , Modelos Animais de Doenças , Progressão da Doença , Fulerenos/química , Fulerenos/uso terapêutico , Ácido Glutâmico/farmacologia , Memória/efeitos dos fármacos , Camundongos , Estrutura Molecular , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Linfócitos T/efeitos dos fármacosRESUMO
Active amyloid beta-peptide (Abeta) immunization of patients with Alzheimer's disease (AD) caused meningoencephalitis in approximately 6% of immunized patients in a clinical trial. In addition, long-term studies of AD patients show varying degrees of Abeta Ab responses, which correlate with the extent of Abeta clearance from the brain. In this study, we examined the contribution of various HLA-DR alleles to these immune-response variations by assessing Abeta T cell reactivity, epitope specificity, and immunogenicity. Analysis of blood samples from 133 individuals disclosed that the abundant DR haplotypes DR15 (found in 36% of subjects), DR3 (in 18%), DR4 (12.5%), DR1 (11%), and DR13 (8%) were associated with Abeta-specific T cell responses elicited via distinct T cell epitopes within residues 15-42 of Abeta. Because the HLA-DRB1*1501 occurred most frequently, we examined the effect of Abeta challenge in humanized mice bearing this allele. The observed T cell response was remarkably strong, dominated by secretion of IFN-gamma and IL-17, and specific to the same T cell epitope as that observed in the HLA-DR15-bearing humans. Furthermore, following long-term therapeutic immunization of an AD mouse model bearing the DRB1*1501 allele, Abeta was effectively cleared from the brain parenchyma and brain microglial activation was reduced. The present study thus characterizes HLA-DR alleles directly associated with specific Abeta T cell epitopes and demonstrates the highly immunogenic properties of the abundant allele DRB1*1501 in a mouse model of AD. This new knowledge enables us to explore the basis for understanding the variations in naturally occurring Abeta-reactive T cells and Abeta immunogenicity among humans.
Assuntos
Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/imunologia , Antígenos HLA-DR/genética , Fragmentos de Peptídeos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/administração & dosagem , Peptídeos beta-Amiloides/genética , Animais , Apresentação de Antígeno/genética , Células Cultivadas , Modelos Animais de Doenças , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Antígenos HLA-DR/imunologia , Cadeias HLA-DRB1 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/genética , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Aging is generally characterized as a gradual increase in tissue damage, which is associated with senescence and chronic systemic inflammation and is evident in a variety of age-related diseases. The extent to which such tissue damage is a result of a gradual decline in immune regulation, which consequently compromises the capacity of the body to repair damages, has not been fully explored. Whereas CD4 T lymphocytes play a critical role in the orchestration of immunity, thymus involution initiates gradual changes in the CD4 T-cell landscape, which may significantly compromise tissue repair. In this review, we describe the lifespan accumulation of specific dysregulated CD4 T-cell subsets and their coevolution with systemic inflammation in the process of declined immunity and tissue repair capacity with age. Then, we discuss the process of thymus involution-which appears to be most pronounced around puberty-as a possible driver of the aging T-cell landscape. Finally, we identify individualized T cell-based early diagnostic biomarkers and therapeutic strategies for age-related diseases.
Assuntos
Linfócitos T , TimoRESUMO
The blood-brain barrier acts as a major barrier for the entrance of most therapeutics into the brain, impeding treatment for neurological disorders. Intracerebroventricular (ICV) injection of T cells is a useful tool for cell therapy of neurological disorders including neurodegenerative and neuropsychiatric diseases and brain tumors. Here, we present an optimized ICV injection of T cells with improved injection efficiency at pathological sites within the brain parenchyma. We describe details of the surgical procedure and verification of injection via immunohistochemistry. For complete details on the use and execution of this protocol, please refer to Fisher et al. (2014); Strominger et al., (2018); Mittal et al. (2019); Eremenko et al. (2019).
Assuntos
Barreira Hematoencefálica/metabolismo , Injeções Intraventriculares/métodos , Injeções/métodos , Animais , Barreira Hematoencefálica/imunologia , Encéfalo/metabolismo , Linfócitos T CD4-Positivos/imunologia , Imuno-Histoquímica/métodos , Infusões Intraventriculares , Sistema Linfático/imunologia , Contagem de Linfócitos/métodos , Camundongos , Tecido Parenquimatoso , Linfócitos T/imunologiaRESUMO
Transduction of primary T cells has become prominent with the introduction of chimeric antigen receptor T-cell therapy. Although there are many protocols for the transduction of human T cells, it remains a challenge to transduce murine T cells. We present an optimized protocol for the retroviral transduction of murine CD4 T cells, which overcomes major challenges including large-scale production and long-term culturing of transduced cells. The optimized protocol combines high transduction efficiency with a low rate of cell death. For complete details on the use and execution of this protocol, please refer to Eremenko et al., 2019.