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Immune-inflammatory mechanisms are promising targets for antidepressant pharmacology. Immune cell abnormalities have been reported in mood disorders showing a partial T cell defect. Following this line of reasoning we defined an antidepressant potentiation treatment with add-on low-dose interleukin 2 (IL-2). IL-2 is a T-cell growth factor which has proven anti-inflammatory efficacy in autoimmune conditions, increasing thymic production of naïve CD4 + T cells, and possibly correcting the partial T cell defect observed in mood disorders. We performed a single-center, randomised, double-blind, placebo-controlled phase II trial evaluating the safety, clinical efficacy and biological responses of low-dose IL-2 in depressed patients with major depressive (MDD) or bipolar disorder (BD). 36 consecutively recruited inpatients at the Mood Disorder Unit were randomised in a 2:1 ratio to receive either aldesleukin (12 MDD and 12 BD) or placebo (6 MDD and 6 BD). Active treatment significantly potentiated antidepressant response to ongoing SSRI/SNRI treatment in both diagnostic groups, and expanded the population of T regulatory, T helper 2, and percentage of Naive CD4+/CD8 + immune cells. Changes in cell frequences were rapidly induced in the first five days of treatment, and predicted the later improvement of depression severity. No serious adverse effect was observed. This is the first randomised control trial (RCT) evidence supporting the hypothesis that treatment to strengthen the T cell system could be a successful way to correct the immuno-inflammatory abnormalities associated with mood disorders, and potentiate antidepressant response.
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Transtorno Bipolar , Humanos , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/diagnóstico , Interleucina-2 , Antidepressivos/uso terapêutico , Biomarcadores , Resultado do TratamentoRESUMO
Acute coronavirus disease 2019 (COVID-19) is paralleled by a rise in the peripheral levels of neurofilament light chain (NfL), suggesting early nervous system damage. In a cohort of 103 COVID-19 patients, we studied the relationship between the NfL and peripheral inflammatory markers. We found that the NfL levels are significantly predicted by a panel of circulating cytokines/chemokines, including CRP, IL-4, IL-8, IL-9, Eotaxin, and MIP-1ß, which are highly up-regulated during COVID-19 and are associated with clinical outcomes. Our findings show that peripheral cytokines influence the plasma levels of the NfL, suggesting a potential role of the NfL as a marker of neuronal damage associated with COVID-19 inflammation.
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Biomarcadores , COVID-19 , Citocinas , Proteínas de Neurofilamentos , SARS-CoV-2 , Humanos , COVID-19/sangue , Proteínas de Neurofilamentos/sangue , Biomarcadores/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Citocinas/sangue , SARS-CoV-2/isolamento & purificação , Inflamação/sangue , AdultoRESUMO
MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1ß), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1ß in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1ß levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1ß-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.
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Fator Neurotrófico Derivado do Encéfalo , Interleucina-1beta , MicroRNAs , Esclerose Múltipla , Polimorfismo de Nucleotídeo Único , Humanos , Fator Neurotrófico Derivado do Encéfalo/genética , MicroRNAs/genética , Feminino , Masculino , Adulto , Esclerose Múltipla/genética , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/patologia , Pessoa de Meia-Idade , Interleucina-1beta/genética , Interleucina-1beta/líquido cefalorraquidiano , Índice de Gravidade de Doença , Predisposição Genética para DoençaRESUMO
Introduction: The visual system is a prominent site of damage in MS since the earliest phases of the disease. Altered low-contrast visual acuity (LCVA) test has been associated with visual impairment and retinal degeneration, predicting medium- and long-term disability. However, it is unclear whether LCVA may also represent a reliable measure of neuroinflammation and a predictor of disease evolution in the very early stages of MS. Methods: We explored in a group of 76 consecutive newly diagnosed relapsing-remitting MS (RR-MS) patients without visual impairment or altered visual evoked potentials, the association between LCVA scores at 2.5% and 1.25% and clinical characteristics, including prospective disability evaluated after 1- and 2 years of follow-up. Associations between LCVA and the CSF levels of IL-10 at diagnosis were also analyzed. Results: A negative correlation was found between LCVA at 2.5% and Expanded Disability Status Scale (EDSS) evaluated at first (Spearman's Rho = -0.349, p = 0.005, n = 62) and second year (Spearman's Rho = -0.418, p < 0.001, n = 62) of follow-up, and negative correlations were found with Multiple Sclerosis Severity Score (MSSS) at first (Spearman's Rho = -0.359, p = 0.004, n = 62) and second year (Spearman's Rho = -0.472, p < 0.001, n = 62). All the data were confirmed by a mixed effect model, considering other clinical variables. A positive correlation was found between the CSF concentrations of IL-10 and LCVA at 2.5% (Spearman's Rho = 0.272, p = 0.020, n = 76), and 1.25% (Spearman's Rho, = 0.276, p = 0.018, n = 76), also evidenced in a linear regression. Discussion: In MS patients at diagnosis, altered LCVA may be associated with CSF inflammation and represent a useful parameter to identify patients with worse disease course.
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In Parkinson's disease (PD), neuroinflammation may be involved in the pathogenesis of mood disorders, contributing to the clinical heterogeneity of the disease. The cerebrospinal fluid (CSF) levels of interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, IL-9, IL-12, IL-17, interferon (IFN)γ, macrophage inflammatory protein 1-alpha (MIP-1a), MIP-1b, granulocyte colony stimulating factor (GCSF), eotaxin, tumor necrosis factor (TNF), and monocyte chemoattractant protein 1 (MCP-1), were assessed in 45 newly diagnosed and untreated PD patients and in 44 control patients. Spearman's correlations were used to explore possible associations between CSF cytokines and clinical variables including mood. Benjamini-Hochberg (B-H) correction for multiple comparisons was applied. Linear regression was used to test significant associations correcting for other clinical variables. In PD patients, higher CSF concentrations of the inflammatory molecules IL-6, IL-9, IFNγ, and GCSF were found (all B-H corrected p < 0.02). Significant associations were found between BDI-II and the levels of IL-6 (Beta = 0.438; 95%CI 1.313-5.889; p = 0.003) and IL-8 (Beta = 0.471; 95%CI 0.185-0.743; p = 0.002). Positive associations were also observed between STAI-Y state and both IL-6 (Beta = 0.452; 95%CI 1.649-7.366; p = 0.003), and IL-12 (Beta = 0.417; 95%CI 2.238-13.379; p = 0.007), and between STAI-Y trait and IL-2 (Beta = 0.354; 95%CI 1.923-14.796; p = 0.012), IL-6 (Beta = 0.362; 95%CI 0.990-6.734; p = 0.01), IL-8 (Beta = 0.341; 95%CI 0.076-0.796; p = 0.019), IL-12 (Beta = 0.328; 95%CI 0.975-12.135; p = 0.023), and IL-17 (Beta = 0.334; 95CI 0.315-4.455; p = 0.025). An inflammatory CSF milieu may be associated with depression and anxiety in the early phases of PD, supporting a role of neuroinflammation in the pathogenesis of mood disturbances.
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Citocinas , Transtornos do Humor , Doença de Parkinson , Humanos , Doença de Parkinson/líquido cefalorraquidiano , Doença de Parkinson/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Citocinas/líquido cefalorraquidiano , Transtornos do Humor/líquido cefalorraquidiano , Transtornos do Humor/etiologia , Transtornos do Humor/diagnóstico , Inflamação/líquido cefalorraquidiano , Doenças Neuroinflamatórias/líquido cefalorraquidiano , Doenças Neuroinflamatórias/etiologiaRESUMO
Proinflammatory cytokines are implicated in promoting neurodegeneration in multiple sclerosis (MS) by affecting excitatory and inhibitory transmission at central synapses. Conversely, the synaptic effects of anti-inflammatory molecules remain underexplored, despite their potential neuroprotective properties and their presence in the cerebrospinal fluid (CSF) of patients. In a study involving 184 newly diagnosed relapsing-remitting (RR)-MS patients, we investigated whether CSF levels of the anti-inflammatory interleukin (IL)-10 were linked to disease severity and neurodegeneration measures. Additionally, we examined IL-10 impact on synaptic transmission in striatal medium spiny neurons and its role in counteracting inflammatory synaptopathy induced by IL-1ß in female C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Our findings revealed a significant positive correlation between IL-10 CSF levels and changes in EDSS (Expanded Disability Status Scale) scores one year after MS diagnosis. Moreover, IL-10 levels in the CSF were positively correlated with volumes of specific subcortical brain structures, such as the nucleus caudate. In both MS patients' CSF and EAE mice striatum, IL-10 and IL-1ß expressions were upregulated, suggesting possible antagonistic effects of these cytokines. Notably, IL-10 exhibited the ability to decrease glutamate transmission, increase GABA transmission in the striatum, and reverse IL-1ß-induced abnormal synaptic transmission in EAE. In conclusion, our data suggest that IL-10 exerts direct neuroprotective effects in MS patients by modulating both excitatory and inhibitory transmission and attenuating IL-1ß-induced inflammatory synaptopathy. These findings underscore the potential therapeutic significance of IL-10 in mitigating neurodegeneration in MS.
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Patients with bipolar disorder (BD) show higher immuno-inflammatory setpoints, with in vivo alterations in white matter (WM) microstructure and post-mortem infiltration of T cells in the brain. Cytotoxic CD8+ T cells can enter and damage the brain in inflammatory disorders, but little is known in BD. Our study aimed to investigate the relationship between cytotoxic T cells and WM alterations in BD. In a sample of 83 inpatients with BD in an active phase of illness (68 depressive, 15 manic), we performed flow cytometry immunophenotyping to investigate frequencies, activation status, and expression of cytotoxic markers in CD8+ and tested for their association with diffusion tensor imaging (DTI) measures of WM microstructure. Frequencies of naïve and activated CD8+ cell populations expressing Perforin, or both Perforin and Granzyme, negatively associated with WM microstructure. CD8+ Naïve cells negative for Granzyme and Perforin positively associates with indexes of WM integrity, while the frequency of CD8+ memory cells negatively associates with index of WM microstructure, irrespective of toxins expression. The resulting associations involve measures representative of orientational coherence and myelination of the fibers (FA and RD), suggesting disrupted oligodendrocyte-mediated myelination. These findings seems to support the hypothesis that immunosenescence (less naïve, more memory T cells) can detrimentally influence WM microstructure in BD and that peripheral CD8+ T cells may participate in inducing an immune-related WM damage in BD mediated by killer proteins.