Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α–dependent pathways

In multiple sclerosis (MS), Th17 cells are critical drivers of autoimmune central nervous system (CNS) inflammation and demyelination. Th17 cells exhibit functional heterogeneity fostering both pathogenic and nonpathogenic, tissue-protective functions. Still, the factors that control Th17 pathogenicity remain incompletely defined. Here, using experimental autoimmune encephalomyelitis, an established mouse MS model, we report that therapeutic administration of activin-A ameliorates disease severity and alleviates CNS immunopathology and demyelination, associated with decreased activation of Th17 cells. In fact, activin-A signaling through activin-like kinase-4 receptor represses pathogenic transcriptional programs in Th17-polarized cells, while it enhances antiinflammatory gene modules. Whole-genome profiling and in vivo functional studies revealed that activation of the ATP-depleting CD39 and CD73 ectonucleotidases is essential for activin-A–induced suppression of the pathogenic signature and the encephalitogenic functions of Th17 cells. Mechanistically, the aryl hydrocarbon receptor, along with STAT3 and c-Maf, are recruited to promoter elements on Entpd1 and Nt5e (encoding CD39 and CD73, respectively) and other antiinflammatory genes, and control their expression in Th17 cells in response to activin-A. Notably, we show that activin-A negatively regulates the metabolic sensor, hypoxia-inducible factor-1α, and key inflammatory proteins linked to pathogenic Th17 cell states. Of translational relevance, we demonstrate that activin-A is induced in the CNS of individuals with MS and restrains human Th17 cell responses. These findings uncover activin-A as a critical controller of Th17 cell pathogenicity that can be targeted for the suppression of autoimmune CNS inflammation

Validity and Reliability of the Lower Extremity Motor Coordination Test (LEMOCOT) in Patients with Multiple Sclerosis

The validity and reliability of the Lower Extremity Motor Coordination Test (LEMOCOT) were assessed in patients with multiple sclerosis (MS). The study involved 60 participants diagnosed with MS (mean age: 48.13 years, range: 24–80 years). Intra-rater reliability was assessed within-day (n = 12), and inter-rater reliability was assessed within-day (n = 45) and between-days (n = 22). For known-groups validity, test scores were compared between participants of different sexes; for convergent validity, test scores were correlated with age, the Five-Repetition Sit-to-Stand test (FSTS), the Berg Balance Scale (BBS), the Lower Extremity Functional Scale (LEFS), and the Expanded Disability Status Scale (EDSS). To test the discriminant validity, the LEMOCOT test scores were correlated with the Mini-Mental State Evaluation (MMSE) and compared according to social history (living alone or not). The LEMOCOT test was tested under three different conditions and found to be very reliable (intraclass correlation coefficient, ICC2,1 > 0.94) with an acceptable error level (standard error of the measurement, SEM, between 1.39 and 3.47 targets and 95% minimum detectable change; MDC95%, between 3.84 and 9.58 targets). Convergent validity was verified, as the LEMOCOT registered very strong correlations with the FSTS test (r = −0.851) and the BBS scale (r = 0.815), a strong correlation with the LEFS scale (r = 0.78), a moderate correlation with the EDSS scale (r = −0.634), all highly significant (p p p = 0.017) and no differences relative to living environment or sex. The LEMOCOT demonstrated excellent reliability and validity for patients with MS

Outside-in induction of the IFITM3 trafficking system by infections, including SARS-CoV-2, in the pathobiology of Alzheimer’s disease

Background: IFITM3 is a viral restriction protein that enables sequestration of viral particles and subsequent trafficking to lysosomes. Recently, IFITM3 upregulation was found to induce gamma – secretase activity and the production of amyloid beta. The purpose of this study was to determine whether dysregulation of IFITM3-dependent pathways was present in neurons and peripheral immune cells donated by AD patients. As a secondary aim, we sought to determine whether these perturbations could be induced by viruses, including SARS-CoV-2. Methods: Gene set enrichment analyses (GSEA) previously performed on publicly available transcriptomic data from tissues donated by AD patients were screened for enriched pathways containing IFITM3. Subsequently, signature containing IFITM3, derived from entorhinal cortex (EC) neurons containing neurofibrillary tangles (NFT) was screened for overlap with curated, publicly available, viral infection-induced gene signatures (including SARS-CoV-2). Results: GSEA determined that IFITM3 gene networks are significantly enriched both in CNS sites (entorhinal and hippocampal cortices) and in peripheral blood mononuclear cells (PBMCs) donated by AD patients. Overlap screening revealed that IFITM3 signatures are induced by several viruses, including SARS-CoV, MERS-CoV, SARS-CoV-2 and HIV-1 (adjusted p-value <0.001; Enrichr Database). Discussion: A data-driven analysis of AD tissues revealed IFITM3 gene signatures both in the CNS and in peripheral immune cells. GSEA revealed that an IFITM3 derived gene signature extracted from EC/NFT neurons overlapped with those extracted from publicly available viral infection datasets, including SARS-CoV-2. Our results are in line with currently emerging evidence on IFITM3’s role in AD, and SARS-CoV-2’s potential contribution in the setting of an expanded antimicrobial protection hypothesis

Probiotics’ Effects in the Treatment of Anxiety and Depression: A Comprehensive Review of 2014–2023 Clinical Trials

Changes in the gut microbiome can affect cognitive and psychological functions via the microbiota–gut–brain (MGB) axis. Probiotic supplements are thought to have largely positive effects on mental health when taken in sufficient amounts; however, despite extensive research having been conducted, there is a lack of consistent findings on the effects of probiotics on anxiety and depression and the associated microbiome alterations. The aim of our study is to systematically review the most recent literature of the last 10 years in order to clarify whether probiotics could actually improve depression and anxiety symptoms. Our results indicate that the majority of the most recent literature suggests a beneficial role of probiotics in the treatment of depression and anxiety, despite the existence of a substantial number of less positive findings. Given probiotics’ potential to offer novel, personalized treatment options for mood disorders, further, better targeted research in psychiatric populations is needed to address concerns about the exact mechanisms of probiotics, dosing, timing of treatment, and possible differences in outcomes depending on the severity of anxiety and depression

Social Cognition Impairments in Association to Clinical, Cognitive, Mood, and Fatigue Features in Multiple Sclerosis: A Study Protocol

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS), characterized by the diffuse grey and white matter damage. Cognitive impairment (CI) is a frequent clinical feature in patients with MS (PwMS) that can be prevalent even in early disease stages, affecting the physical activity and active social participation of PwMS. Limited information is available regarding the influence of MS in social cognition (SC), which may occur independently from the overall neurocognitive dysfunction. In addition, the available information regarding the factors that influence SC in PwMS is limited, e.g., factors such as a patient’s physical disability, different cognitive phenotypes, mood status, fatigue. Considering that SC is an important domain of CI in MS and may contribute to subjects’ social participation and quality of life, we herein conceptualize and present the methodological design of a cross-sectional study in 100 PwMS of different disease subtypes. The study aims (a) to characterize SC impairment in PwMS in the Greek population and (b) to unveil the relationship between clinical symptoms, phenotypes of CI, mood status and fatigue in PwMS and the potential underlying impairment on tasks of SC