The gut microbiota influences the reactivity of the immune system, and Parabacteroides distasonis has emerged as an anti-inflammatory commensal. Here, we investigated whether its lysate could prevent severe forms of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in mice and how this preventive strategy affects the gut microbiota and immune response. Lysate of anaerobically cultured P. distasonis (Pd lysate) was orally administered to C57BL/6 mice in four weekly doses. One week later, EAE was induced and disease severity was assessed three weeks after induction. Fecal microbiota changes in both vehicle- and Pd lysate-treated animals was analyzed by 16S V3-V4 amplicon sequencing and qPCR, antimicrobial peptide expression in the intestinal mucosa was measured by qPCR, and immune cell composition in the mesenteric and inguinal lymph nodes was measured by multicolor flow cytometry. Pd lysate significantly delayed the development of EAE and reduced its severity when administered prior to disease induction. EAE induction was the main factor in altering the gut microbiota, decreasing the abundance of lactobacilli and segmented filamentous bacteria. Pd lysate significantly increased the intestinal abundance of the genera Anaerostipes, Parabacteroides and Prevotella, and altered the expression of antimicrobial peptides in the intestinal mucosa. It significantly increased the frequency of regulatory T cells, induced an anti-inflammatory milieu in mesenteric lymph nodes, and reduced the activation of T cells at the priming site. Pd lysate prevents severe forms of EAE by triggering a T regulatory response and modulating T cell priming to autoantigens. Pd lysate could thus be a future modulator of neuroinflammation that increases the resistance to multiple sclerosis.
- MeSH
- Bacteroidetes imunologie MeSH
- encefalomyelitida autoimunitní experimentální * imunologie prevence a kontrola MeSH
- myši inbrední C57BL * MeSH
- myši MeSH
- střevní mikroflóra * imunologie MeSH
- střevní sliznice imunologie mikrobiologie metabolismus MeSH
- T-lymfocyty imunologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β = -0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; βfemale = 0.8289, P = 3.52 × 10-8), the other in males (rs698805; βmale = -1.5395, P = 4.35 × 10-8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in CNS compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and G-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.
- MeSH
- ischemická cévní mozková příhoda * diagnóza etiologie farmakoterapie MeSH
- komorbidita MeSH
- lidé MeSH
- obrovskobuněčná arteritida diagnóza farmakoterapie komplikace MeSH
- prednison terapeutické užití MeSH
- senioři MeSH
- vzácné nemoci diagnóza farmakoterapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky MeSH
- MeSH
- autoimunitní nemoci nervového systému chemicky indukované MeSH
- encefalitida * chemicky indukované diagnóza farmakoterapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- nežádoucí účinky léčiv MeSH
- nivolumab škodlivé účinky MeSH
- protinádorové látky škodlivé účinky MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- Publikační typ
- tisková chyba MeSH
BACKGROUND: COVID-19 vaccination and infection are speculated to increase the activity of immune-mediated diseases, including multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). The aim of this study was to evaluate a short-term risk of relapse after COVID-19 vaccination and COVID-19 infection in patients with these demyelinating disorders of the central nervous system and to determine disease exacerbation risk factors. METHODS: Data in this retrospective, observational cohort study was collected via the Czech nationwide registry ReMuS from March 1, 2020, to October 30, 2021. We compared the proportion of patients with at least one clinical relapse in the 90 days following vaccination or infection to the 90-day intervals during the year before. For the evaluation of the risk factors of relapse, a comparison between groups with and without relapses after COVID-19 vaccination or infection was made. RESULTS: We identified 1661 vaccinated (90.11% BNT162b2) patients with MS without a history of COVID-19 and 495 unvaccinated patients with MS who experienced COVID-19. A mild increase in the proportion of patients with at least one clinical relapse (-360 to -270 days: 4.46%; -270 to -180: 4.27%; -180 to -90: 3.85%; -90 to 0: 3.79% vs. 0 to +90 days: 5.30%) after vaccination in patients with MS was observed, as well as a rise in the proportion of patients with at least one clinical relapse after COVID-19. Lower age was associated with MS relapse after vaccination or infection. Although there were only 17 vaccinated and eight post-COVID-19 patients with NMOSD, the results were broadly consistent with those of patients with MS. CONCLUSION: There is a mild increase in the relapse incidence after the COVID-19 vaccination. The risks, however, need to be balanced against the risks of COVID-19 itself, also leading to the rise in relapse rate and particularly to morbidity and mortality.
- MeSH
- COVID-19 * prevence a kontrola MeSH
- lidé MeSH
- neuromyelitis optica * komplikace MeSH
- recidiva MeSH
- retrospektivní studie MeSH
- roztroušená skleróza * komplikace MeSH
- vakcína BNT162 MeSH
- vakcinace škodlivé účinky MeSH
- vakcíny proti COVID-19 * škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- Geografické názvy
- Česká republika MeSH
- Publikační typ
- abstrakt z konference MeSH
The composition of microbiota and the gut-brain axis is increasingly considered a factor in the development of various pathological conditions. The etiology of multiple sclerosis (MS), a chronic autoimmune disease affecting the CNS, is complex and interactions within the gut-brain axis may be relevant in the development and the course of MS. In this article, we focus on the relationship between gut microbiota and the pathophysiology of MS. We review the contribution of germ-free mouse studies to our understanding of MS pathology and its implications for treatment strategies to modulate the microbiome in MS. This summary highlights the need for a better understanding of the role of the microbiota in patients' responses to disease-modifying drugs in MS and disease activity overall.
- MeSH
- lidé MeSH
- mikrobiota * MeSH
- myši MeSH
- osa mozek-střevo MeSH
- roztroušená skleróza * MeSH
- střevní mikroflóra * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Perorální kladribin je lékem ze skupiny tzv. chorobu modifikujících léků k terapii relabující‑remitující roztroušené sklerózy. Tento článek má za cíl shrnout nové poznatky o kladribinu, které byly představeny na kongresu ACTRIMS‑ECTRIMS 2020. Uvedeny jsou poznatky o účinnosti kladribinu z registračních studií a jejich extenzí, např. analýza časového rozložení relapsů ve studiích CLARITY a CLARITY Extension, subanalýza zaměřená na zmírnění neurologického postižení pacientů ve studii CLARITY Extension, studie MAGNIFY‑MS zkoumající nástup účinku kladribinu pomocí magnetické rezonance a hrubé výstupy studie CLASSIC‑MS, která zkoumá dlouhodobý efekt kladribinu. Shrnuty jsou prezentované zkušenosti z reálné praxe, které jsou v souladu s výsledky klinických studií. Uvedeny jsou i zkušenosti s léčbou kladribinem u osob, které byly dříve léčeny okrelizumabem a natalizumabem. Stručně jsou představeny údaje o průběhu nemoci COVID‑19 u osob léčených kladribinem. V závěru jsou zmíněny nově zahájené studie týkající se kladribinu, jež v budoucnu přinesou další poznatky o tomto léčivém přípravku.
Cladribine tablets belong to so called disease‑modifying drugs used to treat relapsing‑remitting multiple sclerosis. This paper aims to summarize the new data concerning cladribine presented during the ACTRIMS‑ECTRIMS 2020 convention. Data regarding cladribine efficacy from registration studies and their extensions are presented, for example, an analysis of time distribution of relapses during CLARITY and CLARITY Extension studies, a subanalysis focused on disability improvement during CLARITY Extension study, MAGNIFY‑MS study focusing on efficacy onset of cladribine using magnetic resonance imaging and coarse outcomes of CLASSIC‑MS study examining long‑term effect of cladribine. Real world data about cladribine are summarized which are in congruence with results of clinical studies. Also, experience with cladribine in people previously treated with ocrelizumab and natalizumab is presented. Currently available data about COVID‑19 course in people treated with cladribine are given briefly. Finally, recently initiated studies focusing on cladribine are recounted. These are expected to further contribute to our current knowledge of cladribine.
- Klíčová slova
- Mavenclad (kladribin),
- MeSH
- COVID-19 epidemiologie terapie MeSH
- hodnocení léčiv MeSH
- imunosupresiva škodlivé účinky terapeutické užití MeSH
- kladribin * aplikace a dávkování farmakokinetika farmakologie MeSH
- lidé MeSH
- náhrada léků MeSH
- nežádoucí účinky léčiv MeSH
- pulzní dávkování léků MeSH
- relabující-remitující roztroušená skleróza diagnostické zobrazování farmakoterapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinické zkoušky MeSH
