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Marie, J. C.

Publications and source records attributed to Marie, J. C..

6 recordsLinked to original sources

Characterisation of CD4 Th subsets as well as dietary, exercise and lifestyle factors in an established Rheumatoid Arthritis cohort; pilot study.

BackgroundSex disparities in the incidence and severity of Rheumatoid Arthritis (RA) are well-documented, with females experiencing more aggressive disease and different responses to treatment. While underlying mechanisms remain elusive, immune factors and lifestyle components, such as diet and physical activity, could play a role in shaping disease outcomes. Since Th cells are key drivers of RA, this study characterised CD4 Th subset frequencies, including Th1, Th2, Th17 and Th1/17 cells, in a cohort of males and females with established RA. Considering the role of diet and lifestyle in RA development, we also evaluated participant diet and lifestyle patterns. MethodsAn observational cross-sectional cohort study profiling 39 individuals (19 RA and 20 age and sex matched controls) with no major co-morbidities was conducted. Percentages of Th1, Th2, Th17 and Th1/17 cells from peripheral blood were determined by flow cytometry as well as serum levels of RF and cytokines IL17, IFN-{gamma}, TNF-, GM-CSF, TGF-{beta}, IL-6, and CRP by ELISA. Dietary intake was assessed by Food Frequency Questionnaire (FFQ), the Dietary inflammatory Index (DII) calculated from nutrient intake. Physical activity levels were evaluated by Global Physical Activity Questionnaire (GPAQ). ResultsSex-specific differences of Th17, Th1 an Th2 cells were observed in RA groups. Males had lower levels of Th1 cells and higher levels of Th17 cells than control subjects, while females had lower levels of Th2 cells than controls. Female RA subjects had higher ratio of Th1:Th2 cells than controls, while male RA subjects had higher Th17:Th1 ratio than controls. Interestingly, circulating CD4 Th subset levels were predictive of RA in this cohort. No changes in cytokine levels were observed. The male RA group consumed 30% less carbohydrate (RA = 156g +/-57g, Control = 253g +/-59g; p=0.003), 37% less sugar (RA = 74.1g +/-29g, Control = 118g +/-33g; p=0.004) and 30% less dietary fibre (R = 33g +/-8g, Control = 48g +/-13 g; p=0.008) than the male control group. The female RA group had the lowest consumption of alcohol in comparison to female control group (RA = 0.31g, Control = 8.97g; p=0.047). Male subjects had a 4x higher DII than females (p=0.012). ConclusionsOur findings highlight potential sex-specific differences in CD4+ Th cell subsets in individuals with established RA, indicating that sex may influence immune cell composition in this disease. Furthermore, dietary components showed sex-specific consumption patterns, underscoring the potential role of tailored lifestyle interventions in modulating immune responses in RA. Evaluating immunological sex differences and dietary and lifestyle factors may be important for enhancing management strategies in RA.

immunology↗

Adaptive immunity shapes innate and epithelial cell landscapes by silencing tonic IFN-gamma in innate lymphoid cells during homeostasis.

During homeostasis, innate and epithelial cells undergo continuous maturation, shaped by microbial, molecular and cellular interactions. While these cells influence adaptive immunity during steady-state conditions, the reciprocal homeostatic role of adaptive immune cells in the maturation and function of innate and epithelial cells remains underexplored. Here, through computational approaches and murine models, we establish that adaptive immunity shapes innate immune and epithelial homeostatic landscapes. Mechanistically, adaptive immunity acts as a brake on type 1 polarization and diversification of innate lymphocytes (ILCs). Without adaptive immunity, the innate cellular interactions within the mesenteric lymph nodes are dominated by an interferon-gamma (IFN{gamma}) signaling network. Moreover, the innate immune and epithelial cells follow distinct phenotypic and functional trajectories, including ILCs acquiring myeloid markers, monocytes adopting an inflammatory path, and colonic epithelial cells expressing altered antimicrobial peptides and losing Paneth-like features. Depleting ILCs, abolishing IFN{gamma} signaling, or restoring adaptive immunity reduces these IFN{gamma}-driven changes. Thus, our findings highlight a homeostatic function of adaptive immunity in modulating innate and epithelial cell communication, diversity, composition, function, and differentiation, notably by limiting ILC-derived IFN{gamma}.

immunology↗

Single molecule DNA methylation and hydroxymethylation reveal unique epigenetic identity profiles of T helper cells

Both identity and plasticity of CD4 T helper (Th) cells are regulated in part by epigenetic mechanisms. However, a method that reliably and readily profiles DNA base modifications is still needed to finely study Th cell differentiation. Cytosine methylation (5mC) and cytosine hydroxymethylation (5hmC) are DNA modifications that identify stable cell phenotypes but their potential to characterize intermediate cell transitions has not yet been evaluated. To assess transition states in Th cells, we developed a new method to profile Th cell identity using cas9-targeted single molecule nanopore sequencing and found that 5mC and 5hmC can be used as markers of cellular identity. Targeting as few as 10 selected genomic loci, we were able to distinguish major differentiated T cell subtypes as well as intermediate phenotypes by their native DNA 5mC/5hmC patterns. Moreover, by using off-target sequences we were able to infer transcription factor activities relevant to each cell subtype. Our analysis demonstrates the importance of epigenetic regulation by 5mC and 5hmC modifications in the establishment of Th cell identity. Furthermore, our data highlight the potential to exploit this immune profiling application to elucidate the pathogenic role of Th transition states in autoimmune diseases.

immunology↗

SMAD4 governs a feedforward regulation of the TGF-beta effects in CD8 T cells that contributes to preventing chronic intestinal inflammation

SMAD4, a key mediator of TGF-{beta} signaling, plays a crucial role in T cells to prevent chronic gut inflammation. However, the molecular mechanisms underlying this control remain elusive. Using different genetic and epigenetic approaches, we unexpectedly reveal that SMAD4 in CD8 T cells prevents chronic intestinal inflammation by a feedforward mechanism that is TGF-{beta}-independent. Prior to any TGF-{beta}-receptor engagement, SMAD4 acts as an active and basal repressor of epigenetic, transcriptional and functional TGF-{beta} imprinting in CD8 T cells. Thus, in sharp opposition to total TGF-{beta} signaling deletion, SMAD4 deletion impairs naive CD8 T cell effector predisposition but promotes CD8 T cell accumulation and epithelial retention by promoting their response to IL-7 and their expression of integrins such as Itgae. Besides, SMAD4 deletion unleashes the induction of a wide range of TGF-{beta}-signaling-repressors such as Smad7, Ski, Skil, and Smurf2 and hampers TGF-{beta}-mediated CD8 T cell immunosuppression. Mechanistically, prior to any TGF-{beta} signal, SMAD4 binds to the loci of several TGF-{beta}-target genes, and by regulating histone acetylation, represses their expression. The massive gut epithelial colonization, associated with their escape from the immunoregulatory TGF-{beta} effects overtakes their poor effector preconditioning and elicits microbiota-driven chronic epithelial CD8 T cell activation. Hence, in an anticipatory manner, independently of TGF-{beta}, SMAD4 governs a feedforward regulation of TGF-{beta} effects in CD8 T cells, preventing chronic intestinal inflammation.

immunology↗

The DNA Methylome of Inflammatory Bowel Disease (IBD) reflects intrinsic and extrinsic factors in intestinal epithelial cells

Abnormal DNA methylation has been described in human inflammatory conditions of the gastrointestinal tract, such as inflammatory bowel disease (IBD). As other complex diseases, IBD results from the balance between genetic predisposition and environmental exposures. As such, DNA methylation may be placed as an effector of both, genetic susceptibility variants and/or environmental signals such as cytokine exposure. We attempted to discern between these two non-excluding possibilities by performing a meta-analysis of DNA methylation data in intestinal epithelial cells of IBD and control samples. We identified abnormal DNA methylation at different levels: deviation from mean methylation signals at site and region levels, and differential variability. A fraction of such changes are associated with genetic polymorphisms linked to IBD susceptibility. In addition, by comparing with another intestinal inflammatory condition (i.e. celiac disease) we propose that aberrant DNA methylation can also be the result of unspecific processes such as chronic inflammation. Our characterization suggests that IBD methylomes combine intrinsic and extrinsic responses in intestinal epithelial cells, and could point to knowledge-based biomarkers of IBD detection and progression. Graphical AbstractConceptual representation of the study. Using a meta-analysis strategy we identified differentially methylated positions or regions (DMP/DMR) in IBD. Our assumption is that gene expression changes (IBD phenotype) take place downstream of DNA methylation. In turn, abnormal DNA methylation can be explained by a direct effect of inflammatory cytokines ("signaling") and/or the result of a genetic polymorphism (SNP). SNP-DMP associations are called methylation quantitative trait loci (mQTL). O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/565200v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@b9fc96org.highwire.dtl.DTLVardef@7619c5org.highwire.dtl.DTLVardef@1961352org.highwire.dtl.DTLVardef@1ce9d84_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗