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Differential Pathogenic Th17 Profile in Mesenteric Lymph Nodes of Crohn's Disease and Ulcerative Colitis Patients.

ABSTRACT: The drug targets IL23 and IL12 regulate pathogenicity and plasticity of intestinal Th17 cells in Crohn's disease (CD) and ulcerative colitis (UC), the two most common inflammatory bowel diseases (IBD). However, studies examining Th17 dysregulation in mesenteric lymph nodes (mLNs) of these patients are rare. We showed that in mLNs, CD could be distinguished from UC by increased frequencies of CCR6⁺CXCR3^-ROR?⁺Tbet^-CD4⁺ (Th17) memory T cells enriched in CD62L^low effector memory T cells (T_EM), and their differentially expressed molecular profile. Th17 T_EM cells (expressing IL17A, IL17F, RORC, and STAT3) displayed a higher pathogenic/cytotoxic (IL23R, IL18RAP, and GZMB, CD160, PRF1) gene signature in CD relative to UC, while non-pathogenic/regulatory genes (IL9, FOXP3, CTLA4) were more elevated in UC. In both CD and UC, IL12 but not IL23, augmented IFN? expression in Th17 T_EM and switched their molecular profile toward an ex-Th17 (Th1^*)-biased transcriptomic signature (increased IFNG, and decreased TCF7, IL17A), suggesting that Th17 plasticity occurs in mLNs before their recruitment to inflamed colon. We propose that differences observed between Th17 cell frequencies and their molecular profile in CD and UC might have implications in understanding disease pathogenesis, and thus, therapeutic management of patients with IBD.

SUBMITTER: Bsat M

PROVIDER: S-EPMC6547831 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Differential pathogenic Th17 profile in mesenteric lymph nodes of Crohn's disease and ulcerative colitis patients

Project description:The drug targets IL23 and IL12 regulate pathogenicity and plasticity of intestinal Th17 cells in Crohn’s disease (CD) and ulcerative colitis (UC), the two most common inflammatory bowel diseases (IBD). However, studies examining Th17 dysregulation in mesenteric lymph nodes (mLNs) of these patients are rare. We showed that in mLNs, CD could be distinguished from UC by increased frequencies of CCR6+CXCR3-RORg+Tbet-CD4+ (Th17) memory T cells enriched in CD62Llow effector memory T cells (TEM), and their differentially expressed molecular profile. Th17 TEM cells (expressing IL17A, IL17F, RORC and STAT3) displayed a higher pathogenic/cytotoxic (IL23R, IL18RAP, and GZMB, CD160, PRF1) gene signature in CD relative to UC, while non-pathogenic/regulatory genes (IL9, FOXP3, CTLA4) were more elevated in UC. In both CD and UC, IL12 but not IL23, augmented IFNg expression in Th17 TEM and switched their molecular profile towards an ex-Th17 (Th1*)-biased transcriptomic signature (increased IFNG, and decreased TCF7, IL17A), suggesting that Th17 plasticity occurs in mLNs before their recruitment to inflamed colon. We propose that differences observed between Th17 cell frequencies and their molecular profile in CD and UC might have implications in understanding disease pathogenesis, and thus, therapeutic management of patients with IBD.

2019-05-17 | GSE131359 | GEO

Differential pathogenic Th17 profile in mesenteric lymph nodes of Crohn's disease and ulcerative colitis patients

Project description:Differential pathogenic Th17 profile in mesenteric lymph nodes of Crohn's disease and ulcerative colitis patients

| PRJNA543335 | ENA

The Human Mesenteric Lymph Node Microbiome Differentiates Between Crohn's Disease and Ulcerative Colitis.

Project description:Background and aimsMesenteric lymph nodes are sites in which translocated bacteria incite and progress immunological responses. For this reason, understanding the microbiome of mesenteric lymph nodes in inflammatory bowel disease is important. The bacterial profile of Crohn's disease mesenteric lymph nodes has been analysed using culture-independent methods in only one previous study. This study aimed to investigate the mesenteric lymph node microbiota from both Crohn's disease and ulcerative colitis patients.MethodsMesenteric lymph nodes were collected from Crohn's disease and ulcerative colitis patients undergoing resection. Total DNA was extracted from mesenteric lymph nodes and assessed for the presence of bacterial DNA [16S]. All work was completed in a sterile environment using aseptic techniques. Samples positive for 16S DNA underwent next-generation sequencing, and the identity of bacterial phyla and species were determined.ResultsCrohn's disease mesenteric lymph nodes had a distinctly different microbial profile to that observed in ulcerative colitis. The relative abundance of Firmicutes was greater in nodes from ulcerative colitis patients, whereas Proteobacteria were more abundant in Crohn's disease. Although species diversity was reduced in the mesenteric lymph nodes of patients with Crohn's disease, these lymph nodes contained greater numbers of less dominant phyla, mainly Fusobacteria.ConclusionThis study confirms that there are distinct differences between the Crohn's disease and ulcerative colitis mesenteric lymph node microbiomes. Such microbial differences could aid in the diagnosis of Crohn's disease or ulcerative colitis, particularly in cases of indeterminate colitis at time of resection, or help explain their mechanisms of development and progression.

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Transcriptomic Analysis and High-dimensional Phenotypic Mapping of Mononuclear Phagocytes in Mesenteric Lymph Nodes Reveal Differences Between Ulcerative Colitis and Crohn's Disease.

Project description:Background and aimsCrohn's disease [CD] and ulcerative colitis [UC] are distinct forms of inflammatory bowel disease. Heterogeneity of HLA-DR+SIRPα + mononuclear phagocytes [MNPs], including macrophages [MΦ], monocyte-derived [Mono] cells, and dendritic cells [DCs], was reported in gut tissue but not yet investigated in mesenteric lymph nodes [MLNs] of IBD patients. We here compared the phenotype, function, and molecular profile of HLA-DR+SIRPα + MNPs in CD and UC MLNs.MethodsCell distribution, morphology, immune function, and transcriptomic [bulk RNAseq] and high-dimensional protein expression profiles [CyTOF] of HLA-DR+SIRPα + MNPs were examined in MLNs of UC [n = 14], CD [n = 35], and non-IBD [n = 12] patients.ResultsElevated frequencies of CD14+CD64+CD163+ [Mono/MΦ-like] MNPs displaying monocyte/MΦ morphology and phagocytic function were a distinct feature of UC MLNs. In CD, the proportion of CD14-CD64-CD163- [DC-like] cells was augmented relative to Mono/MΦ-like cells; DC-like cells drove naïve T cell proliferation, Th1 polarisation, and Th17 TCM plasticity. Gene expression profile corroborated the nature of DC-like cells, best represented by BTLA, SERPINF, IGJ and, of Mono/MΦ-like cells, defined by CD163, MARCO, MAFB, CD300E, S100A9 expression. CyTOF analysis showed that CD123+ plasmacytoid cells predominated over conventional DCs in DC-like cells. Four CD163+ clusters were revealed in Mono/MΦ-like cells, two of which were enriched in MARCO-CD68dimHLA-DRdim monocyte-like cells and MARCOhiCD68hiHLA-DRhi Mɸ, whose proportion increased in UC relative to CD.ConclusionsDefining the landscape of MNPs in MLNs provided evidence for expansion of CD163+ Mono/MΦ-like cells in UC only, highlighting a distinction between UC and CD, and thus the potential contribution of monocyte-like cells in driving colitis.

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Plasma microRNA Profile Differentiates Crohn's Colitis From Ulcerative Colitis.

Project description:Background:Inflammatory bowel disease (IBD) is commonly divided into 2 entities: Crohn's disease (CD) and ulcerative colitis (UC). Differentiating between these entities when dealing with IBD confined to the colon is important, especially when planning surgical treatment. Due to ambiguous histological or endoscopic findings, accurate diagnosis is not possible in up to 15% of cases. The aim of this study was to determine whether plasma microRNAs (miRNAs) can help differentiate Crohn's colitis (CC) from ulcerative colitis. Methods:Patients with isolated CC and with UC were enrolled in our study from January 2010 to May 2016. Peripheral blood was collected, and total RNA was isolated from plasma. Screening was performed for 380 common miRNAs. miRNAs that were differentially expressed between these 2 groups were chosen, and their differential expression was confirmed using single miRNA assays in a larger sample size. A predictive model was generated using these data. Significantly differentially expressed miRNAs were then validated utilizing the predictive model to assess blinded data from the single assays. Results:Screening was performed on 8 patients from each group. Seven differentially expressed miRNAs were chosen for single assay confirmation. Two miRNAs (miR-598, miR-642) were consistently different between the patient groups (P = 0.013, P = 0.005). Using blinded data, these 2 miRNAs were validated using the predictive model, achieving an overall accuracy of 75% (95% confidence interval, 40.7-92.9). Conclusions:We identified 2 plasma miRNAs that differentiated CC from UC. Our data indicate the promise and feasibility of a plasma miRNA-based assay to distinguish between these 2 conditions.

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Differential early pathogenic changes in human ileal gene expression in Crohn's disease and ulcerative colitis

Project description:The aim of this study is to identify early pathogenic changes in ileal gene expression that precede the development of macroscopic disease in inflammatory bowel diseases (IBDs). We focused on two IBD phenotypes that were unlikely to overlap: 1) ileal Crohn‚Äôs disease (CD) patients undergoing initial ileocolic resection of diseased ileum; and 2) ulcerative colitis (UC) patients undergoing total colectomy. The Control patients were those patients without IBD undergoing initial right hemicolectomy or total colectomy. In order to identify early pathogenic changes in the human ileum in inflammatory bowel diseases, we analyzed 99 two-color whole human genome expression profiles (Agilent 4410A) of a test human ileal cRNA probe vs. a common reference human ileal RNA from a Control patient (N17). A minimum of four biopsies were taken from the macroscopically disease-unaffected proximal ileal margin of freshly resected specimens from 47 ileal Crohn's disease patients undergoing initial ileocolic resection, 27 ulcerative colitis patients undergoing total colectomy and 25 Control patients undergoing either right hemicolectomy or total colectomy. The test and common reference probes were synthesized using the Agilent Low Input Linear Amplification Kit. Hybridization was carried out in DNA hybridization chambers, washed and scanned on an Axon GenePix 4000B scanner. The preprocessing, filtering and normalization of the array data was carried out using the R package LIMMA.

2010-09-26 | E-GEOD-24287 | biostudies-arrayexpress

Differential early pathogenic changes in human ileal gene expression in Crohn's disease and ulcerative colitis

2010-09-26 | GSE24287 | GEO

Dendritic cell populations in colon and mesenteric lymph nodes of patients with Crohn's disease.

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