Identification of S100A9 as a target for diagnosis and treatment of Crohn’s Disease after Vedolizumab treatment failure
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PROVIDER: PRJNA1148656 | ENA |
REPOSITORIES: ENA
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Project description:Recent advances in Whole-Transcriptome Sequencing technologies enable the complete sequencing of entire genomes and allow us to analyze a number of disease genome profiles. In our study, whole-transcriptome sequencing was performed based on the peripheral blood leukocytes of patients in the Non-responsders group (contain 5 CD patients who are nonresponse to vedolizumab treatment) and the Rseponders group (contain 3 CD patients who are response to vedolizumab treatment). Subsequently, differential messenger RNA (mRNA), circRNA and lncRNA expression analysis was performed of the Non-responsders and Responders groups, followed by functional interaction prediction analysis. This study may provide novel insights into the molecular basis of initiation and progression of IBD, and provide potential biomarkers for distinct prognostic and therapeutic implications.
2025-08-01 | GSE274965 | GEO
Project description:Crohn’s disease (CD) is a debilitating gastrointestinal disorder that can impact the entirety of the GI tract. While substantial progress has been made in the medical management of CD, it remains incurable, frequently relapses, and is a significant financial and medical burden. The pathophysiology of CD is not well understood, but it is thought to arise in genetically susceptible individuals upon an environmental insult. Further elucidation of the disease etiology promises to expose additional therapeutic avenues, with the hope of reducing the burden of CD. One approach to understanding disease pathophysiology is to identify clinically relevant molecular disease subsets using transcriptomics. In this report, we use hierarchical clustering of the ileal transcriptomes of 34 patients to identify two CD subsets. Clinically, these clusters differed in the age of the patients at CD diagnosis, suggesting that age of disease onset impacts the pathophysiology of the disease. We found that the ileal transcriptomes of the early diagnosis cluster are enriched in inflammatory transcripts, including S100A9, which encodes a calprotectin subunit. Furthermore, levels of S100A9 distinguished individuals diagnosed before the age of 30 from those diagnosed after 30. Together, these findings suggest that medical management of CD patients should consider their age at diagnosis and therapeutic blockade of calprotectin may be beneficial in patients diagnosed earlier in life.
2022-06-02 | GSE151686 | GEO
Project description:Ileal S100A9 expression distinguishes Crohn’s disease patients by age at diagnosis
| PRJNA636953 | ENA
Project description:Background: Vedolizumab, an antibody blocking integrin α4β7, is a safe and effective therapy for Crohn’s disease and ulcerative colitis. Blocking α4β7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. Methods: We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect resolving inflammation could have on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 71 case patients receiving vedolizumab were matched with biopsies from 71 control patients, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full mRNA transcriptome sequencing of sorted T cells. Results: No difference was seen between vedolizumab recipients and controls in the quantity of any antigen-experienced lymphocyte subset, nor the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than controls, regardless of response. The only immune population that was significantly reduced exclusively in the colonic mucosa of vedolizumab-responsive patients was CD1c+ (BDCA1+) dendritic cells. In blood, these dendritic cells ubiquitously express more α4β7 per cell than almost any other circulating leukocyte, but rapidly downregulate α4β7 expression upon vedolizumab exposure. Conclusions: The clinical efficacy of vedolizumab thus reveals integrin α4β7-dependent dendritic cell migration to the intestinal mucosa to be central to IBD pathogenesis.
2023-08-01 | GSE234981 | GEO
Project description:Background: Vedolizumab, an antibody blocking integrin α4β7, is a safe and effective therapy for Crohn’s disease and ulcerative colitis. Blocking α4β7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. Methods: We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect resolving inflammation could have on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 71 case patients receiving vedolizumab were matched with biopsies from 71 control patients, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full mRNA transcriptome sequencing of sorted T cells. Results: No difference was seen between vedolizumab recipients and controls in the quantity of any antigen-experienced lymphocyte subset, nor the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than controls, regardless of response. The only immune population that was significantly reduced exclusively in the colonic mucosa of vedolizumab-responsive patients was CD1c+ (BDCA1+) dendritic cells. In blood, these dendritic cells ubiquitously express more α4β7 per cell than almost any other circulating leukocyte, but rapidly downregulate α4β7 expression upon vedolizumab exposure. Conclusions: The clinical efficacy of vedolizumab thus reveals integrin α4β7-dependent dendritic cell migration to the intestinal mucosa to be central to IBD pathogenesis.
2023-08-01 | GSE234736 | GEO
Project description:In this study we wanted to identify baseline predictors of successful vedolizumab therapy in patients with inflammatory bowel disease.
2019-08-23 | E-MTAB-7845 | biostudies-arrayexpress
Project description:In vitro and in vivo data from our lab show that TReg cells exhibit a right-shifted vedolizumab binding profile compared with TEff cells. Consistently, in a certain concentration range, the residual adhesion, transmigration and homing of TReg cells was higher than that of TEff cells. To better understand why vedolizumab binding was different between TReg and TEff in a certain concentration range, we performed single cell RNA sequencing of Memory CD4 T cells expressing α4 and β7 integrin and compared cells binding to vedolizumab or not binding to vedolizumab (previously purified using FACS with fluorescently labelled vedolizumab).
2021-09-10 | GSE162624 | GEO
Project description:Mycobacterium infection gives rise to granulomas predominantly composed of inflammatory M1-like macrophages, with bacteria-permissive M2 macrophages also detected in deep granulomas. Our histological analysis of Mycobacterium bovis bacillus Calmette-Guerin-elicited granulomas in guinea pigs revealed that S100A9-expressing neutrophils bordered a unique M2 niche within the inner circle of concentrically multilayered granulomas. We evaluated the effect of S100A9 on macrophage M2 polarization based on guinea pig studies. S100A9-deficient mouse neutrophils abrogated M2 polarization, which was critically dependent on COX-2 signaling in neutrophils. Mechanistic evidence suggested that nuclear S100A9 interacts with C/EBPβ, which cooperatively activates the Cox-2 promoter and amplifies prostaglandin E2 production, followed by M2 polarization in proximal macrophages. Since the M2 populations in guinea pig granulomas were abolished via treatment with celecoxib, a selective COX-2 inhibitor, we propose the S100A9/Cox-2 axis as a major pathway driving M2 niche formation in granulomas.
2023-03-01 | GSE162991 | GEO
Project description:In order to explore how S100A8 and S100A9 may participate in the kidney stone formation, we used recombinant S100A8, recombinant S100A9, or recombinant S100A8/S100A9 heterodimer to culture the HK-2 cells and then sequenced total cellular mRNAS.
2024-11-06 | GSE265848 | GEO
Project description:Crohn’s disease is a relapsing inflammatory disorder with a variable clinical course. While most patients present with purely an inflammatory phenotype (B1) at diagnosis, a subgroup (~20%) rapidly progresses to complicated disease manifestations that include stricturing (B2) within 5 years. DNA methylation is a key epigenetic mechanism that can regulate gene expression and thereby influence the development and progression of complex diseases. Site-specific DNA methylation differences have been reported in peripheral blood of patients with Crohn’s disease, but investigation of the temporal relationship between methylation and disease is required to establish whether the methylome plays a causal role and can be leveraged for therapeutic benefits. To this end, we conducted an epigenome-wide study of methylation (~850K sites) in peripheral blood at diagnosis and during follow-up from the RISK pediatric Crohn’s disease inception cohort. While some methylation changes associated with Crohn’s disease might be causal, in peripheral blood the vast majority are found to be a transient consequence of inflammation and thus a symptom of disease.
2018-04-03 | GSE112611 | GEO