Selective IgA2 deficiency in a patient with small intestinal Crohn's disease.
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ABSTRACT:
SUBMITTER: Canales-Herrerias P
PROVIDER: S-EPMC10266768 | biostudies-literature | 2023 Jun
REPOSITORIES: biostudies-literature
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Selective IgA2 deficiency in a patient with small intestinal Crohn's disease.
Canales-Herrerias Pablo P Garcia-Carmona Yolanda Y Shang Joan J Meringer Hadar H Yee Debra S DS Radigan Lin L Buta Sofija S Martinez-Delgado Gustavo G Tankelevich Michael M Helmus Drew D Dubinsky Marla M Everts-van der Mind Annelie A Dervieux Thierry T Bogunovic Dusan D Colombel Jean-Frederic JF Brenchley Jason M JM Faith Jeremiah J Cunningham-Rundles Charlotte C Cerutti Andrea A Mehandru Saurabh S
The Journal of clinical investigation 20230615 12
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Project description:Background & aimsCrohn disease (CD) presents as chronic and often progressive intestinal inflammation, but the contributing pathogenic mechanisms are unclear. We aimed to identify alterations in intestinal cells that could contribute to the chronic and progressive course of CD.MethodsWe took an unbiased system-wide approach by performing sequence analysis of RNA extracted from formalin-fixed paraffin-embedded ileal tissue sections from patients with CD (n = 36) and without CD (controls; n = 32). We selected relatively uninflamed samples, based on histology, before gene expression profiling; validation studies were performed using adjacent serial tissue sections. A separate set of samples (3 control and 4 CD samples) was analyzed by transmission electron microscopy. We developed methods to visualize an overlapping modular network of genes dysregulated in the CD samples. We validated our findings using biopsy samples (110 CD samples for gene expression analysis and 54 for histologic analysis) from the UNITI-2 phase 3 trial of ustekinumab for patients with CD and healthy individuals (26 samples used in gene expression analysis).ResultsWe identified gene clusters that were altered in nearly all CD samples. One cluster encoded genes associated with the enterocyte brush border, leading us to investigate microvilli. In ileal tissues from patients with CD, the microvilli were of decreased length and had ultrastructural defects compared with tissues from controls. Microvilli length correlated with expression of genes that regulate microvilli structure and function. Network analysis linked the microvilli cluster to several other down-regulated clusters associated with altered intracellular trafficking and cellular metabolism. Enrichment of a core microvilli gene set also was lower in the UNITI-2 trial CD samples compared with controls; expression of microvilli genes was correlated with microvilli length and endoscopy score and was associated with response to treatment.ConclusionsIn a transcriptome analysis of formalin-fixed and paraffin-embedded ileal tissues from patients with CD and controls, we associated transcriptional alterations with histologic alterations, such as differences in microvilli length. Decreased microvilli length and decreased expression of the microvilli gene set might contribute to epithelial malfunction and the chronic and progressive disease course in patients with CD.
| S-EPMC6378688 | biostudies-literature
Project description:BackgroundIntestinal stem cells (ISCs) play indispensable roles in the maintenance of homeostasis, and also in the regeneration of the damaged intestinal epithelia. However, whether the inflammatory environment of Crohn's disease (CD) affects properties of resident small intestinal stem cells remain uncertain.MethodsCD patient-derived small intestinal organoids were established from enteroscopic biopsy specimens taken from active lesions (aCD-SIO), or from mucosa under remission (rCD-SIO). Expression of ISC-marker genes in those organoids was examined by immunohistochemistry, and also by microfluid-based single-cell multiplex gene expression analysis. The ISC-specific function of organoid cells was evaluated using a single-cell organoid reformation assay.ResultsISC-marker genes, OLFM4 and SLC12A2, were expressed by an increased number of small intestinal epithelial cells in the active lesion of CD. aCD-SIOs, rCD-SIOs or those of non-IBD controls (NI-SIOs) were successfully established from 9 patients. Immunohistochemistry showed a comparable level of OLFM4 and SLC12A2 expression in all organoids. Single-cell gene expression data of 12 ISC-markers were acquired from a total of 1215 cells. t-distributed stochastic neighbor embedding analysis identified clusters of candidate ISCs, and also revealed a distinct expression pattern of SMOC2 and LGR5 in ISC-cluster classified cells derived from aCD-SIOs. Single-cell organoid reformation assays showed significantly higher reformation efficiency by the cells of the aCD-SIOs compared with that of cells from NI-SIOs.ConclusionsaCD-SIOs harbor ISCs with modified marker expression profiles, and also with high organoid reformation ability. Results suggest modification of small intestinal stem cell properties by unidentified factors in the inflammatory environment of CD.
| S-EPMC6132922 | biostudies-literature
Project description:Little is known about the ability for epithelial regeneration and wound healing in patients with inflammatory bowel diseases. We evaluated the epithelial proliferation and wound healing ability of patients with Crohn's disease (CD) using patient-derived intestinal organoids. Human intestinal organoids were constructed in a three-dimensional intestinal crypt culture of enteroscopic biopsy samples from controls and CD patients. The organoid-forming efficiency of ileal crypts derived from CD patients was reduced compared with those from control subjects (p < 0.001). Long-term cultured organoids (≥6 passages) derived from controls and CD patients showed an indistinguishable microscopic appearance and culturing behavior. Under TNFα-enriched conditions (30 ng/mL), the organoid reconstitution rate and cell viability of CD patient-derived organoids were significantly lower than those of the control organoids (p < 0.05 for each). The number of EdU+ cells was significantly lower in TNFα-treated organoids derived from CD patients than in TNFα-treated control organoids (p < 0.05). In a wound healing assay, the unhealed area in TNFα-treated CD patient-derived organoids was significantly larger than that of TNFα-treated control organoids (p < 0.001). The wound healing ability of CD patient-derived organoids is reduced in TNFα-enriched conditions, due to reduced cell proliferation. Epithelial regeneration ability may be impaired in patients with CD.
| S-EPMC8199630 | biostudies-literature
Project description:The diagnosis of Crohn's Disease (CD) is based on a combination of clinical symptoms, laboratory tests, endoscopy, and imaging data. In Small Intestine Contrast Ultrasonography (SICUS), the ingestion of a macrogol solution as an oral contrast medium may optimize image quality. We performed a meta-analysis to evaluate the diagnostic performance of SICUS for CD. A literature search was performed in August 2023. We selected only studies where SICUS was compared to a technique that allows the assessment of the whole gastrointestinal tract, such as an MRE, a CT scan, or a surgical evaluation. We estimated pooled weighted sensitivity, specificity, and likelihood ratio for positive and negative tests (PLR/NLR) of SICUS. Summary receiver operating characteristic curves (SROC) were drawn, and pooled areas under the curve (AUC) were calculated. Five studies with 325 CD patients were included. SICUS showed a pooled sensitivity for the diagnosis of 95% (95% confidence interval CI 89-99%), a specificity = 77% (95% CI 60-90%), and the AUC was 0.94. SICUS demonstrated a pooled sensitivity for strictures of 78% (95% CI 63-88%) and a specificity = 96% (95% CI 85-99%), with AUC = 0.93. For abscesses, SICUS demonstrated a pooled sensitivity of 100% (95% CI 59-100%) and a specificity of 90% (95% CI 74-98%). Fistulae were detected with a pooled sensitivity of 77% (95% CI 46-95%) and a specificity of 92% (95% CI 75-99%). SICUS demonstrated excellent diagnostic performance compared to the gold standard despite some clinical scenarios (stenosis/fistulae) showing suboptimal diagnostic effectiveness.
| S-EPMC10744114 | biostudies-literature
Project description:Paneth cells, specialized secretory epithelial cells of the small intestine, play a pivotal role in host defense and regulation of microbiota by producing antimicrobial peptides especially-but not only-the human α-defensin 5 (HD5) and HD6. In small intestinal Crohn's disease (CD) which is an entity of inflammatory bowel diseases, the expression of HD5 and HD6 is specifically compromised leading to a disturbed barrier and change in the microbial community. Different genetically driven but also non-genetic defects associated with small intestinal CD affect different lines of antimicrobial Paneth cell functions. In this review, we focus on the mechanisms and the crosstalk of Paneth cells and bone marrow-derived cells and highlight recent studies about the role of the Wnt signaling pathway in this connection of ileal CD. In summary, different lines of investigations led by us but also now numerous other groups support and reconfirm the proposed classification of this disease entity as Paneth's disease.
| S-EPMC5622939 | biostudies-literature
Project description:Crohn's disease (CD) is the chronic inflammation of the ileum and colon triggered by bacteria, but insights into molecular perturbations at the bacteria-epithelium interface are limited. We report that membrane mucin MUC17 protects small intestinal enterocytes against commensal and pathogenic bacteria. In non-inflamed CD ileum, reduced MUC17 levels correlated with a compromised glycocalyx, allowing bacterial contact with enterocytes. Muc17 deletion in mice rendered the small intestine prone to atypical infection while maintaining resistance to colitis. The loss of Muc17 resulted in spontaneous deterioration of epithelial homeostasis and extra-intestinal translocation of bacteria. Finally, Muc17-deficient mice harbored specific small intestinal bacterial taxa observed in CD. Our findings highlight MUC17 as an essential line of defense in the small intestine with relevance for early epithelial defects in CD.
| S-EPMC10888976 | biostudies-literature
Project description:BACKGROUND: Sulphydryl compounds are essential for maintaining mucosal integrity in the gastrointestinal tract. AIM: To characterise a model of experimental inflammation in the small intestine induced by a sulphydryl blocker. METHODS: Inflammation in the small intestine was induced in rats by intrajejunal administration of 0.1 ml 2% iodoacetamide. The possible amelioration of the damage induced was modulated by intragastric administration of TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl; 50 mg/100 g body weight), ketotifen (200 micrograms/100 g body weight), or by addition of L-NAME (NG-nitro-L-arginine methyl ester; 0.1 mg/ml) or apocynin (120 micrograms/ml) to the drinking water. Rats were sacrificed at various time intervals, the small intestine resected, weighed, macroscopic lesions were assessed, and mucosal generation of inflammatory mediators and nitric oxide synthase activity were determined. RESULTS: Intrajejunal administration of iodoacetamide induced, after one week, multifocal mucosal erosions, ulcerations with granulomas and giant Langhans cells. At two weeks, the mucosa was almost macroscopically intact but histologically epithelial granuloma and giant cells were present. Myeloperoxidase activity was increased in the first 24 hours, one week later mucosal nitric oxide synthase activity and generation of leukotriene B4, leukotriene C4 and thromboxane B2 were increased, whereas prostaglandin E2 generation was decreased notably. Ketotifen and apocynin significantly decreased the extent of injury which was not affected by TEMPOL or L-NAME. CONCLUSIONS: Jejunal inflammation induced by the sulphydryl blocker, iodoacetamide, resembles the pathological changes in Crohn's disease. The protective effect of ketotifen and apocynin indicates the contribution of O2- and pro-inflammatory mediators to the pathogenesis of the damage, and may be a novel approach to the treatment of inflammatory bowel disease.
| S-EPMC1891507 | biostudies-other
Project description:In healthy gut enteric glial cells (EGC) are essential to intestinal epithelial barrier (IEB) functions. In Crohn's Disease (CD), both EGC phenotype and IEB functions are altered, but putative involvement of EGC in CD pathogenesis remains unknown and study of human EGC are lacking. EGC isolated from CD and control patients showed similar expression of glial markers and EGC-derived soluble factors (IL6, TGF-β, proEGF, GSH) but CD EGC failed to increase IEB resistance and healing. Lipid profiling showed that CD EGC produced decreased amounts of 15-HETE, 18-HEPE, 15dPGJ2 and 11βPGF2α as compared to healthy EGC. They also had reduced expression of the L-PGDS and AKR1C3 enzymes. Produced by healthy EGC, the 11βPGF2 activated PPARγ receptor of intestinal epithelial cells to induce cell spreading and IEB wound repair. In addition to this novel healing mechanism our data show that CD EGC presented impaired ability to promote IEB functions through defect in L-PGDS-AKR1C3-11βPGF2α dependent pathway.
| S-EPMC4853710 | biostudies-other
Project description:Inflammatory Bowel Diseases are associated with marked alterations of IECs with a subsequent loss of barrier function. To identify alterations in signaling pathways in intestinal epithelium upon inflammation, we analyzed the transcriptome of IECs from patients suffering from Crohn’s disease.
2015-12-01 | GSE72780 | GEO
Project description:ObjectivesCurrently, there is no consensus on how to score Crohn's disease (CD) activity assessed by intestinal-ultrasound (IUS) in children. This study aimed to design an easy-to-use IUS score for disease activity in pediatric CD.MethodsChildren undergoing ileo-colonoscopy for CD assessment underwent IUS the day before ileo-colonoscopy, assessed with simple endoscopic score for CD (SES-CD). IUS features were compared to the SES-CD on segmental level. Multiple regression analyses, separately for terminal ileum (TI) and colon, were done to assess predictors of disease activity and to develop a model.ResultsIn 74 CD patients (median 15 years, 48% female), 67 TI and 364 colon segments were assessed. Based on ROC-curves, bowel wall thickness (BWT) was categorized into low (1point: 2-3 mm (TI), 1.6-2 mm (colon)), medium (2points: 3.0-3.7 mm (TI) and 2.0-2.7 mm (colon)) and high (3points: >3.7 mm (TI) and >2.7 mm (colon)). In TI, only BWT was retained in the model (high BWT:OR 11.50, p<0.001). In colon, BWT (high BWT:OR 8.63, p<0.001) and mesenteric fat (1point. OR:3.02, p<0.001) were independent predictors. A PCD-US cut-off of 1 resulted in a sensitivity of 82% (95%CI: 65-93%) and 85% (95% CI 80-89%) and a cut-off of 3 in a specificity of 88% (72-97%) and 92% (87-96%) for TI and colon, respectively. Inter-observer agreement was moderate for TI and colon (K:0.42, K:0.49, respectively).ConclusionsThe PCD-US score is an easy-to-use and reliable score to detect or rule out CD activity on segmental level in children. External validation is needed before applying this score in clinical practice.
| S-EPMC10097488 | biostudies-literature