Reparative immunological consequences of stem cell transplantation as a cellular therapy for refractory Crohn's disease.

Background: Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous haematopoietic stem cell transplantation (SCT) is an emerging therapy for medically refractory CD though the mechanisms through which it circumvents refractory pathophysiology are unknown.

Objective: The objective of this study is to understand how the immune system reconstitutes post-SCT and whether SCT may function as a cellular therapy restoring appropriately responsive immune cell populations from haematopoietic stem cells (HSCs).

The reparative immunologic consequences of stem cell transplantation as a cellular therapy for refractory Crohn's disease.

Background: Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.

Multimodal single-cell analyses reveal mechanisms of perianal fistula in diverse patients with Crohn's disease.

Background: Crohn's disease complicated by perianal fistulae is more prevalent and severe in patients of African ancestry.

Methods: We profiled single cells from diverse patients with Crohn's disease with perianal fistula from colorectal mucosa and fistulous tracts. Immunofluorescence was performed to validate predicted cell-cell interactions.

Unravelling the Oral-Gut Axis: Interconnection Between Periodontitis and Inflammatory Bowel Disease, Current Challenges, and Future Perspective.

As the opposite ends of the orodigestive tract, the oral cavity and the intestine share anatomical, microbial, and immunological ties that have bidirectional health implications. A growing body of evidence suggests an interconnection between oral pathologies and inflammatory bowel disease [IBD], implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an 'oral-gut' axis, marked by a higher prevalence of periodontitis and other oral conditions in IBD patients and vice versa.

Unraveling the Link between Periodontitis and Inflammatory Bowel Disease: Challenges and Outlook.

Periodontitis and Inflammatory Bowel Disease (IBD) are chronic inflammatory conditions, characterized by microbial dysbiosis and hyper-immunoinflammatory responses. Growing evidence suggest an interconnection between periodontitis and IBD, implying a shift from the traditional concept of independent diseases to a complex, reciprocal cycle. This review outlines the evidence supporting an "Oral-Gut" axis, marked by a higher prevalence of periodontitis in IBD patients and vice versa.

NOX1 is essential for TNFα-induced intestinal epithelial ROS secretion and inhibits M cell signatures.

Objective: Loss-of-function mutations in genes generating reactive oxygen species (ROS), such as , are associated with IBD. Mechanisms whereby loss of ROS drive IBD are incompletely defined.

Design: ROS measurements and single-cell transcriptomics were performed on colonoids stratified by genotype and TNFα stimulation.

Neutralizing Anti-Granulocyte Macrophage-Colony Stimulating Factor Autoantibodies Recognize Post-Translational Glycosylations on Granulocyte Macrophage-Colony Stimulating Factor Years Before Diagnosis and Predict Complicated Crohn's Disease.

Background & Aims: Anti-granulocyte macrophage-colony stimulating factor autoantibodies (aGMAbs) are detected in patients with ileal Crohn's disease (CD). Their induction and mode of action during or before disease are not well understood. We aimed to investigate the underlying mechanisms associated with aGMAb induction, from functional orientation to recognized epitopes, for their impact on intestinal immune homeostasis and use as a predictive biomarker for complicated CD.

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS).

A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease.

Crohn's disease is a chronic inflammatory intestinal disease that is frequently accompanied by aberrant healing and stricturing complications. Crosstalk between activated myeloid and stromal cells is critical in the pathogenicity of Crohn's disease, and increases in intravasating monocytes are correlated with a lack of response to anti-TNF treatment. The risk alleles with the highest effect on Crohn's disease are loss-of-function mutations in NOD2, which increase the risk of stricturing.

Inflamed Ulcerative Colitis Regions Associated With MRGPRX2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target.

Background & Aims: Recent literature has implicated a key role for mast cells in murine models of colonic inflammation, but their role in human ulcerative colitis (UC) is not well established. A major advance has been the identification of mrgprb2 (human orthologue, MRGPX2) as mediating IgE-independent mast cell activation. We sought to define mechanisms of mast cell activation and MRGPRX2 in human UC.

Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort.

Background And Aims: Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology.

Methods: PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets.

Labs in the time of COVID: an early-career scientist's view.

The outbreak of COVID-19 has stalled both the basic, clinical and non-COVID medical research. The scientific community has shown extraordinary flexibility and resilience in responding to the pandemic. However, funding restructuring, risk of infection, cancelation of scientific conferences and delayed experiments have already proven detrimental to the career opportunities of early-career scientists.

Single-Cell Analysis of Crohn's Disease Lesions Identifies a Pathogenic Cellular Module Associated with Resistance to Anti-TNF Therapy.

Clinical benefits of cytokine blockade in ileal Crohn's disease (iCD) are limited to a subset of patients. Here, we applied single-cell technologies to iCD lesions to address whether cellular heterogeneity contributes to treatment resistance. We found that a subset of patients expressed a unique cellular module in inflamed tissues that consisted of IgG plasma cells, inflammatory mononuclear phagocytes, activated T cells, and stromal cells, which we named the GIMATS module.

Zebrafish modeling of intestinal injury, bacterial exposures and medications defines epithelial responses relevant to human inflammatory bowel disease.

Genome-wide association studies have identified over 200 genomic loci associated with inflammatory bowel disease (IBD). High-effect risk alleles define key roles for genes involved in bacterial response and innate defense. More high-throughput systems are required to rapidly evaluate therapeutic agents.

Prioritizing Crohn's disease genes by integrating association signals with gene expression implicates monocyte subsets.

Genome-wide association studies have identified ~170 loci associated with Crohn's disease (CD) and defining which genes drive these association signals is a major challenge. The primary aim of this study was to define which CD locus genes are most likely to be disease related. We developed a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets, including bulk RNA-Seq from the terminal ileum of 302 newly diagnosed, untreated CD patients and controls, and in stimulated monocytes.

Functional variants in the gene confer shared effects on risk for Crohn's disease and Parkinson's disease.

Crohn's disease (CD), a form of inflammatory bowel disease, has a higher prevalence in Ashkenazi Jewish than in non-Jewish European populations. To define the role of nonsynonymous mutations, we performed exome sequencing of Ashkenazi Jewish patients with CD, followed by array-based genotyping and association analysis in 2066 CD cases and 3633 healthy controls. We detected association signals in the gene that conferred risk for CD (N2081D variant, = 9.

A Frameshift in CSF2RB Predominant Among Ashkenazi Jews Increases Risk for Crohn's Disease and Reduces Monocyte Signaling via GM-CSF.

Background & Aims: Crohn's disease (CD) has the highest prevalence in Ashkenazi Jewish populations. We sought to identify rare, CD-associated frameshift variants of high functional and statistical effects.

Methods: We performed exome sequencing and array-based genotype analyses of 1477 Ashkenazi Jewish individuals with CD and 2614 Ashkenazi Jewish individuals without CD (controls).

Disease-associated variants in different categories of disease located in distinct regulatory elements.

Background: The invention of high throughput sequencing technologies has led to the discoveries of hundreds of thousands of genetic variants associated with thousands of human diseases. Many of these genetic variants are located outside the protein coding regions, and as such, it is challenging to interpret the function of these genetic variants by traditional genetic approaches. Recent genome-wide functional genomics studies, such as FANTOM5 and ENCODE have uncovered a large number of regulatory elements across hundreds of different tissues or cell lines in the human genome.

Newborn GnRH neurons in the adult forebrain of the ring dove.

The preoptic area of the hypothalamus is a key area that produces gonadotrophin-releasing hormone (GnRH). In birds, the chicken GnRH-I-form neurons are responsible for the hypothalamus-pituitary-gonadal system, which controls reproduction. In the ring dove, electrolytic lesion in the adult hypothalamus induces neurogenesis.

Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis.

Although numerous fundamental aspects of development have been uncovered through the study of individual genes and proteins, system-level models are still missing for most developmental processes. The first two cell divisions of Caenorhabditis elegans embryogenesis constitute an ideal test bed for a system-level approach. Early embryogenesis, including processes such as cell division and establishment of cellular polarity, is readily amenable to large-scale functional analysis.

New genes with roles in the C. elegans embryo revealed using RNAi of ovary-enriched ORFeome clones.

Several RNA interference (RNAi)-based functional genomic projects have been performed in Caenorhabditis elegans to identify genes required during embryogenesis. These studies have demonstrated that the ovary is enriched for transcripts essential for the first cell divisions. However, comparing RNAi results suggests that many genes involved in embryogenesis have yet to be identified, especially those eliciting partially penetrant phenotypes.