Biology subjects

Panes, J.

Publications and source records attributed to Panes, J..

5 recordsLinked to original sources

bioRxiv2025

TL1A-activated T cells remodel the rectal mucosa in Crohn's disease patients with perianal fistulizing disease

BackgroundPerianal fistulizing disease (PFD) is a complication that affects about 20% of Crohns disease (CD) patients whose etiology remains unknown. ObjectivesTo identify predisposing events driving fistula formation. DesignRectal biopsies from CD patients with or without PFD (CD+PFD and CD, respectively; n=31) were collected and subjected to single-cell RNA sequencing (scRNA-seq). Functional analyses were conducted using peripheral CD3+ T cells, intestinal tissue explants, primary fibroblasts and 2D-epithelial monolayer cell cultures. ResultsThe rectal mucosa of CD+PFD patients is imprinted with cellular and transcriptomic alterations specific to PFD and independent of luminal inflammation, potentially driven by TL1A activation in CD4+ T cells. We identified lymphotoxin beta (LTB or its functional heterotrimer LT1{beta}2) as a novel mediator downstream of TL1A that, along with IL-22, induces a PFD-associated signature in rectal fibroblast and epithelial cells, respectively. This signature includes an increased abundance of fibroblasts, an induction of matrix-degrading enzymes, transcriptomic rewiring of the lamina propria S1 fibroblasts, and an anti-bacterial and immune responses in epithelial cells. Notably, the induction of LT1{beta}2 and IL-22 occurs independently of TNF signaling, revealing a new TL1A-LT1{beta}2/IL-22 axis that remains active under anti-TNF therapy. ConclusionOur findings revealed unique cellular alterations in the rectum of CD patients with PFD, highlighting the previously unrecognized involvement of TL1A in mediating this signature and supporting the need for exploring the role of TL1A inhibition as a therapeutic approach for PFD.

immunology↗

bioRxiv2024

Understanding the mechanisms underlying the lack of response to Janus kinase inhibition in ulcerative colitis

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. About one-third of UC patients failed to respond to available drugs, including tofacitinib, a broad Janus kinase (JAK) inhibitor. However, the mechanisms underlying patient response or resistance to oral JAK inhibitors remain unknown. To elucidate the molecular and cellular pathways activated by tofacitinib in responder and non-responder patients, we generated a longitudinal single-cell RNA sequence dataset profiling both immune and non-immune cell populations from colonic biopsies of UC patients. Our analysis revealed that responders exhibited higher baseline JAK-STAT activity, while non-responders had increased baseline NF-kB pathway activation. Longitudinal comparisons showed that disease progression in non-responders was associated with increased abundance and enhanced activation of macrophages and fibroblasts. Our data suggest that resistance to tofacitinib is mediated by the hyperactivation of myeloid cells, and we identified IL-10-dependent macrophages as a cellular subset contributing to this resistance.

immunology↗

bioRxiv2024

Mitochondrial dysfunction: unraveling the elusive biology behind anti-TNF response during ulcerative colitis

BackgroundRecent studies hint at mitochondrial genes influencing UC patient response to anti-TNF treatment. We evaluated this hypothesis by following a targeted strategy to identify gene expression that captures the relationship between mitochondrial dysregulation and response to treatment. Our objective was to initially examine this relationship in colon samples and subsequently assess whether the resulting signal persists in the bloodstream. MethodsWe analyzed the transcriptome of colon samples from an anti-TNF treated murine model characterized by impaired mitochondrial activity and treatment resistance. We then transferred the findings that linked mitochondrial dysfunction and compromised treatment response to an anti-TNF treated UC human cohort. We next matched differential expression in the blood using monocytes from peripheral blood of controls and IBD patients, and we evaluated a classification process at baseline with whole blood samples from UC patients. ResultsIn human colon samples, the derived gene-set from the murine model showed differential expression, primarily enriched metabolic pathways, and exhibited similar classification capacity as genes enriching inflammatory pathways. Moreover, the evaluation of the classification signal using blood samples from UC patients at baseline highlighted the involvement of mitochondrial homeostasis in treatment response. ConclusionOur results highlight the involvement of metabolic pathways and mitochondrial homeostasis in determining treatment response and their ability to provide promising classification signals with detection levels in both colon and bloodstream.

immunology↗

bioRxiv2022

Macrophage and neutrophil heterogeneity at single-cell spatial resolution in inflammatory bowel disease

Ulcerative colitis (UC) and Crohns disease (CD) are chronic inflammatory intestinal diseases that show a perplexing heterogeneity in manifestations and response to treatment. The molecular basis for this heterogeneity remains uncharacterized. We applied single-cell RNA sequencing and CosMx Spatial Molecular Imaging to human colon and found the highest diversity in cellular composition in the myeloid compartment of UC and CD patients. Besides resident macrophage subsets (M0 and M2), patients showed a variety of activated macrophages including classical (M1 CXCL5 and M1 ACOD1) and new inflammation-dependent alternative (IDA) macrophages. In addition, we captured intestinal neutrophils in three transcriptional states. Subepithelial IDA macrophages expressed NRG1, which promotes epithelial differentiation. In contrast, NRG1low IDA macrophages were expanded within the submucosa and in granulomas, in proximity to abundant inflammatory fibroblasts, which we suggest may promote macrophage activation. We conclude that macrophages sense and respond to unique tissue microenvironments, potentially contributing to patient-to-patient heterogeneity.

immunology↗

bioRxiv2022

Diet prevents the expansion of segmented filamentous bacteria and ileo-colonic inflammation in a model of Crohn's disease

Crohns disease (CD) is associated with changes in the microbiota, and murine models of CD-like ileo-colonic inflammation depend on the presence of microbial triggers. Increased abundance of unknown Clostridiales and the microscopic detection of filamentous structures close to the epithelium of Tnf {Delta}ARE mice pointed towards segmented filamentous bacteria (SFB), a commensal well-known to induce the maturation of Th17 cell-derived immune responses that is highly implicated in the pathogenesis of IBD. We show that the abundance of SFB strongly correlates with the severity of CD-like ileal inflammation in Tnf {Delta}ARE and SAMP/Yit mice. SFB mono-colonization of germ-free Tnf {Delta}ARE mice confirmed the causal link and resulted in severe ileo-colonic inflammation, characterized by elevated tissue levels of Tnf and Il-17, neutrophil infiltration and loss of Paneth and goblet cell function. Co-colonization of SFB in human-microbiota associated Tnf {Delta}ARE mice confirmed that SFB presence is indispensable for disease development. Screening of 412 ileal and colonic mucosal biopsies from IBD patients using previously published and newly designed human SFB-specific primer sets showed no presence of SFB in human tissue samples. Simulating the protective effect of exclusive enteral nutrition (EEN) by feeding SFB mono-colonized Tnf {Delta}ARE mice EEN-like purified diet antagonized SFB colonization and prevented disease development in Tnf {Delta}ARE mice, clearly demonstrating the important role of diet in modulating this IBD-related but murine pathobiont.

microbiology↗