Therapeutic TG2 Inhibition Reverses Systemic Multiomic Dysregulation in Celiac Disease
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE319777 | GEO | 2026/06/18
REPOSITORIES: GEO
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Project description:Celiac disease (CeD) is an immune-mediated chronic enteropathy caused by gluten exposure in HLA-DQ2 and/or -DQ8 positive individuals. The hallmarks of CeD include increased intraepithelial lymphocytes and villous atrophy. Clinically, a small subset of individuals with elevated serum tissue transglutaminase antibody (TTG) concentrations but unremarkable duodenal mucosa at initial endoscopy may progress to CeD over time. We hypothesize that these rare CeD precursor cases can allow us to interrogate histologic and molecular signatures to predict those who subsequently develop CeD, and to study the final cascade into overt lesions in CeD.
2025-08-06 | GSE273155 | GEO
Project description:In vitro models of autoimmunity are constrained by an inability to culture affected epithelium alongside the complex tissue-resident immune microenvironment. Celiac disease (CeD) is an autoimmune disease where dietary gluten-derived peptides bind the MHC- II molecules HLA-DQ2 or -DQ8 to initiate immune-mediated duodenal mucosal injury. Here, we generated air-liquid interface (ALI) duodenal organoids from endoscopic biopsies that preserve epithelium alongside native mesenchyme and tissue-resident immune cells as a unit without requiring reconstitution. The ALI organoid immune diversity spanned T, B, plasma, NK and myeloid cells with extensive T and B cell receptor repertoires. HLA-DQ2.5-restricted gluten peptides selectively instigated epithelial destruction in HLA-DQ2.5-expressing CeD patient organoids, which was antagonized by MHC-II or NKG2C/D blockade. Gluten epitopes stimulated a CeD organoid network response in lymphoid and myeloid subsets alongside anti-TG2 autoantibody production. Functional studies in CeD organoids revealed IL-7 as a novel gluten-inducible pathogenic modulator which regulated CD8+ T cell-NKG2C/D expression and was necessary and sufficient for epithelial destruction. Further, endogenous IL-7 was markedly induced in patient biopsies from active CeD versus remission disease, predominantly in lamina propria mesenchyme. By preserving epithelium alongside diverse immune populations, this human in vitro CeD model recapitulates gluten-dependent pathology, facilitates mechanistic investigation, and establishes proof-of-principle for organoid modeling of autoimmunity.
2024-07-12 | GSE200075 | GEO
Project description:Celiac disease (CD) is a chronic inflammation of the small intestine triggered by the ingestion of gluten in genetically predisposed individuals. Tissue transglutaminase (TG2) is a key factor in the pathogenesis of CD, because it catalyzes both the deamidation of specific glutamine residues and the formation of covalent Nε-(γ-glutamyl)-lysine isopeptide crosslinks resulting in TG2-gluten peptide complexes. These complexes are thought to activate B cells causing the secretion of anti-TG2 autoantibodies that serve as diagnostic markers for CD, although their pathogenic role remains unclear. To gain more insight into the molecular structures of TG2-gluten peptide complexes, we developed a reciprocal proteomic analysis strategy, which facilitates the comprehensive identification of isopeptides in a complex protein hydrolysate. The workflow consists of four steps: (1) performance of the model reaction between TG2 and gluten peptide(s) followed by tryptic hydrolysis, clean-up and untargeted nLC-MS/MS analysis (2), prediction of tryptic TG2-derived lysine peptides that serve as potential isopeptide modifications (3) the search for isopeptides by configuring the TG2-modifications in MaxQuant and search against the α-gliadin fasta file and (4) the reciprocal search for isopeptides by configuring the gluten peptide(s) as modification in MaxQuant and search against the TG2 fasta file. After verification by manual data curation and visualization, this strategy enabled the identification of 26 different isopeptides involving 19 TG2 lysine residues, only six of which were known previously. Experiments with different TG2-gluten peptide molar ratios revealed that K-425, K-590, K-600 and K-649 were the most preferred lysine residues involved in isopeptide crosslinking. Further, expanding the model system to three gluten peptides allowed the localization of the preferred glutamine crosslinking sites. The described strategy is generally applicable to any hydrolysate containing isopeptides and these new insights into the structure of TG2-gluten peptide complexes may help clarify the role of extracellular TG2 in CD autoimmunity and in other inflammatory diseases.
2019-09-27 | PXD014067 | Pride
Project description:Barley beers may be rendered gluten-free by specialized brewing processes. One controversial issue is whether these beers contain residual gluten peptides carrying at least one celiac disease (CeD)-active epitope, because routine methods to assess whether the beer is gluten-free like competitive enzyme-linked immunosorbent assays (ELISA) may fail to detect potentially harmful peptides. We used untargeted nano-liquid chromatography-tandem mass spectrometry (nanoLC MS/MS) to identify CeD-active peptides in 21 gluten-free barley beers and four regular or carbohydrate-reducedbeers. While the G12 ELISA confirmed gluten levels below 20 mg/kg in all gluten-free beers, the R5 ELISA detected gluten levels in four beers exceeding this threshold, highlighting method discrepancies. nanoLC-MS/MS identified 44 CeD active peptides in seven gluten-free and four non-gluten-free beers, of which 17 CeD-active peptides had no ELISA epitope and therefore escape detection. Accurate quantitation of thesepeptides combined with in vivo toxicity assessment will be needed to provide guidance on clinical relevance.
2026-04-01 | PXD059719 | Pride
Project description:Background Celiac disease (CeD) is an autoimmune disorder triggered by gluten, with gliadin as the primary antigen. Therapies targeting gliadin to induce antigen-specific immune tolerance are of significant interest. This study investigates the therapeutic potential of a novel rapamycin-gliadin composite nanoparticle (PLN-GR) in enhancing Kupffer cell-mediated hepato-splenic dialogue to promote gluten tolerance in CeD. Methods Rapamycin-gliadin composite nanoparticles were synthesized using a precipitation self-assembly method and characterized for size, zeta potential, and cellular uptake. A CeD delayed-type hypersensitivity (DTH) mouse model was employed to evaluate the immunomodulatory effects of PLN-GR. Cellular biodistribution, immune phenotyping, and metabolic assessments were conducted to elucidate the nanoparticles' mechanism of action. Results Rapamycin-gliadin composite nanoparticles effectively targeted the liver and were internalized by Kupffer cells, inducing a tolerogenic phenotype. In vivo treatment with PLN-GR ameliorated systemic and intestinal inflammation in the CeD DTH mouse model, evidenced by reduced paw swelling and intestinal histopathology. The nanoparticles induced a metabolic shift from glycolysis to oxidative phosphorylation in macrophages, associated with increased itaconate production. This metabolic reprogramming was linked to an increase in PD-L1+ tolerogenic dendritic cells and a decrease in Th1 cell counts in the spleen. Conclusion The study demonstrates that rapamycin-gliadin nanoparticles can induce antigen-specific tolerance in CeD by modulating hepatic and splenic immune responses. The findings suggest a potential therapeutic strategy for CeD by enhancing immunometabolic reprogramming and inter-organ communication.
2025-07-30 | GSE275197 | GEO
Project description:Celiac disease (CeD) is the most common autoimmune disorder in the U.S., affecting at least 1% of the population. The ingestion of gluten-containing proteins triggers an adaptive immune response, causing intestinal damage and leading to both gastrointestinal and systemic symptoms. Despite a strong genetic predisposition, the mechanistic understanding of CeD remains limited. The lack of approved therapy, other than dietary avoidance of gluten which is difficult and often unsuccessful, underscores the need to identify new mechanisms that can provide insights for developing therapeutics. To gain an unbiased view of the transcriptional landscape of the duodenum, we compared duodenal biopsies showing active CeD to normal controls using single-cell RNA sequencing. We analyzed fresh research biopsies from 4 patients with active CeD, confirmed by diagnostic biopsies from the same endoscopy, as well as 2 healthy control biopsies without specific pathological changes. Our analysis captured every major intestinal mucosal cell type including all subsets of immune cells, epithelial cells and stromal cells. Among these, enterocytes and activated T cells exhibited the most significant differences between CeD biopsies and controls. In CeD biopsies, CD8+TCR αβ and TCR γδ T cells were the primary producers of IFNG, a feature that was largely absent in the control biopsies. Moreover, enterocytes that express villous defining marker APOA4+ showed elevated levels of IFNGR1, suggesting an increased responsiveness to IFNγ produced by CeD T cells. We assessed effects of IFNγ on potential target molecules expressed on enterocytes that could activate and trigger killing by CTL. Bioinformatic ligand receptor analyses showed frequent interactions between intraepithelial CTLs and enterocyte HLA-E or HLA-B, suggesting that IFNγ production by the CTLs likely promotes further CTL recruitment and antigen-dependent killing of the villous epithelium.
2026-01-31 | GSE315138 | GEO
Project description:Coeliac Disease (CeD) is a chronic autoimmune disorder affecting 0.5-1% of the general population with a wide geographical distribution. Despite recent efforts to deeply phenotype gluten-specific immune activation at the single cell level, recent clinical studies targeting gluten degradation and other immune tolerance mechanisms have been unsuccessful. To this end, a deeper understanding of immune and non-immune cellular dynamics and interactions are required to characterize tissue-specific mechanisms responsible for CeD pathogenesis, repair, and resolution. Here, we assembled the most comprehensive scRNAseq dataset in Coeliac Disease to date, including 203,555 cells across 21 active CeD and 11 control duodenal samples. Compared to control duodenum, CeD was characterized by single cell differential changes in abundance, gene expression and cell-cell interactions across cellular compartments. In the immune compartments, CeD samples showed expected increases in plasma cell abundance and shifts toward type 1 effector biology (e.g., increase in cycling CD8pos, γδ T cells and IFNG transcriptional shifts) and Tfh-related biology (e.g., increases in IL21 signaling to effector T cells). In addition, activated myeloid subsets, including DC2 and monocytes, were increased in disease and were characterized by increased pro-inflammatory pathway expression, including IL-1β. Non-immune compartments showed increased stem/crypt and secretory enterocytes in CeD samples with a decrease in absorptive enterocytes, reflecting the villus atrophy and crypt hyperplasia hallmarks of CeD epithelial dysfunction. Accompanying the epithelial changes, distinct changes in stromal populations were identified, particularly with increases in abundance and transcriptional activity of NRG1 and SMOC2 fibroblasts. Cell-cell interaction analysis across multiple cellular compartments proposed a distinct increased role of fibroblasts to support the epithelial reprogramming of the increased stem/crypt epithelial fraction in CeD, mediated by myeloid derived IL-1β signal and lymphoid-derived IFN-γ. This dataset reveals a previously unknown role for T-myeloid-stromal-epithelial cell communication in CeD, highlighting key mechanisms of the tissue-level cellular dynamics in response to gluten ingestion.
2025-07-30 | GSE277276 | GEO
Project description:Treatment of acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA) results in terminal differentiation of leukemic cells toward neutrophil granulocytes. Administration of ATRA leads to massive changes in gene expression, including down-regulation of cell proliferation-related genes and induction of genes involved in immune function. One of the most induced genes in APL NB4 cells is transglutaminase 2 (TG2). RNAi-mediated stable silencing of TG2 in NB4 cells (TG2-KD NB4) coupled with whole genome microarray analysis revealed that TG2 is involved in the expression of a large number of ATRA-regulated genes. The affected genes participate in granulocyte functions and their silencing lead to reduced adhesive, migratory and phagocytic capacity of neutrophils and less superoxide production. The expression of genes related to cell cycle control also changed, suggesting that TG2 regulates myeloid cell differentiation. CC chemokines CCL2, 3, 22, 24 and cytokines IL1B and IL8 involved in the development of differentiation syndrome (DS) are expressed at significantly lower levels in TG2-KD NB4 cells than in wild-type NB4 cells upon ATRA treatment. Based on our results, we propose that reduced expression of TG2 in differentiating APL cells may suppress effector functions of neutrophil granulocytes and attenuate the ATRA-induced inflammatory phenotype of DS. We used microarrays to detail the global program of gene expression underlying ATRA-induced differentiation of TG2 knockout NB4 cells. TG2 knockout NB4 cells were differentiated for 48 and 72 hours in the presence of ATRA and their gene expression profiles were compared to the wild-type cells at the same time points. Undifferentiated wild-type and TG2 knockout NB4 cells were used as untreated controls. Three biological replicates each.
2010-12-01 | E-GEOD-23702 | biostudies-arrayexpress
Project description:Treatment of acute promyelocytic leukemia (APL) with all-trans-retinoic acid (ATRA) results in terminal differentiation of leukemic cells toward neutrophil granulocytes. Administration of ATRA leads to massive changes in gene expression, including down-regulation of cell proliferation-related genes and induction of genes involved in immune function. One of the most induced genes in APL NB4 cells is transglutaminase 2 (TG2). RNAi-mediated stable silencing of TG2 in NB4 cells (TG2-KD NB4) coupled with whole genome microarray analysis revealed that TG2 is involved in the expression of a large number of ATRA-regulated genes. The affected genes participate in granulocyte functions and their silencing lead to reduced adhesive, migratory and phagocytic capacity of neutrophils and less superoxide production. The expression of genes related to cell cycle control also changed, suggesting that TG2 regulates myeloid cell differentiation. CC chemokines CCL2, 3, 22, 24 and cytokines IL1B and IL8 involved in the development of differentiation syndrome (DS) are expressed at significantly lower levels in TG2-KD NB4 cells than in wild-type NB4 cells upon ATRA treatment. Based on our results, we propose that reduced expression of TG2 in differentiating APL cells may suppress effector functions of neutrophil granulocytes and attenuate the ATRA-induced inflammatory phenotype of DS.
2010-12-01 | GSE23702 | GEO
Project description:Celiac disease (CeD) is an intestinal immune-mediated disorder caused by gluten ingestion in genetically predisposed subjects. CeD is characterized by villous atrophy, altered intestinal permeability, crypt hyperplasia and innate and adaptive immune response. This study aimed to develop and validate the use of intestinal organoids from celiac patients to study CeD. A repository of organoids from duodenum of non-celiac and celiac patients was generated and characterized accordingly to standard procedures. RNA-seq analysis was employed to study the global gene expression program of CeD (n=3) and non-CeD (n=3) organoids sets. While the three celiac derived organoids shared similar transcriptional signatures the NC samples set appeared more heterogeneous. We found 486 genes differentially expressed between the two groups. Of them, 299 genes were downregulated (FC<2; FDR<0.05) and 187 were upregulated in CeD (FC >2; FDR<0.05). We observed CeD organoids had significantly altered expression of genes associated with barrier function, innate immunity, and stem cell function.
2019-05-29 | GSE113492 | GEO