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Antigen presentation via major histocompatibility complex (MHC) class I and class II receptors plays a fundamental role in T cell-mediated adaptive immunity. A dysregulation of this fine-tuned recognition might result in the development of autoimmune diseases such as inflammatory bowel diseases that are characterized by chronic relapsing inflammation of the intestinal tract and a damaged intestinal epithelial barrier. While MHCII receptors are usually expressed by professional antigen presenting cells (APC) only, there is increasing evidence that non-immune cells such as intestinal epithelial cells (IEC) might express MHCII upon stimulation with IFN-γ and thus act as non-professional APC. However, little is known about other factors regulating intestinal epithelial MHC expression. Here, we identify IL-27 as an inducer of different MHCI and MHCII receptor subtypes and the invariant chain (CD74/li) in IEC via the STAT1/IRF1/CIITA axis. CIITA, MHCII, and CD74 expression was significantly increased in IEC from Crohn’s disease (CD) patients with active disease compared to controls or CD patients in remission. IEC phagocytosed and digested external antigens and apoptotic cells. IL-27 strongly stimulated antigen processing via the immunoproteasome in a IRF1-dependent manner. In co-culture experiments, antigen-primed IEC strongly enhanced lymphocyte proliferation and IL-2 secretion, dependent on direct cell-cell contact. IL-27 pretreatment of IEC significantly increased CD4 + T cell proliferation and reduced IL-2 levels in lymphocytes in coculture. In summary, we identified IL-27 as a novel regulator of IEC antigen processing and presentation via MHCI and MHCII receptors, underscoring the importance of IEC as non-professional APC.

Background: Treatment of inflammatory bowel diseases (IBD) has tremendously improved during the last 20 years; however, a substantial fraction of patients does not respond to available therapies or lose response, and new strategies are needed. Summary: Two pharmacological principles have been successfully used for IBD treatment: inhibition of cellular signaling and interference with leukocyte trafficking. Besides tumor necrosis factor, interleukin (IL)-23 is a promising drug target, and antibodies for the combined inhibition of IL-23 and IL-12 (ustekinumab and briakinumab) or selective IL-23 inhibition (brazikumab, risankizumab, and mirikizumab) seem to be effective in Crohn’s disease (CD) with emerging evidence also for ulcerative colitis (UC). Janus kinase (JAK) mediates intracellular signaling of a large number of cytokines. Tofacitinib is the first JAK inhibitor approved for UC, and the JAK inhibitors filgotinib and upadacitinib showed potential in CD. Leukocyte trafficking can be inhibited by interference with lymphocyte integrin-α4β7 or endothelial MadCAM-1. The α4β7 integrin inhibitor vedolizumab is an established treatment in IBD, and long-term data of pivotal studies are now available. Additional molecules with therapeutic potential are α4β7-specific abrilumab, β7-specific etrolizumab, and the α4-specific small molecule AJM300. PF-00547659, an antibody against endothelial MadCAM-1, also showed therapeutic potential in UC. Modulation of sphingosine-1-phosphate receptor (S1PR) activity is necessary for the egress of lymphocytes into the circulation, and S1PR modulation results in lymphocyte trapping in lymphatic organs. Ozanimod, an S1PR1 and S1PR5 inhibitor, has been successfully tested in initial studies in UC. Mesenchymal stem cell therapy has been approved for the treatment of complex, active CD fistula, and mesenchymal stem cell therapy might be a paradigm shift for this condition. Autologous stem cell transplantation (ASCT) has been successfully used in CD case series; however, in a randomized trial, a highly stringent endpoint was not met. However, considering positive effects in secondary endpoints, ASCT might be a future treatment of last resort in severe, refractory CD cases, provided that safer protocols can be provided. Key messages: New IBD treatments are successful for a significant fraction of patients. However, new strategies for patient selection, treatment combinations, and/or additional therapies must be developed to serve the need of all IBD patients.

Here, the presentation of lipid antigens by CD1d is shown to induce retrograde anti-inflammatory signalling in intestinal epithelial cells, resulting in the production of IL-10. Anti-inflammatory IL-10 in the intestinal mucosa Intestinal epithelial cells (IECs) are crucial to mucosal homeostasis, serving as a physical barrier and regulating the responses of mucosal immune cells to environmental factors. This paper shows that CD1d, a glycoprotein involved in the presentation of lipid antigens, induces a self-reinforcing pathway of protective mucosal immunity within the intestinal epithelium. The pathway is mediated by regulatory cytokines and heat shock proteins, and interference with any molecules involved (including CD1d, IL-10 and HSP110) is associated with uncontrolled intestinal inflammation. These findings could have relevance for inflammatory bowel disease and similar conditions. The mechanisms by which mucosal homeostasis is maintained are of central importance to inflammatory bowel disease. Critical to these processes is the intestinal epithelial cell (IEC), which regulates immune responses at the interface between the commensal microbiota and the host 1 , 2 . CD1d presents self and microbial lipid antigens to natural killer T (NKT) cells, which are involved in the pathogenesis of colitis in animal models and human inflammatory bowel disease 3 , 4 , 5 , 6 , 7 , 8 . As CD1d crosslinking on model IECs results in the production of the important regulatory cytokine interleukin (IL)-10 (ref. 9 ), decreased epithelial CD1d expression—as observed in inflammatory bowel disease 10 , 11 —may contribute substantially to intestinal inflammation. Here we show in mice that whereas bone-marrow-derived CD1d signals contribute to NKT-cell-mediated intestinal inflammation, engagement of epithelial CD1d elicits protective effects through the activation of STAT3 and STAT3-dependent transcription of IL-10, heat shock protein 110 (HSP110; also known as HSP105), and CD1d itself. All of these epithelial elements are critically involved in controlling CD1d-mediated intestinal inflammation. This is demonstrated by severe NKT-cell-mediated colitis upon IEC-specific deletion of IL-10, CD1d, and its critical regulator microsomal triglyceride transfer protein (MTP) 12 , 13 , as well as deletion of HSP110 in the radioresistant compartment. Our studies thus uncover a novel pathway of IEC-dependent regulation of mucosal homeostasis and highlight a critical role of IL-10 in the intestinal epithelium, with broad implications for diseases such as inflammatory bowel disease.

Intestinal epithelial overexpression of the Th17 cell chemoattractant CCL20 is implicated in inflammatory bowel disease and influenced by NOD2 mutations in Crohn’s disease. Vitamin D metabolites have been shown to ameliorate inflammatory bowel disease. Considering NOD2 mutations in Crohn’s disease, we investigated whether Vitamin D deficiency (serum 25-hydroxyvitamin D concentration < 20 ng/mL) increases circulating CCL20 levels in inflammatory bowel disease patients and healthy controls and whether active 1,25-dihydroxyvitamin D (calcitriol) downregulates systemic and intestinal CCL20 expression. In a cross-sectional study, serum concentrations of CCL20, 25-hydroxyvitamin D, and calcitriol were measured in 170 NOD2 -genotyped Crohn’s disease patients, 80 ulcerative colitis patients, and 60 healthy controls. Additionally, the effect of calcitriol on experimentally induced CCL20 expression was examined using human intestinal epithelial HT-29 cells. Multivariable linear regression analyses revealed that both the diagnosis of inflammatory bowel disease and vitamin D deficiency were independently associated with elevated CCL20 levels. Compared to healthy controls, Crohn’s disease patients and ulcerative colitis patients exhibited significantly higher circulating CCL20 levels. Unlike in Crohn’s disease patients, vitamin D deficiency was associated with higher CCL20 levels in healthy controls and ulcerative colitis patients, whereas the calcitriol/25-hydroxyvitamin D activation ratios were negatively correlated with serum CCL20 levels in healthy controls and ulcerative colitis patients with sufficient serum 25-hydroxyvitamin D status. Furthermore, calcitriol markedly inhibited intestinal epithelial induction of CCL20. In Crohn’s disease patients, cholecalciferol supplementation was associated with lower serum CCL20 levels, which were unaffected by NOD2 mutations. These findings suggest that although vitamin D metabolites may downregulate CCL20 expression in healthy controls and ulcerative colitis patients, this regulatory effect appears to be impaired in Crohn’s disease patients.

Dendritic cells (DCs) and macrophages are critical to innate and adaptive immunity to the intestinal bacterial microbiota. Here, we identify a myeloid-derived mucosal DC in mice, which populates the entire lamina propria of the small intestine. Lamina propria DCs were found to depend on the chemokine receptor CX₃CR1 to form transepithelial dendrites, which enable the cells to directly sample luminal antigens. CX₃CR1 was also found to control the clearance of entero-invasive pathogens by DCs. Thus, CX₃CR1-dependent processes, which control host interactions of specialized DCs with commensal and pathogenic bacteria, may regulate immunological tolerance and inflammation.

Oncostatin M (OSM) is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of gp130 and LIFR (I) or OSMR-β and gp130 (II), respectively. Aim of this study was to analyze the role of OSM in intestinal epithelial cells (IEC) and intestinal inflammation. OSM expression and OSM receptor distribution was analyzed by PCR and immunohistochemistry experiments, signal transduction by immunoblotting. Gene expression studies were performed by microarray analysis and RT-PCR. Apoptosis was measured by caspases-3/7 activity. IEC migration and proliferation was studied in wounding and water soluble tetrazolium assays. The IEC lines Caco-2, DLD-1, SW480, HCT116 and HT-29 express mRNA for the OSM receptor subunits gp130 and OSMR-β, while only HCT116, HT-29 and DLD-1 cells express LIFR mRNA. OSM binding to its receptor complex activates STAT1, STAT3, ERK-1/2, SAPK/JNK-1/2, and Akt. Microarray analysis revealed 79 genes that were significantly up-regulated (adj.-p ≤ 0.05) by OSM in IEC. Most up-regulated genes belong to the functional categories \"immunity and defense\" (p = 2.1 × 10(-7)), \"apoptosis\" (p = 3.7 × 10(-4)) and \"JAK/STAT cascade\" (p = 3.4 × 10(-6)). Members of the SERPIN gene family were among the most strongly up-regulated genes. OSM significantly increased STAT3- and MEK1-dependent IEC cell proliferation (p<0.05) and wound healing (p = 3.9 × 10(-5)). OSM protein expression was increased in colonic biopsies of patients with active inflammatory bowel disease (IBD). OSM promotes STAT3-dependent intestinal epithelial cell proliferation and wound healing in vitro. Considering the increased OSM expression in colonic biopsy specimens of patients with active IBD, OSM upregulation may modulate a barrier-protective host response in intestinal inflammation. Further in vivo studies are warranted to elucidate the exact role of OSM in intestinal inflammation and the potential of OSM as a drug target in IBD.

Introduction: Sartan-induced enteropathy is an uncommon side effect of treatment with angiotensin II receptor antagonists (ARBs), which has predominantly been described for olmesartan. Case Presentation: For the first time, we describe sartan-induced enteropathy as an adverse drug reaction associated with azilsartan in a 74-year-old male patient who was admitted to the hospital twice within 5 months because of excessive non-bloody diarrhea and weight loss. In this case, histopathological findings of intraepithelial lymphocytosis and intestinal villous atrophy resembled celiac disease; however, celiac disease-specific antibodies remained negative, and a gluten-free diet did not result in significant clinical recovery, while symptoms stopped rapidly after stopping azilsartan. When the patient was seen 5 months later, he was free of clinical symptoms, and histological changes disappeared after stopping azilsartan. Conclusion: This case illustrates sprue-like enteropathy as a potential side effect of azilsartan, emphasizing to consider this differential diagnosis in ARB-treated patients with chronic diarrhea. The causality of our findings was confirmed by drug de-challenge and re-challenge resulting in typical histological changes.

NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort. 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses. Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10.sup.-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery. Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.

Interleukin (IL)-17F, produced in IL-23R-expressing Th17 cells, is a novel member of the IL-17 cytokine family. Given the association of IL23R with inflammatory bowel disease (IBD), we characterized the role of IL-17F in IBD including its intestinal gene expression and the effect of the IL17F p.His161Arg polymorphism on disease susceptibility and phenotype of Crohn's disease (CD) and ulcerative colitis (UC). In addition, we analyzed the IL17F p.His161Arg polymorphism for potential epistasis with IL23R and NOD2/CARD15 variants.MethodsIntestinal IL-17F mRNA expression was measured by quantitative polymerase chain reaction (PCR). Genomic DNA from 1682 individuals (CD: n = 499; UC: n = 216; controls: n = 967) was analyzed for the presence of the IL17F p.His161Arg polymorphism, the 3 NOD2 variants, p.Arg702Trp, p.Gly908Arg, and p.Leu1007fsX1008, and 10 CD-associated IL23R variants.ResultsIntestinal IL-17F mRNA expression was 4.4-fold increased in inflamed colonic lesions compared to uninflamed biopsies in CD (P = 0.016) but not in UC. However, the mean intestinal IL-17F mRNA expression was higher in UC than in CD (P < 0.0001). The IL17F p.His161Arg substitution was observed with similar frequencies in IBD patients and controls and was not associated with a certain disease phenotype, but weakly associated with a low body mass index (BMI; P = 0.009) and an earlier age of disease onset (P = 0.039) in UC. There was no evidence for epistasis between the IL17F p.His161Arg polymorphism and IBD-associated single nucleotide polymorphisms within the IL23R gene.ConclusionsIntestinal IL17F gene expression is increased in active CD. The IL17F p.His161Arg polymorphism is not associated with IBD susceptibility and has no epistatic interaction with CD-associated IL23R variants.(Inclamm Bowel Dis 2007)

Introduction: The medical treatment of refractory collagenous colitis with a concomitant symptomatic lymphocytic disorder of the upper gastrointestinal tract is very challenging with scarce evidence. Case Presentation: We present a 61-year-old female patient with a long-standing highly refractory collagenous colitis with a concomitant symptomatic lymphocytic disorder with villous atrophy and intraepithelial lymphocytes of the upper gastrointestinal tract causing severe watery diarrhoea with severe hypokalemia and recurrent episodes of prerenal kidney injuries requiring several hospital admissions. Celiac serology as well as genetic analyses (HLA-DQ2/DQ8) were negative, and other common etiologies of intraepithelial lymphocytosis and villous atrophy were ruled out. Considering the similar course of the disease in the upper and lower gastrointestinal tract for a time period of more than 20 years, a common etiologic relationship, particularly an autoimmune disorder seems to be very likely in this patient. Several therapies such as budesonide, immunomodulators, and the biologics infliximab and vedolizumab had to be stopped due to either non-response, loss-of-response or drug-related side effects. However, the patient responded immediately to the JAK-1 inhibitor upadacitinib, with documented remission for more than 1 year. Conclusion: For the first time, a prompt and significant response to upadacitinib in a patient with refractory collagenous colitis with upper gastrointestinal tract involvement was shown, suggesting upadacitinib as therapy of choice in severe therapy-refractory cases of collagenous colitis, particularly with concomitant upper gastrointestinal tract involvement.