Elevated levels of Th17 cells and Th17-related cytokines are associated with disease activity in patients with inflammatory bowel disease

Objective

Interleukin-17(IL-17)-producing T helper(Th)17 cells are considered as a new subset of cells critical to the development of inflammatory bowel disease (IBD). We aimed to investigate the distribution of Th17 cells, the expressions of Th17-related cytokines (IL-17, IL-21 and IL-22) and their association with disease activity in IBD patients.

Methods

We collected intestinal tissue biopsies from 40 patients with active ulcerative colitis (UC), 20 patients with active Crohn’s disease (CD) and 20 healthy controls. The distribution of Th17 cells and expressions of Th17-related cytokines in colonic tissues were evaluated by a standard immunohistochemical procedure. Serum IL-17, IL-21 and IL-22 levels were determined by ELISA. Pearson’s and Spearman’s correlation analyses were performed to analyze the correlation between the number of Th17 cells, the expressions of Th17-related cytokines and disease activity index, endoscopic and histological grading, and CRP and PLT levels, respectively.

Results

Compared with healthy controls, the number of Th17 cells and the expressions of IL-17, IL-21 and IL-22 were significantly increased in active IBD patients (P < 0.05). In addition, Pearson’s and Spearman’s correlation analyses showed that the number of Th17 cells and the expressions of Th17-related cytokines were correlated with disease activity index, endoscopic and histological grading, CRP and PLT levels (P < 0.05).

Conclusions

Th17 cells and Th17-related cytokines (IL-17, IL-21 and IL-22) were increased in the intestinal mucosa in active IBD patients and may play an important role in disease activity and mucosal damage.     

Th17及Th17型细胞因子与炎症性肠病

Th17细胞已被划分为一个不同于Th1、Th2和Treg的新的T细胞亚群,以分泌IL-17为主要特征。Th17在防御胞外细菌感染、介导慢性炎症和自身免疫性疾病的发病机制中发挥重要作用。炎症性肠病属于自身免疫性疾病的一种,免疫调节紊乱是其发病的关键因素。免疫学和基因学的发现表明Th17及Th17效应因子在炎症性肠病发病机理中起重要作用。对Th17的进一步深入研究可以加深我们对相关疾病发病机制的认识并指导临床治疗。     

Differential mucosal expression of three superoxide dismutase isoforms in inflammatory bowel disease

Mucosal tissue damage and dysfunction in chronic inflammatory bowel disease (IBD) are partly caused by an enduring exposure to excessive amounts of reactive oxygen metabolites (ROMs). Although the three human isoforms of superoxide dismutase (SOD), copper/zinc (Cu/Zn)-SOD, manganese (Mn)-SOD, and extracellular (EC)-SOD, form the primary endogenous defence against ROMs, their expression levels and cellular localization in IBD mucosa are largely unknown. The present study used enzyme-linked immunosorbent assays (ELISAs), spectrophotometric activity assays, and immunohistochemistry to evaluate the protein concentration, enzymatic activity, and distribution of Cu/Zn-, Mn-, and EC-SOD in paired inflamed and non-inflamed mucosal resection specimens of patients with Crohn's disease (CD) or ulcerative colitis (UC) and compared these with the levels obtained in normal control mucosa. Gut mucosal SOD isoform expression was found to be differentially affected in IBD patients, without major differences between CD and UC. A marked step-wise increase in Mn-SOD protein levels was observed in non-inflamed and inflamed IBD mucosae, whereas the Cu/Zn-SOD content decreased with inflammation. EC-SOD was only found in low amounts, which tended to be decreased in IBD patients. Immunohistochemical evaluation confirmed these observations. Mn-SOD and Cu/Zn-SOD were both predominantly expressed in intestinal epithelial cells and the percentage of epithelial cells positive for Mn-SOD was considerably increased in IBD, whereas epithelial Cu/Zn-SOD expression was much less affected. Within the lamina propria, SOD expression was much lower. Cu/Zn-SOD and Mn-SOD were prominently present in neutrophils and macrophages, and EC-SOD was mainly localized in small vessels, stromal cells, and neutrophils. The percentage of lamina propria cells positive for Cu/Zn-, Mn-, or EC-SOD was not affected by inflammation. Enzyme activity measurements showed consistent results for Cu/Zn-SOD and EC-SOD, but the activity of Mn-SOD did not concordantly increase with the immunological assessments, which may indicate that a proportion of the Mn-SOD in IBD is present in an enzymatically inactive form. This study reveals remarkable changes in the expression levels of the three SOD isoforms in IBD, particularly in the epithelium. Disturbances in the carefully orchestrated mucosal antioxidant cascade may contribute to the induction and perpetuation of intestinal inflammation in IBD, and may have important implications for the development of antioxidant treatment of IBD patients.     

Polymorphisms in Th17-related genes and the pathogenesis of autoimmune thyroid disease

Abstract

The prognosis of autoimmune thyroid disease (AITD) including Graves’ disease (GD) and Hashimoto’s disease (HD) is difficult to predict. We previously suggested that Th17 cells may be associated with the pathogenesis of AITD. However, the association between gene polymorphisms in Th17-related genes and the prognosis of AITD was not clarified. To clarify this association, we genotyped 12 polymorphisms in 11 Th17-related genes (IL1Ra, IL6R, IL17R, IL21R, IL23R, CCR6, SOCS3, RORC, IL17A, IL17F and IL21) in 142?HD patients including 58 patients with severe HD and 48 patients with mild HD, 170 patients with GD including 81 patients with intractable GD and 49 patients with GD in remission, and 84 healthy volunteers. The frequency of the IL17F rs763780 T allele was higher in patients with severe HD than in patients with mild HD (p?=?.008). The frequency of the IL17R rs9606615 T allele was higher in patients with HD than in normal subjects (p?=?.011). The frequencies of the SOCS3 rs4969170 AA genotype, CCR6 rs3093024 AA genotype, and IL21 rs907715 AA genotype were higher in patients with intractable GD than in patients with GD in remission (p?=?.035, p?=?.002 and p?=?.030, respectively). In conclusion, IL17R rs9607715 and IL17F rs763780 polymorphisms are associated with the susceptibility and severity of HD, respectively. IL21 rs907715, SOCS3 rs4969170 and CCR6 rs3093024 polymorphisms are associated with the intractability of GD.     

Differential expression of the TRAIL/TRAIL-receptor system in patients with inflammatory bowel disease

TNF-related apoptosis inducing-ligand (TRAIL) is a potent inducer of apoptosis and plays an important role in immune regulation. To explore the role of TRAIL in inflammatory bowel disease (IBD), we examined the expression of the TRAIL/TRAIL-receptor system in colonic resections from patients with ulcerative colitis and Crohn's disease in comparison to normal colon and appendicitis.     

Differential expression profile of Th1/Th17/Th2-related chemokines and their receptors in patients with acquired bone marrow failure syndromes

Th1/Th17/Th2-related chemokines (CXCL10/CCL20/CCL2) and their receptors (CXCR3/CCR6/CCR2) have rarely been studied in acquired bone marrow failure syndromes (BMFs). We evaluated the concentrations of CXCL10, CCL20 and CCL2 in plasma and BM fluid from aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and myelodysplastic syndromes (MDS) patients by enzyme-linked immunosorbent assay (ELISA). Real-time quantitative polymerase chain reaction (RT-PCR) was performed to determine mRNA expressions of those chemokines and their receptors. CCL20 levels in both plasma and BM fluid from AA, PNH and MDS patients were significantly higher than those in the corresponding samples from healthy controls; there were no differences in terms of CXCL10 and CCL2 levels. Significantly higher expressions of CXCR3 and CCL20 mRNA, meanwhile significantly lower expression of CCR2 mRNA in both peripheral blood mononuclear cells (PBMNCs) and bone marrow MNCs (BMMNCs) from AA and PNH patients were observed, with no differences in terms of CXCL10, CCL2 and CCR6 mRNA expressions. CCR6 mRNA expressions in both PBMNCs and BMMNCs from MDS patients were significantly higher than of the corresponding samples from controls. Our study implicated that CXCL10–CXCR3, CCL20–CCR6 and CCL2–CCR2 interaction might play important roles in Th1 and Th17 (but not for Th2) cells trafficking toward BM in acquired bone marrow failure syndromes.     

Th17 cells: interactions with predisposing factors in the immunopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory state of the GI tract of unknown etiology. Classically, tissue injury in IBD is thought to be primarily mediated by Th1 cells in Crohn’s disease or Th2 cells in ulcerative colitis. The discoveries of new subsets of T-helper cells, especially Th17 cells, have revolutionized our understanding of the disease immunopathology. Th17 cells seem to affect both innate and adaptive immune responses by the release of regulatory cytokines. Understanding the role of Th17 cells in IBD pathogenesis and targeting their regulatory cytokines may provide potential therapeutic approaches for the treatment of IBD in the future.     

Th17 cells: interactions with predisposing factors in the immunopathogenesis of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory state of the GI tract of unknown etiology. Classically, tissue injury in IBD is thought to be primarily mediated by Th1 cells in Crohn's disease or Th2 cells in ulcerative colitis. The discoveries of new subsets of T-helper cells, especially Th17 cells, have revolutionized our understanding of the disease immunopathology. Th17 cells seem to affect both innate and adaptive immune responses by the release of regulatory cytokines. Understanding the role of Th17 cells in IBD pathogenesis and targeting their regulatory cytokines may provide potential therapeutic approaches for the treatment of IBD in the future.     

Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease

The composition and spatial organization of the mucosal flora in biopsy specimens from patients with inflammatory bowel disease (IBD; either Crohn's disease or ulcerative colitis), self-limiting colitis, irritable-bowel syndrome (IBS), and healthy controls were investigated by using a broad range of fluorescent bacterial group-specific rRNA-targeted oligonucleotide probes. Each group included 20 subjects. Ten patients who had IBD and who were being treated with antibiotics were also studied. Use of nonaqueous Carnoy fixative to preserve the mucus layer was crucial for detection of bacteria adherent to the mucosal surface (mucosal bacteria). No biofilm was detectable in formalin-fixed biopsy specimens. Mucosal bacteria were found at concentrations greater than 10⁹/ml in 90 to 95% of IBD patients, 95% of patients with self-limiting colitis, 65% of IBS patients, and 35% of healthy controls. The mean density of the mucosal biofilm was 2 powers higher in IBD patients than in patients with IBS or controls, and bacteria were mostly adherent. Bacteroides fragilis was responsible for >60% of the biofilm mass in patients with IBD but for only 30% of the biofilm mass in patients with self-limiting colitis and <15% of the biofilm mass in patients with IBS. In contrast, bacteria which positively hybridized with the probe specific for Eubacterium rectale-Clostridium coccoides accounted for >40% of the biofilm in IBS patients but for <15% of the biofilm in IBD patients. In patients treated with (5-ASA) or antibiotics, the biofilm could be detected with 4,6-diamidino-2-phenylindole but did not hybridize with fluorescence in situ hybridization probes. A Bacteroides fragilis biofilm is the main feature of IBD. This was not previously recognized due to a lack of appropriate tissue fixation. Both 5-ASA and antibiotics suppress but do not eliminate the adherent biofilm.     

Association of celiac disease genes with inflammatory bowel disease in Finnish and Swedish patients

Some genetic loci may affect susceptibility to multiple immune system-related diseases. In the current study, we investigated whether the known susceptibility loci for celiac disease (CelD) also associate with Crohn's disease (CD) and/or ulcerative colitis (UC), the two main forms of inflammatory bowel disease (IBD), in Finnish patients. A total of 45 genetic markers were genotyped in a Finnish data set comprising 699 IBD patients and 2482 controls. Single-marker association with IBD and its subphenotypes was tested. A meta-analysis with a Swedish UC data set was also performed. A total of 12 single-nucleotide polymorphisms associated with CD and/or UC (P<0.05). In the subphenotype analysis, rs6974491-ELMO1 (P=0.0002, odds ratio (OR): 2.20) and rs2298428-UBE2L3 (P=5.44 × 10(-5), OR: 2.59) associated with pediatric UC and CD, respectively. In the meta-analysis, rs4819388-ICOSLG (P=0.00042, OR: 0.79) associated with UC. In the subphenotype meta-analysis, rs1738074-TAGAP (P=7.40 × 10(-5), OR: 0.61), rs6974491-ELMO1 (P=0.00052, OR: 1.73) and rs4819388-ICOSLG (P=0.00019, OR: 0.75) associated with familial UC, pediatric UC and sporadic UC, respectively. Multiple CelD risk loci also confer susceptibility for CD and/or UC in the Finnish and Swedish populations. Certain genetic risk variants may furthermore predispose an individual for developing a particular disease phenotype.     

Synovial expression of Th17-related and cancer-associated genes is regulated by the arthritis severity locus Cia10

We have previously identified Cia10 as an arthritis severity and articular damage quantitative trait locus. In this study, we used Illumina RatRef-12 microarrays to analyze the expression of 21,922 genes in synovial tissues from arthritis-susceptible DA and arthritis-protected DA.ACI(Cia10) congenics with pristane-induced arthritis. 310 genes had significantly different expression. The genes upregulated in DA, and reciprocally downregulated in DA.ACI(Cia10) included IL-11, Ccl12 and Cxcl10, as well as genes implicated in Th17 responses such as IL-17A, IL-6, Ccr6, Cxcr3 and Stat4. Suppressors of immune responses Tgfb and Vdr, and inhibitors of oxidative stress were upregulated in congenics. There was an over-representation of genes implicated in cancer and cancer-related phenotypes such as tumor growth and invasion among the differentially expressed genes. Cancer-favoring genes like Ctsd, Ikbke, and Kras were expressed in increased levels in DA, whereas inhibitors of cancer phenotypes such as Timp2, Reck and Tgfbr3 were increased in DA.ACI(Cia10). These results suggest that Cia10 may control arthritis severity, synovial hyperplasia and joint damage via the regulation of the expression of cancer-related genes, inflammatory mediators and Th17-related markers. These new findings have the potential to generate new targets for therapies aimed at reducing arthritis severity and joint damage in rheumatoid arthritis.     

Tissue hemostasis and chronic inflammation in colon biopsies of patients with inflammatory bowel disease

Inflammatory bowel disease (IBD) is characterized by a chronic inflammation accompanied by procoagulation settings. However, tissue hemostasis in IBD patients was only incidentally reported. Accordingly, the current study characterizes changes in tissue hemostasis components in a colon inflammatory setting. Serial cryostat sections of endoscopic mucosal biopsy specimens taken from 26 consecutive IBD patients diagnosed de novo and normal colon resection specimens taken from 6 patients were immunohistochemically stained with monoclonal anti-human tissue factor (TF), tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), as well as CD3 and CD68 positive cells. The hemostatic components studied differed significantly from the control subjects. Up-regulation predominated in the case of TF while down-regulation was mainly found in TM and TFPI in IBD. In the control sections, TF was observed in a few fibroblast-shaped cells in the lamina propria, while in the majority of IBD sections, TF positively stained small microvessels, infiltrating mononuclear cells and fibroblast-shaped cells tightly surrounding the colon crypts. Thrombomodulin intensively stained the endothelium of the small capillary vessels in the control, whereas such staining mainly accompanied infiltrating mononuclear cells of the IBD subjects. Tissue factor pathway inhibitor positively stained the endothelium of the small capillary vessels in the control group, whereas in the IBD group endothelial cells presented only weak TFPI staining. The mean number of CD3-positive lymphocytes in IBD was 23.3±14.3, but the mean number of CD68-positive cells was 114.5±55.8. In the control sections, it was 4.1±2.4 and 39.6±17.9, respectively. There was no relationship between CD3 and CD68 (+) cells and the hemostasis markers studied. The results of the current study indicate a shift of tissue hemostasis toward the procoagulant state irrespective of the severity of inflammatory infiltration. In addition, TF distribution in the colon sections of IBD patients may indicate a role in the restoration of the barrier function in injured intestinal mucosa.     

CD11c+ cells are significantly decreased in the duodenum, ileum and colon of dogs with inflammatory bowel disease

CD11c serves as a marker for human and murine dendritic cells (DCs) and cells expressing this marker have been shown to have similar morphological and functional characteristics in the canine immune system. The aim of this study was to quantify CD11c⁺ cells in the duodenum, ileum and colon of healthy dogs and dogs with inflammatory bowel disease (IBD). Endoscopic biopsies from the duodenum (n = 12 cases), ileum (n = 8 cases) and colon (n = 12 cases) were obtained from dogs diagnosed with IBD. Intestinal tissue from 10 healthy beagle dogs was used as control. Immunofluorescence microscopy was carried out using an anti-canine CD11c monoclonal antibody. Labelled cells were recorded as cells per 120,000 μm². The canine chronic enteropathy clinical activity index (CCECAI) was calculated for all dogs with IBD. In addition, sections from all dogs with IBD were evaluated according to the guidelines of the World Small Animal Veterinary Association Gastrointestinal Standardization Group. The number of CD11c⁺ cells in the duodenum, ileum and colon of dogs with IBD was significantly reduced compared with controls (P < 0.01, P < 0.01 and P < 0.05, respectively). There was a significant negative correlation between the number of CD11c⁺ cells in the colon of dogs with IBD and the CCECAI (P = 0.044, r² = −0.558). Chronic inflammation in canine IBD appears to involve an imbalance in the intestinal DC population. Future studies will determine whether reduced expression of CD11c could be a useful marker for the diagnosis and monitoring of canine IBD.     

Differential expression of vasoactive intestinal peptide receptor 1 expression in inflammatory bowel disease

There is conflicting evidence regarding the significance of vasoactive intestinal peptide (VIP) in inflammatory bowel disease (IBD). Involvement of the VIP receptor in IBD has not been reported. We examined the expression and localization of the VIP receptor in IBD. We determined the location of VIP receptor 1 (VIPR1) immunohistologically in surgically resected intestinal samples from 10 controls, 15 patients with ulcerative colitis, and 10 patients with Crohn's disease. A fluorescein-linked immunohistological study was performed using anti-VIPR1 antibody, with double-staining with antibodies to CD3, CD19, and CD68. Correlations with interleukin (IL)-4 and TNF-alpha expression were also investigated. Results showed that the number of VIPR1-positive cells was significantly increased in the inflammatory mucosa. VIPR1 was expressed in CD3-, CD19-, and CD68-positive cells. The proportion of VIPR1-positive cells among CD3-positive cells was significantly higher in the lamina propria of patients with ulcerative colitis than in those with Crohn's disease and the controls. The proportion of VIPR1-positive cells among CD68-positive cells was significantly higher in patients with ulcerative colitis and Crohn's disease than in the controls. A correlation between the numbers of VIPR1- and IL-4-positive cells was found in patients with ulcerative colitis, and between the numbers of VIPR1- and TNF-alpha-positive cells in patients with Crohn's disease. In conclusion, VIPR1 was widely expressed in infiltrating inflammatory cells, especially CD3- and CD68-positive cells in ulcerative colitis mucosa and CD68-positive cells in Crohn's disease mucosa. The differential expression of VIPR1 in ulcerative colitis and Crohn's disease mucosa suggests that the VIP system plays different roles in the pathogenesis of IBD.     

Gene expression in mononuclear cells from patients with inflammatory bowel disease

OBJECTIVES: Discovery of Nod2 as the inflammatory bowel disease 1 (IBD1) susceptibility gene has brought to light the significance of mononuclear cells in inflammatory bowel disease pathogenesis. The purpose of this study was to examine changes in gene expression in peripheral blood mononuclear cells in patients with untreated Crohn's disease (CD) and ulcerative colitis (UC) as compared to patients with other inflammatory gastrointestinal disorders and to healthy controls. METHODS: We used a 2400 gene cDNA glass slide array (MICROMAX) to examine gene expression in peripheral blood mononuclear cells from seven patients with Crohn's disease, five patients with ulcerative colitis, 10 patients with other inflammatory gastrointestinal disorders, and 22 age- and sex-matched controls. Results. Novel categories of genes differentially expressed in Crohn's disease and ulcerative colitis patients included genes regulating hematopoietic cell differentiation and leukemogenesis, lipid raft-associated signaling, the actin cytoskeleton, and vesicular trafficking. Conclusions: Altered gene expression in mononuclear cells may contribute to inflammatory bowel disease pathogenesis.     

The increased mucosal mRNA expressions of complement C3 and interleukin-17 in inflammatory bowel disease

Recent studies have demonstrated that the complement system participates in the regulation of T cell functions. To address the local biosynthesis of complement components in inflammatory bowel disease (IBD) mucosa, we investigated C3 and interleukin (IL)‐17 mRNA expression in mucosal samples obtained from patients with IBD. The molecular mechanisms underlying C3 induction were investigated in human colonic subepithelial myofibroblasts (SEMFs). IL‐17 and C3 mRNA expressions in the IBD mucosa were evaluated by real‐time polymerase chain reaction. The C3 levels in the supernatant were determined by enzyme‐linked immunosorbent assay. IL‐17 and C3 mRNA expressions were elevated significantly in the active lesions from ulcerative colitis (UC) and Crohn's disease (CD) patients. There was a significant positive correlation between IL‐17 and C3 mRNA expression in the IBD mucosa. IL‐17 stimulated a dose‐ and time‐dependent increase in C3 mRNA expression and C3 secretion in colonic SEMFs. The C3 molecules secreted by colonic SEMFs were a 115‐kDa α‐chain linked to a 70‐kDa β‐chain by disulphide bonds, which was identical to serum C3. The IL‐17‐induced C3 mRNA expression was blocked by p42/44 mitogen‐activated protein kinase (MAPK) inhibitors (PD98059 and U0216) and a p38 MAPK inhibitor (SB203580). Furthermore, IL‐17‐induced C3 mRNA expression was inhibited by an adenovirus containing a stable mutant form of IκBα. C3 and IL‐17 mRNA expressions are enhanced, with a strong correlation, in the inflamed mucosa of IBD patients. Part of these clinical findings was considered to be mediated by the colonic SEMF response to IL‐17.     

Characterization of antigen-presenting activity of intestinal mononuclear cells isolated from normal and inflammatory bowel disease colon and ileum.

Antigen-presenting activity in mononuclear cells, isolated from normal and inflamed human ileum and colon, has been characterized using allogeneic mixed lymphocyte reaction with resting T cells as responders. Greatest proliferation was induced by fibronectin-adherent (macrophage-enriched) cells, and least by fibronectin non-adherent (macrophage-depleted) cells and by mononuclear cells depleted of macrophages by panning with monoclonal antibody 3C10. When intestinal mononuclear cells and allogeneic T cells were incubated in large numbers, clusters were observed. These clusters contained cells with a dendritic morphology that were strongly HLA-D-positive and which also stained with macrophage-specific monoclonal antibodies 3C10, EMB11 and Y1/82A. These cells were closely associated with proliferating T cells. Studies comparing mononuclear cells isolated from normal and inflamed colonic mucosa suggest that the latter may have enhanced antigen-presenting capacity.     

High endothelial venules associated with T cell subsets in the inflamed gut of newly diagnosed inflammatory bowel disease patients

Naive and central memory T lymphocytes (T_N and T_CM) can infiltrate the inflamed gut mucosa in inflammatory bowel disease (IBD) patients. Homing of these subsets to the gut might be explained by ectopic formation of tertiary lymphoid organs (TLOs), containing high endothelial venules (HEVs). We aimed to evaluate the presence of HEVs and TLOs in inflamed intestinal mucosa of newly diagnosed, untreated IBD patients in relation to the presence of T_N and T_CM lymphocytes. IBD patients (n = 39) and healthy controls (n = 8) were included prospectively. Biopsy samples of inflamed and normal intestine, respectively, were analysed by immunohistochemistry for lymphocytes (CD3/CD20), blood vessels (CD31) and peripheral lymph node addressin (PNAd) expression (MECA‐79). T_N and T_CM lymphocyte subsets were identified by flow cytometric immunophenotyping. A higher number of HEVs was found in the inflamed colon of patients with ulcerative colitis [median 3·05 HEV/mm²; interquartile range (IQR) = 0–6·39] and ileum of Crohn's disease patients (1·40; 0‐4·34) compared to healthy controls (both 0; P = 0·033). A high density of colonic HEVs (HEV^high) was associated with increased infiltration of T_N and T_CM in the inflamed gut (median 87%; IQR = 82–93% of T cell population), compared to HEV^low patients (58%; 38–81%; P = 0·003). The number of colonic follicles was higher in HEV^high patients (median 0·54/mm²; IQR 0·28–0·84) compared to HEV^low patients (0·25/mm²; 0·08–0·45; P = 0·031) and controls (0·31/mm²; 0·23–0·45; P = 0·043). Increased homing of T_N and T_CM lymphocytes to inflamed gut tissue in IBD patients might be facilitated by ectopic formation of extrafollicular HEVs and TLOs in a subgroup of patients.     

CD73 is a phenotypic marker of effector memory Th17 cells in inflammatory bowel disease

Purinergic signaling and associated ectonucleotidases, such as CD39 and CD73, have been implicated in the pathogenesis of inflammatory bowel disease (IBD). CD39 is known to be a Treg memory cell marker, and here we determine the phenotype and function of CD73⁺CD4⁺ T lymphocytes in patients with IBD. We describe elevated levels of CD73⁺CD4⁺ T cells in the peripheral blood and intestinal lamina propria of patients with active IBD. The functional phenotype of these CD73⁺CD4⁺ T cells was further determined by gene expression, ecto‐enzymatic activity, and suppressive assays. Increased numbers of CD73⁺CD4⁺ T cells in the periphery and lamina propria were noted during active inflammation, which returned to baseline levels following anti‐TNF treatment. Peripheral CD73⁺CD4⁺ T cells predominantly expressed CD45RO, and were enriched with IL‐17A⁺ cells. The CD73⁺CD4⁺ cell population expressed higher levels of RORC, IL‐17A, and TNF, and lower levels of FOXP3 and/or CD25, than CD73^?CD4⁺ T cells. Expression of CD73 by peripheral CD4⁺ T cells was increased by TNF, and decreased by an anti‐TNF monoclonal antibody (infliximab). In vitro, these peripheral CD73⁺CD4⁺ T cells did not suppress proliferation of CD25^? effector cells, and expressed higher levels of pro‐inflammatory markers. We conclude that the CD73⁺CD4⁺ T‐cell population in patients with active IBD are enriched with cells with a T‐helper type 17 phenotype, and could be used to monitor disease activity during treatment.