Cells In Colitis Research Articles

Refractory neutrophils and monocytes in patients with inflammatory bowel disease after repeated bouts of prolonged exercise.

BackgroundNeutrophils and monocytes are key immune effector cells in inflammatory bowel disease (IBD) that is associated with chronic inflammation in the gut. Patients with stable IBD who perform exercise have significantly fewer flare‐ups of the disease, but no underlying mechanism has been identified. Therefore, the aim of this study was to compare the responsiveness/refractoriness of these innate immune cells after repeated bouts of prolonged exercise in IBD patients and controls.MethodsPatients with IBD and age‐ and gender‐matched healthy controls were recruited from a cohort of walkers participating in a 4‐day walking event. Blood analysis was performed at baseline and after 3 days of walking. Responsiveness to the bacterial/mitochondrial‐stimulus N‐Formylmethionine‐leucyl‐phenylalanine (fMLF) was tested in granulocytes and monocytes by measuring the expression of activation markers after adding this stimulus to whole blood.ResultsIn total 38 participants (54 ± 12 years) were included in this study: 19 walkers with and 19 walkers without IBD. After 3 days of prolonged exercise, a significant increase in responsiveness to fMLF was observed in all participants irrespective of disease. However, IBD patients showed significantly less responsiveness in neutrophils and monocytes, compared with non‐IBD walkers.ConclusionsIncreased responsiveness of neutrophils and monocyte to fMLF was demonstrated after repetitive bouts of prolonged exercise. Interestingly, this exercise was associated with relative refractoriness of both neutrophils and monocytes in IBD patients. These refractory cells might create a lower inflammatory state in the intestine providing a putative mechanism for the decrease in flare‐ups in IBD patients after repeated exercise.

Wnt-β-catenin activation epigenetically reprograms Treg cells in inflammatory bowel disease and dysplastic progression.

The diversity of regulatory T (Treg) cells in health and in disease remains unclear. Individuals with colorectal cancer harbor a subpopulation of RORγt+ Treg cells with elevated expression of β-catenin and pro-inflammatory properties. Here we show progressive expansion of RORγt+ Treg cells in individuals with inflammatory bowel disease during inflammation and early dysplasia. Activating Wnt-β-catenin signaling in human and murine Treg cells was sufficient to recapitulate the disease-associated increase in the frequency of RORγt+ Treg cells coexpressing multiple pro-inflammatory cytokines. Binding of the β-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt-β-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Treg cells. Activation of β-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.

Update: Innate Lymphoid Cells in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic and nonspecific intestinal inflammatory condition with high relapse rate. Its pathogenesis has been linked to dysbacteriosis, genetic and environmental factors. In recent years, a new type of lymphocytes, termed innate lymphoid cells, has been described and classified into three subtypes of innate lymphoid cells-group 1, group 2 and group 3. An imbalance among these subsets' interaction with gut microbiome, and other immune cells affects intestinal mucosal homeostasis. Understanding the role of innate lymphoid cells may provide ideas for developing novel and targeted approaches for treatment of IBD.

Th17 Cells in Inflammatory Bowel Disease: Cytokines, Plasticity, and Therapies.

Autoimmune diseases (such as rheumatoid arthritis, asthma, autoimmune bowel disease) are a complex disease. Improper activation of the immune system or imbalance of immune cells can cause the immune system to transform into a proinflammatory state, leading to autoimmune pathological damage. Recent studies have shown that autoimmune diseases are closely related to CD4+ T helper cells (Th). The original CD4 T cells will differentiate into different T helper (Th) subgroups after activation. According to their cytokines, the types of Th cells are different to produce lineage-specific cytokines, which play a role in autoimmune homeostasis. When Th differentiation and its cytokines are not regulated, it will induce autoimmune inflammation. Autoimmune bowel disease (IBD) is an autoimmune disease of unknown cause. Current research shows that its pathogenesis is closely related to Th17 cells. This article reviews the role and plasticity of the upstream and downstream cytokines and signaling pathways of Th17 cells in the occurrence and development of autoimmune bowel disease and summarizes the new progress of IBD immunotherapy.

Targeting pathogenic T cells by metabolic checkpoint inhibition

A recent study in Science Immunology describes a new approach to selectively eliminate pathogenic CD4+ T cells in inflammatory bowel disease by activating them in the presence of metabolic checkpoint inhibition.

Increased HLA-G Expression in Tissue-Infiltrating Cells in Inflammatory Bowel Diseases.

Since HLA-G is an immune checkpoint molecule and since Crohn's disease (CD) and ulcerative colitis (UC) exhibit deregulated immune-mediated mechanisms, we aimed to evaluate intestinal HLA-G expression and soluble HLA-G (sHLA-G) levels in CD/UC patients stratified according to the CD phenotype/localization and UC extension. HLA-G tissue expression was assessed by immunohistochemistry in biopsies collected from 151 patients (90 CD, 61 UC) and in surgical resection specimens (28 CD, 12 UC). Surgical material from 24 healthy controls was also assessed. Plasma sHLA-G levels (97 CD, 81 UC, and 120 controls) were evaluated using ELISA. HLA-G expression was similarly observed in the intestinal epithelial cells of control and CD/UC specimens. However, in biopsies, the plasma cells/lymphocytes infiltrating the lamina propria in CD/UC presented (1) increased HLA-G expression compared to controls (P < 0.0001), (2) greater cell staining in UC cells than in CD cells irrespective of disease extent (P = 0.0011), and (3) an increased number of infiltrating cells in the inflammatory CD phenotype compared to that in the stenosing and fistulizing phenotypes (P = 0.0407). In surgical specimens, CD/UC patients exhibited higher infiltrating cell HLA-G expression in lesion areas than in margins. sHLA-G levels were higher in UC/CD patients (P < 0.0001) than in controls, but no difference was observed between diseases. Increased infiltrating cell HLA-G expression associated with increased sHLA-G levels in CD/UC patients may reflect ongoing host strategies to suppress chronic inflammation.

Distribution and Cytokine Profile of Peripheral B Cell Subsets Is Perturbed in Pediatric IBD and Partially Restored During a Successful IFX Therapy.

The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 µg/g or achieving levels of <10% of the baseline value at initiation than at the end of the 12-month follow-up period. Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients.The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 µg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient's immune system in responding patients. The achievement of an IFX trough level of ~10 µg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.

The Mechanisms of Up-Regulation of K+ Channels in CD4+ T Cells of Inflammatory Bowel Disease

The Mechanisms of Up-Regulation of K+ Channels in CD4+ T Cells of Inflammatory Bowel Disease

Th17 Cells in Inflammatory Bowel Disease: An Update for the Clinician.

Studies in humans strongly implicate Th17 cells in the pathogenesis of inflammatory bowel disease. Thus, Th17 cells are major targets of approved and emerging biologics. Herein, we review the role of Th17 in IBD with a clinical focus.

P095 PD-1 expressing T cells in patients with different types of colitis

Abstract Background Immunotherapy-related colitis is a frequent adverse event in patients with malignancies, treated with inhibitors targeting programmed death-1 (PD-1). This treatment leads to enhancement of lymphocyte activity, thereby generating antitumor T-cell activity. The role of PD-1+ T cells in the pathophysiology of different types of colitis is unclear. Therefore, we aimed to study the presence of PD-1+ T cells in inflammatory bowel disease (IBD), infectious colitis and healthy controls compared with anti-PD-1-related colitis. Methods We performed a prospective cohort study. Newly diagnosed patients with ulcerative colitis (UC, n = 51), Crohn’s disease (CD, n = 29), infectious colitis (n = 4), anti-PD-1-related colitis (n = 5) and healthy controls (n = 6) were included. Baseline colonic biopsy specimens were collected for immunohistochemistry identifying PD-1+ and PD-L1+ lymphocytes in the epithelium and lamina propria separately and for immunophenotyping by flow cytometry identifying PD-1+ T-cell subsets. Results Using immunohistochemistry, PD-1 was not present on lymphocytes in the epithelium of patients with any type of colitis, nor in healthy controls. Of all lymphocytes in the lamina propria, % PD-1 expression was 40% in UC, 5% in infectious colitis, 3% in anti-PD-1-related colitis and 0% in healthy controls. PD-L1 was expressed on lymphocytes in the epithelium and lamina propria of UC patients (12.5% and 40%) and in infectious colitis (1% and 30%), whereas in anti-PD-1-related colitis (0% and 15%) and healthy controls (0% and 15%) no PD-L1+ lymphocytes were demonstrated in the epithelium. Flowcytometry showed higher percentages of PD-1+ T cells in biopsy specimens of UC patients (25.2% (IQR 17.9–35.6)) compared with all other groups; CD patients (13.5% (5.0–25.3), p = 0.001), infectious colitis (9.8% (4.7–17.4), p = 0.005), anti-PD-1-related colitis (1.5% (1.1–2.1), p = 0.001) and healthy controls (14.3% (4.9–28.2), p = 0.08). In IBD and infectious colitis, the majority of PD-1+ T cells were CD4+ (84.8% (76.5–90.5), while in anti-PD-1-related colitis the majority of PD-1+ T cells were CD8+ (76.2% (68.5–82.1)). PD-1+ T cells in all patient groups were mainly effector T cells (CD45Ro+). Conclusion In patients with different types of colitis and in healthy controls, PD-1 was only expressed on T cells in the lamina propria and not in the epithelium. The percentage of PD-1+ T cells was significantly higher in patients with UC compared with patients with CD or infectious colitis and healthy controls. As expected PD-1+ T cells were nearly absent in patients with anti-PD-1-related colitis.

DOP70 High-dimensional analysis reveals a novel signature for IL-17 producing CD8 T cells in inflammatory bowel disease

Abstract Background The pathogenesis of IBD has previously mainly been associated with a dysregulation of CD4 T-cell responses, and active disease is linked to induction of pathogenic IL-17 producing T helper cells. Importantly, CD8 T cells can also produce IL-17 and demonstrate a significant increase in active IBD. However, it remains unclear whether this is due to conventional or unconventional T-cell responses and whether these CD8 responses could play a role as novel biomarkers or therapeutic targets of active IBD. Methods We isolated lymphocytes from the peripheral blood and intestinal tissue of IBD patients (n = 56) and performed a detailed analysis of CD8 T-cell phenotype and function using high-parametric flow cytometry and mass cytometry in combination with algorithm-aided bioinformatic analysis. Results We observe a significant increase in IL-17 production by CD8 T cells in active IBD, primarily produced by conventional CD8 T cells. Unconventional T-cell subsets (e.g. MAIT cells, γδ T cells and NKT cells) represented only ~30% (peripheral blood) or ~25% (intestinal tissue) of IL-17 producing CD8 T cells (Tc17). The mass cytometric analysis identified Tc17 cells as a distinct cell population within the intestinal CD8 T-cell compartment that can be further subdivided into 3 subsets which share expression of phenotypic markers such as CD6, CD39, CD69 and PD1 and a low expression of CD27. This novel signature was validated in a separate cohort of IBD patients. Moreover, at initial IBD diagnosis, the IL-17 signature is associated with flare-free survival in a retrospective cohort analysis based on published transcriptome data. Conclusion Our data indicate that conventional IL-17 producing CD8 T cells are a very distinct cell population that is linked to IBD activity. The identification of a novel IL-17 CD8 signature may help guide treatment decisions as a biomarker and for immunotherapeutic approaches.

P164 HLA G expression is differentially expressed in infiltrating cells in inflammatory bowel disease and in healthy specimens

Abstract Background Since HLA-G is an immune checkpoint molecule and since Crohn’s disease (CD) and ulcerative colitis (UC) exhibit immune-mediated mechanism deregulation, we aimed to evaluate HLA-G intestinal expression and soluble (sHLA-G) levels in CD/UC patients, stratified according to CD phenotype/localisation and UC extension. Methods HLA-G tissue expression was assessed by immunohistochemistry in biopsies collected from 151 patients (90 CD, 61 UC) and 24 healthy controls, and in surgical resections (28 CD, 12 UC). Plasma sHLA-G levels (97 CD, 81 UC and 120 controls) were evaluated using ELISA Results HLA-G expression was observed in intestinal epithelial cells of controls and CD/UC specimens, exhibiting closely similar profiles, and in lamina propria infiltrating cells, exhibiting differential patterns. In biopsies, CD/UC lamina propria plasma cells/lymphocytes presented: i) increased HLA-G expression compared with controls (p &amp;lt; 0.0001), ii) irrespective of the extent, UC cell staining was greater compared with CD cells (p = 0.0011), and iii) the inflammatory CD phenotype presented increased number of infiltrating cells compared with stenosing and fistulizing phenotypes (p = 0.0407). In surgical resections, CD/UC patients exhibited increased infiltrating cell HLA-G expression in lesion areas compared with margins. sHLA-G levels were increased in UC/CD patients (p &amp;lt; 0.0001) when compared with controls, but no difference was observed between patients. Conclusion Increased infiltrating cell HLA-G expression associated with increased sHLA-G levels in CD/UC patients may reflect host on-going strategies to suppress chronic inflammation. References

Analysis of Flagellin-Specific Adaptive Immunity Reveals Links to Dysbiosis in Patients With Inflammatory Bowel Disease.

Background & AimsBacterial flagellin is an important antigen in inflammatory bowel disease, but the role of flagellin-specific CD4+ T cells in disease pathogenesis remains unclear. Also unknown is how changes in intestinal microbiome intersect with those in microbiota-specific CD4+ T cells. We aimed to quantify and characterize flagellin-specific CD4+ T cells in Crohn’s disease (CD) and ulcerative colitis (UC) patients and study their relationship with intestinal microbiome diversity.MethodsBlood was collected from 3 cohorts that included CD patients, UC patients, and healthy controls. Flow cytometry analyzed CD4+ T cells specific for Lachnospiraceae-derived A4-Fla2 and Escherichia coli H18 FliC flagellins, or control vaccine antigens. Serum antiflagellin IgG and IgA antibodies were detected by enzyme-linked immunosorbent assay and stool samples were collected and subjected to 16S ribosomal DNA sequencing.ResultsCompared with healthy controls, CD and UC patients had lower frequencies of vaccine-antigen–specific CD4+ T cells and, as a proportion of vaccine-specific cells, higher frequencies of flagellin-specific CD4+ T cells. The proportion of flagellin-specific CD4+ T cells that were CXCR3negCCR4+CCR6+ Th17 cells was reduced in CD and UC patients, with increased proportions of CD39+, PD-1+, and integrin β7+ cells. Microbiome analysis showed differentially abundant bacterial species in patient groups that correlated with immune responses to flagellin.ConclusionsBoth CD and UC patients have relative increases in the proportion of circulating Fla2-specific CD4+ T cells, which may be associated with changes in the intestinal microbiome. Evidence that the phenotype of these cells strongly correlate with disease severity provides insight into the potential roles of flagellin-specific CD4+ T cells in inflammatory bowel disease.

Mechanism and therapeutic effect of umbilical cord mesenchymal stem cells in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a persistent and chronic disease that is characterized by destructive gastrointestinal (GI) inflammation. Researchers are trying to identify and develop new and more effective treatments with no side effects. Acute and chronic mouse models of IBD were established using dextran sulfate sodium (DSS) solution. To evaluate the efficacy and mechanism, umbilical cord mesenchymal stem cells (UCMSCs) were obtained from Kunming (KM) mice and humans. In the chronic IBD study, the survival rates of the normal control, model, mouse UCMSC (mUCMSC) and human UCMSC (hUCMSC) groups were 100%, 40%, 86.7%, and 100%, respectively. The histopathological scores of the normal control, intraperitoneal injection, intravenous treatment, and model groups were 0.5 ± 0.30, 5.9 ± 1.10, 8.7 ± 1.39, and 8.8 ± 1.33 (p = 0.021). UCMSCs promoted the expression of the intestinal tight junction protein occludin, downregulated the protein expression of the autophagy marker LC3A/B in colon tissue, and upregulated the expression of VEGF-A and VEGFR-1 at the injured site. This study provides an experimental model for elucidating the therapeutic effects of UCMSCs in IBD. We provide a theoretical basis and method for the clinical treatment of IBD using UCMSCs.

Long non-coding RNA CRNDE promotes cell apoptosis by suppressing miR-495 in inflammatory bowel disease

ObjectiveThis article aims to investigate the mechanism of microRNA-495 (miR-495) and long non-coding RNA CRNDE on the apoptosis of colonic epithelial cells in inflammatory bowel diseases (IBDs). MethodsThe mouse model of IBD was induced by dextran sulfate sodium (DSS), and human colonic epithelial cell lines (HT-29, LOVO, and Caco-2) were treated with DSS, and received cell transfection. RNA interference was used to down-regulate CRNDE expression. ResultsCRNDE and SOCS1 were highly expressed, but miR-495 was lowly expressed in the DSS-induced colitis tissues and colonic epithelial cell lines. Interference of CRNDE inhibited cell apoptosis of DSS-induced colonic epithelial cells. The interaction between CRNDE and miR-495 was confirmed by RNA immunoprecipitation and RNA pull-down assay. The target relationship between miR-495 and SOCS1 was confirmed by the luciferase reporter assay. CRNDE promoted DSS-induced colonic epithelial cell apoptosis via miR-495/SOCS1. CRNDE interference in DSS-induced colitis mouse model alleviated clinical manifestations of IBD. ConclusionsOur findings demonstrated that CRNDE promoted DSS-induced colonic epithelial cell apoptosis via suppressing miR-495 and increasing SOCS1, indicating CRNDE as a novel target of treating IBD.

Evaluation of 6-mercaptopurine in a cell culture model of adaptable triple-negative breast cancer with metastatic potential

Progenitor-like cancer cells that can survive in reversible quiescence when faced with various challenges in the body are often behind disease progression. A lack of glutamine in culture medium, which eliminates >99.9% of proliferating SUM149 triple-negative breast cancer cells, selects such adaptable, pan-resistant cells. Our data support the hypothesis that a lack of glutamine forces the selection of an epigenetic state that does not require a high level of TET2, thus selecting an “undifferentiated” therapy-resistant phenotype as seen in TET2-mutant cancers. Our data suggesting that highly adaptable cells are generated through reprograming of the epigenome and transcriptome led us to evaluate low-dose 6-mercaptopurine as a potential therapy in our model. We found that a long treatment with low-dose 6-mercaptopurine inhibited the proliferation of these adaptable cells to a greater extent than it inhibited parental cells. Importantly, a small percentage of adaptable cells survived a low-dose 6-mercaptopurine treatment in a reversible quiescence, analogous to the persistence of abnormal progenitor-like cells in inflammatory bowel disease, which stays in a durable remission with a 6-mercaptopurine treatment. Based on a biomarkers analysis, a long treatment with 6-mercaptopurine or aspirin partially reversed epithelial to mesenchymal transition in adaptable cancer cells. A cell culture model of adaptable cancer cells that persist in the body will help in discovering superior therapies that can be offered before the disease advances to metastasis.

Regulation of CD11b by HIF-1α and the STAT3 signaling pathway contributes to the immunosuppressive function of B cells in inflammatory bowel disease

B cells have been reported to have a suppressive function in autoimmune diseases, which appears to require an increase of CD11b expression on B cells. However, little is known how CD11b is induced in B cells to play the function. In this study, we found that the high expression of CD11b in B cells occurred not only in the mucosal immune organs, but also in systemically immune organs such as the spleen during dextran sulfate sodium (DSS)-induced colitis. Since the inflammatory lesions in mouse models of inflammatory bowel disease (IBD) were revealed to be significantly hypoxic or even anoxic, the B cells from colitic mice Peyer’s patches (PP) were investigated to express higher levels of hypoxia-inducible factor-1α (HIF-1α) than naïve B cells from wildtype (WT) mice. HIF-1α siRNA transfection or HIF-1α protein inhibition led to decreased CD11b expression at both the mRNA and protein levels in vitro. B cells with HIF-1α specific knockdown were then adoptively transferred to Rag-1−/− mice. The result displayed that CD11b expression was decreased in B cells and an exacerbated colitis occurred. The bio-informatics promoter analysis and ChIP assay showed that HIF-1α was the critical transcription factor for CD11b and cooperatively formed a complex with the p-STAT3 homodimers to bind onto hypoxia-responsive element (HRE) regions, which was guaranteed by MEK/ERK pathway activation and IL-10 secretion. In conclusion, our study demonstrated the key function of the hypoxia-associated transcription factor HIF-1α together with p-STAT3 in driving CD11b transcription in B cells and controlling B cell’s protective activity in experimental inflammatory bowel disease (IBD).

Pharmacological effects of TAK-828F: an orally available RORγt inverse agonist, in mouse colitis model and human blood cells of inflammatory bowel disease.

To evaluate the potency of RORγt blockade for treatment of Inflammatory Bowel Disease (IBD), the efficacy of TAK-828F, a novel RORγt inverse agonist, in anti-TNF-α mAb non-responsive mouse colitis model and effect of TAK-828F on IL-17 production in peripheral mononuclear blood cells (PBMCs) of anti-TNF-α naive and treatment-failure patients of IBD was investigated. The colitis model showed Th17-dependent pathogenicity and response to anti-IL-12/23p40 monoclonal antibody (mAb), but no response to anti-TNF-α mAb. In the model, TAK-828F, at oral dosages of 1 and 3mg/kg, inhibited progression of colitis and reduced the immune reaction that characterize Th17 cells. Anti-IL-17A mAb showed neither efficacy nor change in the T cell population and colonic gene expression in the model. In the normal mouse, a 4-week treatment of TAK-828F at 30mg/kg did not severely reduce lymphocyte cell counts in peripheral and intestinal mucosa, which was observed in RORγ-/- mice. TAK-828F strongly inhibited IL-17 gene expression with IC50 values from 21.4 to 34.4nmol/L in PBMCs from anti-TNF mAb naive and treatment-failure patients of IBD. These results indicate that RORγt blockade would provide an effective approach for treating refractory patients with IBD by blocking IL-23/Th17 pathway.

Impact of Autophagy of Innate Immune Cells on Inflammatory Bowel Disease.

Autophagy, an intracellular degradation mechanism, has many immunological functions and is a constitutive process necessary for maintaining cellular homeostasis and organ structure. One of the functions of autophagy is to control the innate immune response. Many studies conducted in recent years have revealed the contribution of autophagy to the innate immune response, and relationships between this process and various diseases have been reported. Inflammatory bowel disease is an intractable disorder with unknown etiology; however, immunological abnormalities in the intestines are known to be involved in the pathology of inflammatory bowel disease, as is dysfunction of autophagy. In Crohn’s disease, many associations with autophagy-related genes, such as ATG16L1, IRGM, NOD2, and others, have been reported. Abnormalities in the ATG16L1 gene, in particular, have been reported to cause autophagic dysfunction, resulting in enhanced production of inflammatory cytokines by macrophages as well as abnormal function of Paneth cells, which are important in intestinal innate immunity. In this review, we provide an overview of the autophagy mechanism in innate immune cells in inflammatory bowel disease.

Protein Tyrosine Phosphatases: Regulators of CD4 T Cells in Inflammatory Bowel Disease.

Protein tyrosine phosphatases (PTPs) play a critical role in co-ordinating the signaling networks that maintain lymphocyte homeostasis and direct lymphocyte activation. By dephosphorylating tyrosine residues, PTPs have been shown to modulate enzyme activity and both mediate and disrupt protein-protein interactions. Through these molecular mechanisms, PTPs ultimately impact lymphocyte responses to environmental cues such as inflammatory cytokines and chemokines, as well as antigenic stimulation. Mouse models of acute and chronic intestinal inflammation have been shown to be exacerbated in the absence of PTPs such as PTPN2 and PTPN22. This increase in disease severity is due in part to hyper-activation of lymphocytes in the absence of PTP activity. In accordance, human PTPs have been linked to intestinal inflammation. Genome wide association studies (GWAS) identified several PTPs within risk loci for inflammatory bowel disease (IBD). Therapeutically targeting PTP substrates and their associated signaling pathways, such as those implicated in CD4+ T cell responses, has demonstrated clinical efficacy. The current review focuses on the role of PTPs in controlling CD4+ T cell activity in the intestinal mucosa and how disruption of PTP activity in CD4+ T cells can contribute to intestinal inflammation.