Inflammatory bowel disease requires the interplay between innate and adaptive immune signals

Inflammatory bowl disease （IBD） is a type 1 T helper cell （Th1）-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progression of this disease. Interestingly, the pathogenesis of IBD has been shown to be related to nitric oxide （NO） released from innate immune cells. Although NO is known to be highly toxic to the gut epithelia, there is very little information about the regulation of NO production, One major question in the etiology of IBD is how Thl cells and pathogens interact in the induction of IBD. In present study, we focused on the regulation of NO. We show that macrophages require both interferon-γ, （IFN-γ）-mediated and TLR4-mediated signals for the production of NO, which causes inflammation in the intestine and subsequently IBD. Thus, IBD is the result of concerted actions of innate immune signals, such as the binding of LPS to TLR-4, and adaptive immune signals, such as IFN-γ produced by Thl cells.     

MiRNAs and inflammatory bowel disease: An interesting new story

Inflammatory bowel disease (IBD), as a chronic and recurrent inflammatory disorder, is caused by a dysregulated and aberrant immune response to exposed environmental factors in genetically susceptible individuals. Despite huge efforts in determining the molecular pathogenesis of IBD, an increasing worldwide incidence of IBD has been reported. MicroRNAs (miRNAs) are a set of noncoding RNA molecules that are about 22 nucleotides long, and these molecules are involved in the regulation of the gene expression. By clarifying the important role of miRNAs in a number of diseases, their role was also considered in IBD; numerous studies have been performed on this topic. In this review, we attempt to summarize a number of studies and discuss some of the recent developments in the roles of miRNAs in the pathophysiology, diagnosis, and treatment of IBD.     

IL-21/IL-21R信号在IBD病变形成机制中作用的研究进展

炎症性肠病(Inflammatory bowel disease,IBD)的发病机制至今尚不明确,普遍认为是由肠黏膜免疫调节异常、持续性肠道感染、肠黏膜屏障缺损、遗传和环境等多种因素相互作用导致的。近年来,研究发现IBD患者血清中IL-21水平异常升高,提示IL-21/IL-21R信号可能在IBD的病变形成中发挥重要作用。IL-21是一种重要的具有多重生物学功能的细胞因子,通过对CD4+T细胞、CD8+T细胞、Th17细胞、B细胞、巨噬细胞、树突状细胞等多种细胞产生影响,从而参与IBD的发生发展。本文就IL-21/IL-21R信号在炎症性肠病发病机制中的研究进展进行综述。     

Somatostatin in inflammatory bowel disease

Intestinal inflammation is controlled by various immunomodulating cells, interacting by molecular mediators. Neuropeptides, released by enteric nerve cells and neuroendocrine mucosa cells, are able to affect several aspects of the general and intestinal immune system, with both pro- as well as anti-inflammatory activities. In inflammatory bowel disease (IBD) there is both morphological as well as experimental evidence for involvement of neuropeptides in the pathogenesis. Somatostatin is the main inhibitory peptide in inflammatory processes, and its possible role in IBD is discussed.     

Inflammatory bowel disease - glycomics perspective

BackgroundInflammatory bowel disease (IBD) pathogenesis is still not well understood. It is considered to result from genetic susceptibility, environment, microbiota composition and aberrant immune response. Crohn's disease (CD) and ulcerative colitis (UC), forms of IBD, are sometimes indistinguishable by typical laboratory and clinical characteristics making timely diagnosis and subsequent therapy hit-and-miss. Glycosylation has shown a promising biomarker potential for early IBD diagnosis and effective response to treatment prediction.Scope of reviewThis mini-review briefly covers present knowledge of IBD pathophysiology, with a focus on recent research on the role of glycosylation in IBD pathogenesis and disease progression.Major conclusionsAberrant glycosylation significantly changes functionality of key proteins in intestinal niche and is involved in IBD etiology.General significanceElucidating mechanisms of IBD development is one of critical goals in managing this disease. Glycans are important for fine-tuning of intestinal processes that ensure homeostatic conditions which, if disrupted, lead to IBD.     

Immunology of inflammatory bowel diseases.

The pathogenesis of inflammatory diseases involves complex interactions among genetic, environmental and immunologic factors, where the immune system plays a crucial role. The initiating factor may be a commonly present environmental antigen, but the defective mucosal immune response can't downregulate the inflammatory process, the resulting in chronic inflammation and tissue damage. The abnormal amplification of the immune system seems more likely to be a secondary and not a primary factor in the disease. IBD patients exhibit abnormalities in epithelial antigen presentation, and in the cellular and humoral immune system. The role of autoimmunity is unclear in IBD. The inflammatory mediator production and balance is also altered in IBD. Crohn's disease is characterised by a Th1 cytokine profile, while ulcerative colitis is characterised rather by a Th2 cytokine profile. Recent advances in the understanding of the pathogenesis of IBD led to major changes in the treatment of the disease. The newer agents target the key mediators involved in the inflammatory process.     

NKX2-3 transcriptional regulation of endothelin-1 and VEGF signaling in human intestinal microvascular endothelial cells

BACKGROUND: NKX2-3 is associated with inflammatory bowel disease (IBD). NKX2-3 is expressed in microvascular endothelial cells and the muscularis mucosa of the gastrointestinal tract. Human intestinal microvascular endothelial cells (HIMECs) are actively involved in the pathogenesis of IBD and IBD-associated microvascular dysfunction. To understand the cellular function of NKX2-3 and its potential role underlying IBD pathogenesis, we investigated the genes regulated by NKX2-3 in HIMEC using cDNA microarray. METHODOLOGY/PRINCIPAL FINDINGS: NKX2-3 expression was suppressed by shRNA in two HIMEC lines and gene expression was profiled by cDNA microarray. Pathway Analysis was used to identify gene networks according to biological functions and associated pathways. Validation of microarray and genes expression in intestinal tissues was assessed by RT-PCR. NKX2-3 regulated genes are involved in immune and inflammatory response, cell proliferation and growth, metabolic process, and angiogenesis. Several inflammation and angiogenesis related signaling pathways that play important roles in IBD were regulated by NKX2-3, including endothelin-1 and VEGF-PI3K/AKT-eNOS. Expression levels of NKX2-3, VEGFA, PI3K, AKT, and eNOS are increased in intestinal tissues from IBD patients and expression levels of EDN1 are decreased in intestinal tissues from IBD patients. These results demonstrated the important roles of NKX2-3, VEGF, PI3K, AKT, eNOS, and EDN1 in IBD pathogenesis. Correlation analysis showed a positive correlation between mRNA expression of NKX2-3 and VEGFA and a negative correlation between mRNA expression of NKX2-3 and EDN1 in intestinal tissues from IBD patients. CONCLUSION/RELEVANCE: NKX2-3 may play an important role in IBD pathogenesis by regulating endothelin-1 and VEGF signaling in HIMECs.     

Intermittent administration of a fasting-mimicking diet reduces intestinal inflammation and promotes repair to ameliorate inflammatory bowel disease in mice

Recent studies have revealed that calorie restriction is able to modulate immune system and aid in intervention of immune disorders. Inflammatory bowel disease (IBD) is an immune disease in the intestine caused by interplay between genetic susceptibility and environmental factors such as diets. Here we analyzed the therapeutic effect of intermittent calorie restriction with a fasting-mimicking diet (FMD) on dextran sodium sulfate (DSS)-induced chronic IBD model in mice. Two cycles of FMD was administered after IBD symptoms occurred in the mice. FMD administration significantly reduced the score of disease activity index. FMD reversed DSS-mediated shortening of colon length, infiltration of lymphocytes in the crypt of colon, and accumulation of CD4⁺ cells in the colon and small intestine. The expression of an inflammation marker NLRP3 was also reduced by FMD administration. The percentage of CD4⁺ T cells in both peripheral blood and spleen was also reduced by FMD. In addition, FMD application reversed DSS-mediated reduction in intestinal stem cell marker Lgr5, while the cell proliferation markers Ki67 and PCNA were increased by FMD. Taken together, these results indicate that in the mouse model of IBD, application of the FMD can effectively ameliorate the symptoms and pathogenesis of IBD through reducing the inflammation of intestine and promoting the regeneration and repair of the damaged intestinal epithelium.     

Intestinal mast cells in gut inflammation and motility disturbances

Mast cells may be regarded as prototypes of innate immune cells that can be controlled by neuronal mediators. Their activation has been implicated in many types of neuro-inflammatory responses, and related disturbances of gut motility, via direct or indirect mechanisms that involve several mechanisms relevant to disease pathogenesis such as changes in epithelial barrier function or activation of adaptive or innate immune responses. Here we review the evidence for the involvement of mast cells in the inflammation of the bowel wall caused by bowel manipulation that leads to motility disturbances such as postoperative gastroparesis and ileus. Also in IBD there is substantial evidence for the involvement of mast cells and a mast cell-mediated neuroimmune interaction showing an increased number and an increased degranulation of mast cells. We discuss the potential of mast cell inhibition as a bona fide drug target to relief postoperative ileus. Further research on mast cell-related therapy either by stabilizing the mast cells or by blocking specific mast cell mediators as adjunctive therapy in IBD is encouraged, bearing in mind that several drugs currently used in the treatment of IBD possess properties affecting mast cell activities. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Biological functions of NLRP3 inflammasome: A therapeutic target in inflammatory bowel disease

Cases of inflammatory bowel disease (IBD), a debilitating intestinal disorder with complex pathological mechanisms, have been increasing in recent years, straining the capacity of healthcare systems. Thus, novel therapeutic targets and innovative agents must be developed. Notably, the NLRP3 inflammasome is upregulated in patients with IBD and/or in animal experimental models. As an innate immune supramolecular assembly, the NLRP3 inflammasome is persistently activated during the pathogenesis of IBD by multiple stimuli. Moreover, this protein complex regulates pro-inflammatory cytokines. Thus, targeting this multiprotein oligomer may offer a feasible way to relieve IBD symptoms and improve clinical outcomes. The mechanisms by which the NLRP3 inflammasome is activated, its role in IBD pathogenesis, and the drugs administered to target this protein complex are reviewed herein. This review establishes that the use of inflammasome-targeting drugs are effective for IBD treatment. Moreover, this review suggests that the value and potential of naturally sourced or derived medicines for IBD treatment must be recognized and appreciated.     

A novel function of the herpes simplex virus type 1 Fc receptor: participation in bipolar bridging of antiviral immunoglobulin G

We describe a novel function of the Fc receptor of herpes simplex virus type 1 (HSV-1), its ability to participate in antibody bipolar bridging. This refers to the binding of a single immunoglobulin G (IgG) molecule by its Fab end to its antigenic target and by its Fc end to an Fc receptor (FcR). We demonstrate that various immune IgG antibodies, including polyclonal rabbit antibodies to HSV-1 glycoproteins gC1 and gD1 and monoclonal human antibody to gD1 blocked rosetting of IgG-coated erythrocytes at IgG concentrations 100- to 2,000-fold lower than required for rosette inhibition with nonimmune IgG. Steric hindrance did not account for the observed differences between immune and nonimmune IgG since rabbit anti-gC1 F(ab')2 fragments did not block rosetting. Murine anti-gC1 or anti-gD1 IgG, a species of IgG incapable of binding by its Fc end to the HSV-1 FcR, also did not block rosetting. When cells were infected with a gC1-deficient mutant, anti-gC1 IgG inhibited rosetting to the same extent as nonimmune IgG. This indicates that binding by the Fab end of the IgG molecule was required for maximum inhibition of rosetting. Bipolar bridging was shown to occur even when small concentrations of immune IgG were present in physiologic concentrations of nonimmune IgG. The biologic relevance of antibody bipolar bridging was evaluated by comparing antibody- and complement-dependent virus neutralization of an FcR-negative mutant and its parent HSV-1 strain. By engaging the Fc end of antiviral IgG, the parent strain resisted neutralization mediated by the classical complement pathway. These observations provide insight into the role of the HSV-1 FcR in pathogenesis and may help explain the function of FcR detected on other microorganisms.     

核酸药物及其给药系统用于炎症性肠病治疗的研究进展

炎症性肠病是一种常见的免疫功能紊乱所致慢性顽固性胃肠道炎性疾病,现有的治疗手段难以根治。随着炎症性肠病分子机制研究的不断深入,在基因水平上应用核酸药物及其给药系统,对炎症性肠病发挥的独特治疗作用,已受到越来越多的关注, 并取得一定进展。本文简介炎症性肠病的发病机制,综述近年来核酸药物及其给药系统用于炎症性肠病治疗的研究进展。     

Carcinoembryonic antigen (CEACAM) family members and Inflammatory Bowel Disease

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic intestinal inflammatory condition with increasing incidence worldwide and whose pathogenesis remains largely unknown. The collected evidence indicates that genetic, environmental and microbial factors and a dysregulated immune response are responsible for the disease. IBD has an early onset and long term sufferers present a higher risk of developing colitis associated cancer (CAC). The carcinoembryonic antigen-related adhesion molecules (CEACAM) are a subgroup of the CEA family, found in a range of different cell types and organs including epithelial cells in the intestine. They can act as intercellular adhesions molecules for e.g. bacteria and soluble antigens. CEACAMs are involved in a number of different processes including cell adhesion, proliferation, differentiation and tumour suppression. Some CEACAMs such as CEACAM1, CEACAM5 and CEACAM6 are highly associated with cancer and are even recognised as valid clinical markers for certain cancer forms. However, their role in IBD pathogenesis is less understood. The purpose of this review is to provide a comprehensive summary of published literature on CEACAMs and intestinal inflammation (IBD). The interactions between CEACAMs and bacteria adhesion in relation to IBD pathophysiology will be addressed and potential new therapeutic and diagnostic opportunities will be identified.     

Characterization of human cytotoxic lymphocytes directed against cells infected with typhus group rickettsiae: evidence for lymphokine activation of effectors

An in vitro culture and assay system was used to determine whether cytotoxic lymphocytes are generated in humans after rickettsial infection. Peripheral blood mononuclear cells (PBMC) were obtained from six individuals with serologic evidence of prior infection with typhus group rickettsiae and from six nonimmune individuals. After PBMC from immune individuals were stimulated in vitro for 7 days with rickettsial antigen, they were capable of lysing typhus group rickettsia-infected, autologous phytohemagglutinin (PHA)-induced blasts, but not uninfected PHA-blasts. No cytotoxic effector cells were generated when either PBMC from immune individuals were placed in culture for 7 days without antigenic stimulation, or when PBMC from nonimmune individuals were stimulated in vitro with antigen for 7 days. Freshly isolated PBMC from immune donors were also unable to lyse typhus group rickettsia-infected autologous PHA-blasts or an autologous rickettsia-infected lymphoblastoid cell line (LCL). Neither supernatants from antigen-stimulated cultures of PBMC from immune donors nor recombinant human interferon-gamma were capable of significantly lysing typhus group rickettsia-infected PHA blasts by this assay. Populations of cytotoxic effector cells depleted of OKT3, OKT4, or OKT8-positive cells by treatment with the respective monoclonal antibodies and complement were assayed for their cytotoxic capacity. The results suggest that the cytotoxic effector cell population is predominantly OKT3 and OKT8-positive, but OKT4-negative. Positive selection with the use of a fluorescence-activated cell sorter also suggested that most of the cytotoxic effector cells are OKT8-positive. PBMC from immune donors after in vitro stimulation with rickettsial antigen were capable of significantly lysing infected autologous LCL or infected HLA-mismatched LCL as compared with the respective uninfected controls. In addition, PBMC from either immune donors or nonimmune donors after stimulation in vitro for 7 days with media containing purified lymphokines were capable of significantly lysing autologous infected LCL as compared with the uninfected autologous control. We conclude that lysis of cells infected with typhus group rickettsiae is mediated by a lymphokine-activated killer.     

Antibody-dependent harmful effect of non-immune spleen cells in acute experimental tick-borne encephalitis in mice

The injection of nonprotective dilutions of immune serum and nonimmune spleen cells into mice infected with tick-borne encephalitis virus induced a sharply pronounced immunopathological effect: the mean survival time of the recipients decreased by 3.6 days in comparison with the control animals. This effect was not linked with the increased replication of the virus in the brain. The antibody-dependent damaging action of spleen cells could be reproduced by using the cells of both syngeneic and allogeneic donors. This phenomenon developed only in those cases when antibodies to the infective agent under study were used. The combination of immune serum to Japanese encephalitis virus and nonimmune spleen cells produced no damaging effect. The hypothesis stating that the antibody-dependent damaging action of nonimmune spleen cells arises from the antibody-dependent cytotoxic action of immunocompetent cells on the infected cells of the central nervous system is discussed.     

Roles of microRNAs in inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract that mainly affects young people. IBD is associated with various gastrointestinal symptoms, and thus, affects the quality of life of patients. Currently, the pathogenesis of IBD is poorly understood. Although intestinal bacteria and host immune response are thought to be major factors in its pathogenesis, a sufficient explanation of their role in its pathophysiologic mechanism has not been presented. MicroRNAs (miRNAs), which are small RNA molecules that regulate gene expression, have gained attention as they are known to participate in the molecular interactions of IBD. Recent studies have confirmed the important role of miRNAs in targeting certain molecules in signaling pathways that regulate the homeostasis of the intestinal barrier, inflammatory reactions, and autophagy of the intestinal epithelium. Several studies have identified the specific miRNAs associated with IBD from colon tissues or serum samples of IBD patients and have attempted to use them as useful diagnostic biomarkers. Furthermore, some studies have attempted to treat IBD through intracolonic administration of specific miRNAs in the form of nanoparticle. This review summarizes the latest findings on the role of miRNAs in the pathogenesis, diagnosis, and treatment of IBD.     

Lysis of P3HR-1 cells induced to enter the viral cycle by antibody-dependent and independent immunological mechanisms

The P3HR-1 Burkitt lymphoma line carries the Epstein-Barr virus (EBV) genome and a small proportion of the cells (1-3%) enter the lytic cycle spontaneously. Treatment with TPA and n-butyrate elevates considerably the number of virus-producing cells (25-35%). Cells which enter the lytic cycle express the EBV early antigen EA, the viral capsid antigen VCA, and the membrane antigen MA. Antibodies against these antigens are present in EBV-immune human sera. The expression of virus envelope protein on the plasma membrane renders the cells sensitive to immune effector mechanisms. These were shown to be initiated by the alternative complement pathway (ACP)-activating capacity of the cells and by their reactivity with antibodies directed to the MA. When incubated with EBV-immune or nonimmune human serum, the induced (P3HR-1-V) cells activated C3 through ACP and fixed the generated C3 fragments. The efficiency of opsonization was higher in immune serum. By varying the experimental conditions we showed the damage of the induced cells by the complement system and by blood lymphocytes, and analysed the involvement of antibodies and the activated C3 fragments in the lymphocyte-mediated lysis. P3HR-1-V cells were lysed by immune serum and also by nonimmune serum though with lower efficiency. The induced cells had elevated sensitivity to the NK effect which was potentiated if the conditions allowed their opsonization. In the presence of antibodies the lymphocyte-mediated lysis was considerably higher and the ADCC mechanism was also potentiated by opsonization. These experiments suggest that B cells which enter the virus-producing cycle may be eliminated in EBV nonimmune host by NK cells. After the antibody response against the virus develops, the attack on these cells is more efficient through complement and lymphocyte-mediated antibody-dependent mechanisms. These effector mechanisms are enhanced by opsonization which is the consequence of the C3-activating capacity of the cells. The multiple ways of the immune attack on the B cells prepared to produce EBV may explain the absence of EA and VCA positive B cells in tumor cell populations and during the acute phase of infectious mononucleosis.