Immunopathology of inflammatory bowel disease

Inflammatory bowel disease(IBD)results from a complex series of interactions between susceptibility genes,the environment,and the immune system.The host microbiome,as well as viruses and fungi,play important roles in the development of IBD either by causing inflammation directly or indirectly through an altered immune system.New technologies have allowed researchers to be able to quantify the various components of the microbiome,which will allow for future developments in the etiology of IBD.Various components of the mucosal immune system are implicated in the pathogenesis of IBD and include intestinal epithelial cells,innate lymphoid cells,cells of the innate(macrophages/monocytes,neutrophils,and dendritic cells)and adaptive(T-cells and B-cells)immune system,and their secreted mediators(cytokines and chemokines).Either a mucosal susceptibility or defect in sampling of gut luminal antigen,possibly through the process of autophagy,leads to activation of innate immune response that may be mediated by enhanced toll-like receptor activity.The antigen presenting cells then mediate the differentiation of na?ve T-cells into effector T helper(Th)cells,including Th1,Th2,and Th17,which alter gut homeostasis and lead to IBD.In this review,the effects of these components in the immunopathogenesis of IBD will be discussed.     

Recent progress on the role of gut microbiota in the pathogenesis of inflammatory bowel disease

In recent years investigations of inflammatory bowel disease (IBD) have advanced rapidly with regard to the relationship between the host immune response and gut microbiota. Patients with IBD have been shown to have an abnormal composition of gut microbiota and host immune dysregulation. Abnormal components of gut microbiota, to which the host mounts aberrant immune responses in genetically vulnerable individuals, appear to play a critical role in the pathogenesis of IBD. Therefore, inappropriate innate and adaptive host immune responses to abnormal components of gut microbiota and their products form the basis of IBD pathogenesis. Modern molecular genetic methods should be utilized to help to illuminate the pathogenetic mechanism of IBD and to develop personalized therapeutic strategies for this disease.     

Contribution of the IL-17/IL-23 axis to the pathogenesis of inflammatory bowel disease

Inflammatory bowel diseases(IBDs) are chronic disorders of modern society, requiring management strategies aimed at prolonging an active life and establishing the exact etiology and pathogenesis.These idiopathic diseases have environmental, genetic,immunologic, inflammatory, and oxidative stress components. On the one hand, recent advances have shown that abnormal immune reactions against the microorganisms of the intestinal flora are responsible for the inflammation in genetically susceptible individuals. On the other hand, in addition to T helper cell-type(Th) 1 and Th2 immune responses,other subsets of T cells, namely regulatory T cells and Th17 maintained by IL-23 are likely to develop IBD. IL-23 acts on innate immune system members and also facilitates the expansion and maintenance of Th17 cells. The IL-17/IL-23 axis is relevant in IBD pathogenesis both in human and experimental studies. Novel biomarkers of IBD could be calprotectin,microRNAs, and serum proinflammatory cytokines.An efficient strategy for IBD therapy is represented by the combination of IL-17 A and IL-17 F in acute IL-17 A knockout TNBS-induced colitis, and also definite decrease of the inflammatory process in IL-17 F knockout, DSS-induced colitis have been observed.Studying the correlation between innate and adaptive immune systems, we hope to obtain a focused reviewin order to facilitate future approaches aimed at elucidating the immunological mechanisms that control gut inflammation.     

Role of the gut microbiota in inflammatory bowel disease pathogenesis: What have we learnt in the past 10 years?

Our understanding of the microbial involvement in inflammatory bowel disease(IBD) pathogenesis has increased exponentially over the past decade. The development of newer molecular tools for the global assessment of the gut microbiome and the identification of nucleotide-binding oligomerization domain-containing protein 2 in 2001 and other susceptibility genes for Crohn’s disease in particular has led to better understanding of the aetiopathogenesis of IBD. The microbial studies have elaborated the normal composition of the gut microbiome and its perturbations in the setting of IBD. This altered microbiome or "dysbiosis" is a key player in the protracted course of inflammation in IBD. Numerous genome-wide association studies have identified further genes involved in gastrointestinal innate immunity(including polymorphisms in genes involved in autophagy: ATG16L1 and IGRM), which have helped elucidate the relationship of the local innate immunity with the adjacent luminal bacteria. These developments have also spurred the search for specific pathogens which may have a role in the metamorphosis of the gut microbiome from a symbiotic entity to a putative pathogenic one. Here we review advances in our understanding of microbial involvement in IBD pathogenesis over the past 10 years and offer insight into how this will shape our therapeutic management of the disease in the coming years.     

Deregulation of intestinal anti-microbial defense by the dietary additive,maltodextrin

Inflammatory bowel disease (IBD) is a complex, multi-factorial disease thought to arise from an inappropriate immune response to commensal bacteria in a genetically susceptible person that results in chronic, cyclical, intestinal inflammation. Dietary and environmental factors are implicated in the initiation and perpetuation of IBD; however, a singular causative agent has not been identified. As of now, the role of environmental priming or triggers in IBD onset and pathogenesis are not well understood, but these factors appear to synergize with other disease susceptibility factors. In previous work, we determined that the polysaccharide dietary additive, maltodextrin (MDX), impairs cellular anti-bacterial responses and suppresses intestinal anti-microbial defense mechanisms. In this addendum, we review potential mechanisms for dietary deregulation of intestinal homeostasis, postulate how dietary and genetic risk factors may combine to result in disease pathogenesis, and discuss these ideas in the context of recent findings related to dietary interventions for IBD.     

Current view of the immunopathogenesis in inflammatory bowel disease and its implications for therapy

Although the aetiology of inflammatory bowel disease （IBD） remains unknown, the pathogenesis is gradually being unravelled, seeming to be the result of a combination of environmental, genetic, and immunological factors in which an uncontrolled immune response within the intestinal lumen leads to inflammation in genetically predisposed individuals. Multifactorial evidence suggests that a defect of innate immune response to microbial agents is involved in IBD. This editorial outlines the immunopathogenesis of IBD and their current and future therapy. We present IBD as a result of dysregulated mucosal response in the intestinal wall facilitated by defects in epithelial barrier function and the mucosal immune system with excessive production of cytokines growth factors, adhesion molecules, and reactive oxygen metabolites, resulting in tissue injury. Established and evolving therapies are discussed in the second part of this editorial and at the end of this section we review new therapies to modulate the immune system in patients with IBD.     

Inflammatory bowel disease: review from the aspect of genetics

Regardless of how inflammatory bowel disease (IBD) is defined, the term “genetic susceptibility” is always included. Due to substantial progress in the characterization of susceptible genes that interact with environmental influences, a number of review articles offering the latest insights continue to be presented. To date, more than 30 novel IBD susceptible loci have been found, while several promising associations between IBD and gene variants have also been identified and replicated effectively. The present review highlights recent insights regarding linkage analysis and genome-wide association presented in studies of IBD susceptible genes, which provide additional evidence supporting their involvement in disease pathogenesis, based on linking to innate immune systems as a result of interactions with intestinal microbial flora. An improved understanding of IBD genetics will promote the identification of novel therapeutic agents, making it possible to identify environmental factors related to intestinal inflammation.     

Inflammatory bowel disease: Established and evolving considerations on its etiopathogenesis and therapy

Modern studies of inflammatory bowel disease (IBD) pathogenesis have been pursued for about four decades, a period of time where the pace of progress has been steadily increasing. This progress has occurred in parallel with and is largely due to developments in multiple basic scientific disciplines that range from population and social studies, genetics, microbiology, immunology, biochemistry, cellular and molecular biology, and DNA engineering. From this cumulative and constantly expanding knowledge base the fundamental pillars of IBD pathogenesis appear to have been identified and consolidated during the last couple of decades. Presently there is a general consensus among basic IBD investigators that both Crohn's disease (CD) and ulcerative colitis (UC) are the result of the combined effects of four basic components: global changes in the environment, the input of multiple genetic variations, alterations in the intestinal microbiota, and aberrations of innate and adaptive immune responses. There is also agreement on the conclusion that none of these four components can by itself trigger or maintain intestinal inflammation. A combination of various factors, and most likely of all four factors, is probably needed to bring about CD or UC in individual patients, but each patient or set of patients seems to have a different combination of alterations leading to the disease. This would imply that different causes and diverse mechanisms underlie IBD, and this could also explain why every patient displays his or her own clinical manifestations and a personalized response to therapy, and requires tailored approaches with different medications. While we are becoming increasingly aware of the importance of this individual variability, we have only a superficial notion of the reasons why this occurs, as hinted by the uniqueness of the genetic background and of the gut flora in each person. So, we are apparently facing the paradox of having to deal with the tremendous complexity of the mechanisms responsible for chronic intestinal inflammation in the setting of each patient's individuality in the response to this biological complexity. This obviously poses considerable challenges to reaching a full understanding of IBD pathogenesis, but being aware of the difficulties is the first step in finding answers to them.     

Etiopathogenesis of inflammatory bowel diseases

Theories explaining the etiopathogenesis of inflammatory bowel disease (IBD) have been proposed ever since Crohn's disease (CD) and ulcerative colitis (UC) were recognized as the two major forms of the disease. Although the exact cause(s) and mechanisms of tissue damage in CD and UC have yet to be completely understood, enough progress has occurred to accept the following hypothesis as valid: IBD is an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. Among an almost endless list of environmental factors, smoking has been identified as a risk factor for CD and a protective factor for UC. Among microbial factors, no convincing evidence indicates that classical infectious agents cause IBD, while mounting evidence points to an abnormal immune response against the normal enteric flora as being of central importance. Gut inflammation is mediated by cells of the innate as well as adaptive immune systems, with the additional contribution of non-immune cells, such as epithelial, mesenchymal and endothelial cells, and platelets.     

Lymphocyte homing and its role in the pathogenesis of IBD

Inflammatory bowel disease (IBD) is an idiopathic disorder of chronic inflammation of the gastrointestinal tract. Experimental models of IBD and results from human genomewide linkage studies suggest that the primary defect that leads to IBD is an inappropriate mucosal immune response to normal intestinal microbes. Genetic alterations not only confer increased susceptibility to IBD but also appear to determine the nature and location of the intestinal inflammation, as is evident in patients with genetic alterations of NOD2 and their susceptibility for ileal Crohn's disease. IBD has traditionally been classified into 2 subtypes, namely, ulcerative colitis (UC) and Crohn's disease (CD), based on histological appearance and anatomical distribution. However, an increasing body of data supports the concept that IBD is an umbrella diagnosis encompassing a variety of disorders with distinct genetic, microbial, and environmental determinants that cluster either into a UC or CD phenotype. The shared common pathway is uncontrolled intestinal inflammation. A key element in the pathogenesis of intestinal inflammation in both UC and CD is increased leukocyte recruitment from the circulation, and this provides a potential target for pharmaceutical inhibition. In this article we review the current understanding of the molecules that determine leukocyte trafficking to the gut and highlight opportunities where their inhibition could be exploited to treat IBD.(Inflamm Bowel Dis 2008).     

Role of cytokines in inflammatory bowel disease

Inflammatory bowel disease （IBD）, which includes Crohn’s disease （CD） and ulcerative colitis （UC）, rep- resents a group of chronic disorders characterized by inflammation of the gastrointestinal tract, typically with a relapsing and remitting clinical course. Mucosal mac- rophages play an important role in the mucosal im- mune system, and an increase in the number of newly recruited monocytes and activated macrophages has been noted in the inflamed gut of patients with IBD. Activated macrophages are thought to be major con- tributors to the production of inflammatory cytokines in the gut, and imbalance of cytokines is contributing to the pathogenesis of IBD. The intestinal inflammation in IBD is controlled by a complex interplay of innate and adaptive immune mechanisms. Cytokines play a key role in IBD that determine T cell differentiation of Th1, Th2, T regulatory and newly described Th17 cells. Cytokines levels in time and space orchestrate the development, recurrence and exacerbation of the inflammatory process in IBD. Therefore, several cyto- kine therapies have been developed and tested for the treatment of IBD patients.     

Roles of G protein-coupled receptors in inflammatory bowel disease

Inflammatory bowel disease(IBD) is a complex disease with multiple pathogenic factors. Although the pathogenesis of IBD is still unclear, a current hypothesis suggests that genetic susceptibility, environmental factors, a dysfunctional immune system, the microbiome, and the interactions of these factors substantially contribute to the occurrence and development of IBD. Although existing and emerging drugs have been proven to be effective in treating IBD,none can cure IBD permanently. G protein-coupled receptors(GPCRs) are critical signaling molecules implicated in the immune response, cell proliferation,inflammation regulation and intestinal barrier maintenance. Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases, thereby leading to the development of GPCR-targeted medication. To date, a number of GPCRs have been shown to be associated with IBD, significantly advancing the drug discovery process for IBD. The associations between GPCRs and disease activity, disease severity, and disease phenotypes have also paved new avenues for the precise management of patients with IBD. In this review, we mainly focus on the roles of the most studied proton-sensing GPCRs, cannabinoid receptors,and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.     

Deregulation of intestinal anti-microbial defense by the dietary additive,maltodextrin

Inflammatory bowel disease (IBD) is a complex, multi-factorial disease thought to arise from an inappropriate immune response to commensal bacteria in a genetically susceptible person that results in chronic, cyclical, intestinal inflammation. Dietary and environmental factors are implicated in the initiation and perpetuation of IBD; however, a singular causative agent has not been identified. As of now, the role of environmental priming or triggers in IBD onset and pathogenesis are not well understood, but these factors appear to synergize with other disease susceptibility factors. In previous work, we determined that the polysaccharide dietary additive, maltodextrin (MDX), impairs cellular anti-bacterial responses and suppresses intestinal anti-microbial defense mechanisms. In this addendum, we review potential mechanisms for dietary deregulation of intestinal homeostasis, postulate how dietary and genetic risk factors may combine to result in disease pathogenesis, and discuss these ideas in the context of recent findings related to dietary interventions for IBD.     

Autoantibodies and an immune-based rat model of inflammatory bowel disease

The exact causes of inflammatory bowel disease(IBD)are not yet fully defined.From a vast body of literature,we know that the immune response has long been involved in the pathogenesis of IBD,including both ulcerative colitis and Crohn’s disease.A variety of specific alterations can lead to immune activation and inflammation directed to the colon,as revealed by some animal models.Current research has focused on the role of antibodies in downstream events and mechanisms of autoimmunity and inflammation.It is not well known whether the production of antibodies is a serologic consequence of IBD,or if it is a result of barrier dysfunction induced by inflammation.Here,we present a new hypothesis to distinguish the complex links between genetic susceptibility,barrier dysfunction,commensal and pathologic microbial factors and inflammatory response(especially autoantibodies)in the pathogenesis of IBD.To ascertain the hypothesis,we developed a pilot model with the concept of the presence of antibodies against enteric bacterial antigens in IBD.Results confirmed our hypothesis.Our hypothesis suggests the possibility of subcutaneous vaccination of animals with administration of all or specific enteric bacterial antigens.     

Novel genetic markers in inflammatory bowel disease

Genetic factors play a significant role in determining inflammatory bowel disease （IBD） susceptibility. Epidemiologic data support genetic contribution to the pathogenesis of IBD, which include familial aggregation, twin studies, racial and ethnic differences in disease prevalence. Linkage studies have identified several susceptibility genes contained in different genomic regions named IBD1 to IBD9. Nucleotide oligomerization domain （NOD2） and human leukocyte antigen （HLA） genes are the most extensively studied genetic regions （IBD1 and IBD3 respectively） in IBD. Mutations of the NOD2 gene are associated with Crohn＇s disease （CD） and several HLA genes are associated with ulcerative colitis （UC） and CD. Toll like receptors （TLRs） have an important role in the innate immune response against infections by mediating recognition of pathogen-associated microbial patterns. Studying single-nucleotide polymorphisms （SNPs） in molecules involved in bacterial recognition seems to be essential to define genetic backgrounds at risk of IBD. Recently, numerous new genes have been identified to be involved in the genetic susceptibility to IBD： NOD1/Caspase-activation recruitment domains 4 （CARD4）, Chemokine ligand 20 （CCL20）, IL-11, and IL-18 among others. The characterization of these novel genes potentially will lead to the identification of therapeutic agents and clinical assessment of phenotype and prognosis in patients with IBD.     

Etiopathogenesis of inflammatory bowel diseases

Theories explaining the etiopathogenesis of inflammatory bowel disease (IBD) have been proposed ever since Crohn's disease (CD) and ulcerative colitis (UC) were recognized as the two major forms of the disease. Although the exact cause(s) and mechanisms of tissue damage in CD and UC have yet to be completely understood, enough progress has occurred to accept the following hypothesis as valid: IBD is an inappropriate immune response that occurs in genetically susceptible individuals as the result of a complex interaction among environmental factors, microbial factors, and the intestinal immune system. Among an almost endless list of environmental factors, smoking has been identified as a risk factor for CD and a protective factor for UC. Among microbial factors, no convincing evidence indicates that classical infectious agents cause IBD, while mounting evidence points to an abnormal immune response against the normal enteric flora as being of central importance. Gut inflammation is mediated by cells of the innate as well as adaptive immune systems, with the additional contribution of non-immune cells, such as epithelial, mesenchymal and endothelial cells, and platelets.     

Genetics of inflammatory bowel diseases: A comparison between Western and Eastern perspectives

Inflammatory bowel disease (IBD) is a chronic relapsing intestinal inflammatory disorder with unidentified causes. Currently, studies indicate that IBD results from a complex interplay between various genetic and environmental factors that produce intestinal inflammation. However, these factors may differ for Asians and Caucasians. Thus, differences in epidemiology, genetic variants, and clinical phenotypes of IBD have been observed between the two populations. Understanding the discrepancies between data from populations with different genetic backgrounds and environmental factors may reveal fundamental aspects of IBD pathogenesis. Accordingly, this review will summarize the current knowledge of IBD genetics studied in Asian countries and compare it with that from Western countries, with special focus on innate bacterial sensing, autophagy, and the interleukin‐23 receptor‐T helper cell 17 pathway. The epigenetic nature of IBD pathogenesis as well as the pharmacogenetics related to the use of immunomodulators will also be briefly covered.     

Innate and adaptive immune responses related to IBD pathogenesis

Although the adaptive immune system traditionally has been the primary focus of investigations into the pathogenesis of inflammatory bowel disease (IBD), it is now clear that innate immune responses play an equally important, or perhaps even primary, role in disease initiation. Intestinal barrier function defects and genetic associations with the nucleotide-binding oligomerization domain and Toll-like receptor pathways suggest that the innate immune system has failed to protect the host against the vast array of commensal bacteria in the gut. This hypothesis is supported further by the observation that probiotic agents exert anti-inflammatory effects in the intestine through stimulation, rather than suppression, of the mucosal innate immune system. Moreover, it is now clear that adaptive immune responses involved in IBD pathogenesis are more complex than the traditionally dichotomous Th1/Th2 paradigm. Finally, mounting evidence suggests that the Th17 effector pathway may contribute to Crohn’s disease pathogenesis.     

Growth Factors as Treatment for Inflammatory Bowel Disease: A Concise Review of the Evidence Toward Their Potential Clinical Utility

In the process of inflammation and repair of the intestinal mucosa in inflammatory bowel disease (IBD), there occurs a complex and an unknown interplay of innate and adaptive immune mechanisms. This interaction of factors may explain why IBD is characterized by a relapsing and remitting clinical course. Different components of innate immunity, hormones and interleukins in IBD have been suggested to be impaired. The growth hormone, epidermal growth factor, keratinocyte growth factor and colony-stimulating factors have emerged as potential tools for the modulation of intestinal inflammation and repair. Despite promising results of initial studies, the evidence that justify treatment of patients in clinical practice is not enough as some of the trials are nonrandomized or included a small number of patients. In this concise review, we provide a summary of the most recent and relevant evidence regarding the potential therapeutic effects of growth factors in IBD.     

Damage-associated molecular patterns in inflammatory bowel disease: From biomarkers to therapeutic targets

The chronic inflammatory process underlying inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, derives from the interplay of several components in a genetically susceptible host. These components include environmental elements and gut microbiota a dysbiosis. For decades, immune abnormalities have been investigated as critically important in IBD pathogenesis, and attempts to develop effective therapies have predominantly targeted the immune system. Nevertheless, immune events represent only one of the constituents contributing to IBD pathogenesis within the context of the complex cellular and molecular network underlying chronic intestinal inflammation. These factors need to be appreciated within the milieu of nonimmune components. Damage-associated molecular patterns (DAMPs), which are essentially endogenous stress proteins expressed or released as a result of cell or tissue damage, have been shown to act as direct proinflammatory mediators. Excessive or persistent signalling mediated by such molecules can underlie several chronic inflammatory disorders, including IBD. The release of endogenous DAMPs amplifies the inflammatory response driven by immune and non-immune cells and promotes epigenetic reprogramming in IBD.The effects determine pathologic changes,which may sustain chronic intestinal inflammation and also underlie specific disease phenotypes.In addition to highlighting the potential use of DAMPs such as calprotectin as biomarkers,research on DAMPs may reveal novel mechanistic associations in IBD pathogenesis and is expected to uncover putative therapeutic targets.