The immune response in inflammatory bowel disease

Ulcerative colitis (UC) and Crohn's disease (CD), collectively referred to as inflammatory bowel disease (IBD), present with differing histologic and cytokine profiles. While the precise mechanisms underlying the development of IBD are not known, sufficient data have been collected to suggest that it results from a complex interplay of genetic, environmental, and immunologic factors. Animal models of colitis, along with a more detailed understanding of the immune response in the normal bowel, have led to unifying hypotheses regarding the pathogenesis. An inappropriate mucosal immune response to normal intestinal constituents is a key feature, leading to an imbalance in local pro- and anti-inflammatory cytokines. Neutrophil and monocyte influx occurs with subsequent secretion of oxygen radicals and enzymes, leading to tissue damage. Therapy of IBD has improved and expanded as the understanding of disease mechanisms has evolved. Pharmacologic agents such as aminosalicylates, azathioprine/6-mercaptopurine, or steroids are the mainstays of therapy. Newer agents including monoclonal antibodies targeted to specific proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), have emerged and provide great clinical benefit, but unknown long-term toxicity and immunogenicity may limit their use.     

Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors： Pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take ＂toll＂ ？

The pathogenesis of inflammatory bowel disease(IBD)is only partially understood.Various environmentaland host(e.g.genetic-,epithelial-,immune and non-immune)factors are involved.It is a multifactorialpolygenic disease with probable genetic heterogeneity.Some genes are associated with IBD itself,while othersincrease the risk of ulcerative colitis(UC)or Crohn's disease(CD)or are associated with disease locationand/or behaviour.This review addresses recent advancesin the genetics of IBD.The article discusses the currentinformation on the crosstalk between microbial andgenetic factors(e.g.NOD2/CARD15,SLC22A46A5 andDLG5).The genetic data acquired in recent years help inunderstanding the pathogenesis of IBD and can identify anumber of potential targets for therapeutic intervention.In the future,genetics may help more accurately diagnoseand predict disease course in IBD.     

炎症性肠病发病机制的研究新进展

炎症性肠病(inflammatory bowel disease,IBD)是一组反复发作的慢性炎症性肠道疾病,主要包括溃疡性结肠炎(ulcerative colitis,UC)和克罗恩病(Crohn’s disease,CD)。其确切的发病机制目前尚不明确,本文主要对遗传因素、免疫因素、环境因素、内质网应激和肠道微生物这五个方面在IBD中的新观点作一概述。     

Pharmacological- and non-pharmacological therapeutic approaches in inflammatory bowel disease in adults

Inflammatory bowel diseases(IBDs) are a group of chronic inflammatory conditions mainly of the colon and small intestine. Crohn's disease(CD) and ulcerative colitis(UC) are the most frequent types of IBD. IBD is a complex disease which arises as a result of the interaction of environmental, genetic and immunological factors. It is increasingly thought that alterations of immunological reactions of the patients to their own enterable bacteria(microfilm) may contribute to inflammation. It is characterized by mucosal and sub mucosal inflammation, perpetuated by infiltration of activated leukocytes. CD may affect the whole gastrointestinal tract while UC only attacks the large intestine. The therapeutic goal is to achieve a steroidfree long lasting remission in both entities. UC has the possibility to be cured by a total colectomy, while CD never can be cured by any operation. A lifelong intake of drugs is mostly necessary and essential. Medical treatment of IBD has to be individualized to each patient and usually starts with anti-inflammatory drugs. The choice what kind of drugs and what route administered(oral, rectal, intravenous) depends on factors including the type, the localization, and severity of the patient's disease. IBD may require immune-suppression to control symptoms such as prednisolone, thiopurines, calcineurin or sometimes folic acid inhibitors or biologics like TNF-α inhibitors or anti-integrin antibodies. For both types of disease(CD, UC) the same drugs are available but they differ in their preference in efficacy between CD and UC as 5-aminosalicylic acid for UC or budesonide for ileocecal CD. As therapeutic alternative the main mediators of the disease, namely the activated pro-inflammatory cytokine producing leukocytes can be selectively removed via two apheresis systems(Adacolumn and Cellsorba) in steroid-refractory or dependent cases. Extracorporeal photopheresis results in an increase of regulatory B cells, regulatory CD8~+ T cells and T-regs Type 1. Both types of apheresis were able to induce clinical remission and mucosal healing accompanied by tapering of steroids.     

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.     

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.     

Immunogenetic phenotypes in inflammatory bowel disease

The currently accepted etiopathogenic hypothesis suggests that the chronic intestinal inflammation and related systemic manifestations characteristic of inflammatory bowel disease (IBD) are due to an overly aggressive or pathologic immune response to resident luminal bacterial constituents. Predisposing factors are genetic dysregulation of mucosal immune responses and/ or barrier function, with onset triggered by environmental stimuli. These factors and their interactions may also be important determinants of disease phenotype and disease progression. The emergence of immunogenetic phenotypes lends support to the proposed hypothesis that susceptibility genes regulate distinct immune processes, driven by luminal antigens, expressed as specific immune phenotypes which in turn influence clinical phenotypes in IBD patient     

Lack of association of the CD14 promoter polymorphism--159C/T with Caucasian inflammatory bowel disease

OBJECTIVE: The inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial diseases resulting from a complex interaction of genetic and environmental factors. The recently described CARD15 and TNF-alpha risk alleles are believed to be contributors to disease by disrupting inflammatory pathways via impaired response to bacteria. Other bacterial receptors, such as CD14, may also have a role in disease. A promoter polymorphism (-159C/T) in CD14 has been implicated in IBD in a number of studies. MATERIAL AND METHODS: We have analysed this CD14 promoter polymorphism in probands from 206 multiplex IBD families, 110 sporadic IBD individuals and 189 healthy controls from the Australian population, all of whom are Caucasian. RESULTS: We could not replicate the described association between the CD14-159T allele and CD or UC, nor did we find any evidence for an interaction between the CARD15 or TNF-alpha risk alleles and the CD14-159T allele. CONCLUSIONS: It is possible that the association seen in other studies may be due to population stratification or to the CD14 polymorphism being in linkage with the real disease-causing variant(s).     

Enteric bacteria, lipopolysaccharides and related cytokines in inflammatory bowel disease: biological and clinical significance

Ulcerative colitis (UC) and Crohn's disease (CD) [inflammatory bowel disease (IBD)] are both characterized by an exaggerated immune response at the gut associated lymphoreticular tissue level. Such an abnormal and dysregulated immune response may be directed against luminal and/or enteric bacterial antigens, as also supported by murine models of inflammatory bowel disease (IBD) caused by organisms such as Citrobacter rodentium and Helicobacter hepaticus. Bacterial endotoxins or lipopolysaccharides (LPS) have been detected in the plasma of IBD patients and an abnormal microflora and/or an increased permeability of the intestinal mucosa have been invoked as cofactors responsible for endotoxemia. At the same time, the evidence that phagocytosis and killing exerted by polymorphonuclear cells and monocytes and the T-cell dependent antibacterial activity are decreased in IBD patients may also explain the origin of LPS in these diseases. In IBD, pro-inflammatory cytokines and chemokines have been detected in elevated amounts in mucosal tissue and/or in peripheral blood, thus suggesting a monocyte/macrophage stimulation by enteric bacteria and/or their constituents (e.g. LPS). On these grounds, in experimental models and in human IBD, anti-cytokine monoclonal antibodies and interleukin receptor antagonists are under investigation for their capacity to neutralize the noxious effects of immune mediators. Finally, the administration of lactobacilli is beneficial in human IBD and, in murine colitis, this treatment leads to a normalization of intestinal flora, reducing the number of colonic mucosal adherent and translocated bacteria.     

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).     

Signaling for inflammation and repair in inflammatory bowel disease

In patients with inflammatory bowel diseases (IBD) the immune system leads to the polarization of intestinal immune cells towards a T helper one (Th1) pro-inflammatory response. The immunologic factors intervene in intestinal homeostasis and initiate the development of intestinal mucosal inflammation. Cytokines, which are important regulators of inflammation and repair as wells as leukocyte trafficking have become apparent as key immune molecules in the pathogenesis of IBD. In this review, recent advances in our understanding of the cytokine involvement in inflammation and repair in patients with ulcerative colitis (UC) and Crohn's disease (CD) are discussed. Knowledge of objective evidence of inflammatory activity may allow targeted treatment at an earlier stage to avoid the relapse, as well as assessment of new therapeutic strategies for maintenance of remission.     

Characterization of colonic and mesenteric lymph node dendritic cell subpopulations in a murine adoptive transfer model of inflammatory bowel disease

Ulcerative colitis and Crohn's disease, collectively termed inflammatory bowel diseases (IBD), are chronic inflammatory diseases of the intestine that afflict more than 4 million people worldwide. Intestinal inflammation is characterized by an abnormal mucosal immune response to normally harmless antigens in the gut flora. In Crohn's disease, the pathogenic mucosal immune response is a typical T helper (TH1) type cell response, whereas ulcerative colitis is predominantly associated with a TH2 response. We are interested in the role of dendritic cells in early immunologic events leading to T cell activation and chronic intestinal inflammation. Using a murine adoptive transfer model of IBD, we found an accumulation of dendritic cells in colon and mesenteric lymph nodes during the early stage of IBD before the appearance of epithelial lesions and tissue degradation. In situ immunostaining and flow-cytometric analysis revealed that approximately 50% of colonic dendritic cells were CD11b B220 myeloid dendritic cells and 50% expressed the CD11b B220 plasmacytoid phenotype. In corresponding mesenteric lymph nodes, approximately 16% were plasmacytoid dendritic cells. Colonic myeloid dendritic cells were shown to express the co-stimulatory molecule CD40. Both, colonic myeloid and plasmacytoid dendritic cells released interferon-alpha in situ and stimulated T cell proliferation ex vivo. Our results show that dendritic cells can mature in the intestine without migrating to mesenteric lymph nodes. Mature intestinal dendritic cells may form a nucleation site for a local T cell response and play an important role in the pathogenesis of IBD.     

白细胞介素33在IBD炎症进展和黏膜愈合中的作用

炎症性肠病(IBD)主要包括溃疡性结肠炎(UC)和克罗恩病(CD),近年其发病呈上升趋势。IBD的发病机制尚不明确,研究表明免疫炎症反应起重要作用。白细胞介素33(IL-33)是新近发现的炎症因子,越来越多证据表明其参与IBD发病。本文就IL-33在IBD炎症进展和黏膜愈合中的作用作一综述。     

Composition and function of the pediatric colonic mucosal microbiome in untreated patients with ulcerative colitis

Inflammatory bowel diseases (IBD) are chronic intestinal inflammatory disorders characterized by a complex disruption of the physiologic interaction between the host immune system and intestinal microbes precipitated by environmental factors. Numerous observations indicate the altered composition and function of the intestinal microbiome of patients with ulcerative colitis (UC), a subtype of IBD. The accuracy of these results may be limited by confounding factors, such as concurrent medication use. To address these limitations, we examined the colonic mucosal microbiome of pediatric patients with UC prior to initiating treatment. Based on bacterial 16S rRNA gene sequencing, we identified a significant decrease in the phylum Verrucomicrobia in patients with UC. At the genus level, we observed a significant decrease in the short chain fatty acid producer Roseburia. Despite these compositional changes, we did not identify inferred gene content differences between the UC and control groups. To determine if microbial taxa may be associated with clinical outcomes, we retrospectively assessed the clinical course of the UC patients. Despite similar metrics of OTU richness and diversity, multiple OTU differences were observed between patients who responded to therapy and those who did not. Our observations regarding the mucosal microbiome and the associations with differential clinical outcomes support the contributions of gut microbes to disease onset and modulation.     

A polymorphism in the CD14 gene is associated with Crohn disease

BACKGROUND: Inflammatory bowel diseases (IBD) are multifactorial disorders, characterized by failure to limit the inflammatory response to luminal antigens. Although genetic factors play an important role in the pathogenesis, little is known about the genes accountable. Immune response to intestinal bacteria seems to be crucial in the pathogenesis of IBD. METHODS: To evaluate the role of the CD14 gene in IBD, a functionally relevant polymorphism in the promoter region (T/C at position -159) has been genotyped in 219 patients with Crohn disease (CD), 142 patients with ulcerative colitis (UC) and 410 healthy controls by RFLP analysis. RESULTS: T allele and TT genotype frequencies were found increased in CD patients compared to controls (Pc=0.044 and 0.005, respectively). CONCLUSION: An altered immune response to LPS seems to play a role in the genetic predisposition to CD but not to UC.     

Potential role of Th17 cells in the pathogenesis of inflammatory bowel disease

The etiopathology of inflammatory bowel disease (IBD) remains elusive. Accumulating evidence suggests that the abnormality of innate and adaptive immunity responses plays an important role in intestinal inflammation. IBD including Crohn's disease (CD) and ulcerative colitis (UC) is a chronic inflammatory disease of the gastrointestinal tract, which is implicated in an inappropriate and overactive mucosal immune response to luminal flora. Traditionally, CD is regarded as a Th1mediated inflammatory disorder while UC is regarded as a Th2like disease. Recently, Th17 cells were identified as a new subset of T helper cells unrelated to Th1 or Th2 cells, and several cytokines [e.g. interleukin (IL)-21, IL-23] are involved in regulating their activation and differentiation. They not only play an important role in host defense against extracellular pathogens, but are also associated with the development of autoimmunity and inflammatory response such as IBD. The identification of Th17 cells helps us to explain some of the anomalies seen in the Th1/Th2 axis and has broadened our understanding of the immunopathological effects of Th17 cells in the development of IBD.     

In siblings with similar genetic susceptibility for inflammatory bowel disease,smokers tend to develop Crohn's disease and non-smokers develop ulcerative colitis

BACKGROUND AND AIMS: Smoking tobacco has opposite effects on the different forms of inflammatory bowel disease (IBD). It predisposes to the development of Crohn's disease (CD) yet is associated with a reduced incidence of ulcerative colitis (UC). We have studied sib pairs discordant for both smoking and IBD phenotype (UC or CD) to investigate whether smoking determines the type of IBD that develops in individuals with very similar genetic susceptibility. PATIENTS: Smoking habits and disease characteristics were analysed in 242 IBD pedigrees (658 patients). Within this group there were 339 affected sibling pairs of whom 89 were discordant for smoking when diagnosed. RESULTS: Smoking at diagnosis was associated with development of CD (odds ratio (OR) 3.55; 95% confidence limits 2.50-5.02; p<0.001) in all of the familial patients, with increases when analysed for ileocaecal disease, fibrostenosis, and intestinal resection. Smokers were also protected from UC (OR 0.28; 0.2-0.4; p<0.001). Of 89 sibling pairs discordant for smoking at diagnosis, 23 were also discordant for disease type-in 21 of these, CD occurred in the smoker and UC in the non-smoker (OR 10.5; 2.6-92; p<0.0001). CONCLUSIONS: Smoking is a strong environmental risk factor for Crohn's disease and increases the likelihood of needing surgery. However, sib pairs who are discordant for both smoking and IBD type almost always show CD in the smoker and UC in the non-smoker, and so in some cases tobacco consumption acts on IBD genetic predisposition to shift the phenotype from UC towards CD. The explanation of part of the apparent "protective" effect of smoking on sporadic UC may be that the form of IBD that develops in a proportion of smokers is not UC but CD.     

A genetic contribution to inflammatory bowel disease in Iceland: a genealogic approach.

BACKGROUND AND AIMS: Both genetic and environmental factors play a role in the development of Crohn's disease (CD) and ulcerative colitis (UC), collectively known as inflammatory bowel disease (IBD). The aim of this study was to estimate the genetic component in IBD in Iceland. METHODS: A population-based sample, representing everyone diagnosed with IBD in Iceland from 1950 to 1996, was studied using a computerized population-wide genealogic database. The relationships among the patients were analyzed by calculating the kinship coefficient and the relative risk. RESULTS: The kinship coefficients for the patients were significantly greater than the mean kinship coefficient for the controls ( P < 10 -6 ). The risk ratio for siblings of IBD, UC, and CD patients was 5.0 ( P < 0.001), 5.9 ( P < 0.001), and 4.1 ( P = 0.033), respectively. The cross-risk ratio for siblings of UC patients developing CD (or vice versa) was 2.6 ( P = 0.015). CONCLUSIONS: The results indicate that the IBD patients are more closely related than the controls, which strongly supports the involvement of a genetic component in the development of IBD in Icelandic patients. We find that the increase in risk for relatives of UC probands to develop UC, or relatives of CD probands to develop CD, is greater than the increase in risk for relatives of UC probands to develop CD, or relatives of CD probands to develop UC.     

Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria.

In contrast with normal subjects where IgA is the main immunoglobulin in the intestine, patients with active inflammatory bowel disease (IBD) produce high concentrations of IgG from intestinal lymphocytes, but the antigens at which these antibodies are directed are unknown. To investigate the specificities of these antibodies mucosal immunoglobulins were isolated from washings taken at endoscopy from 21 control patients with irritable bowel syndrome, 10 control patients with intestinal inflammation due to infection or ischaemia, and 51 patients with IBD: 24 Crohn's disease (CD, 15 active, nine quiescent), 27 ulcerative colitis (UC, 20 active, seven inactive). Total mucosal IgG was much higher (p < 0.001) in active UC (median 512 micrograms/ml) and active CD (256 micrograms/ml) than in irritable bowel syndrome controls (1.43 micrograms/ml), but not significantly different from controls with non-IBD intestinal inflammation (224 micrograms/ml). Mucosal IgG bound to proteins of a range of non-pathogenic commensal faecal bacteria in active CD; this was higher than in UC (p < 0.01); and both were significantly greater than controls with non-IBD intestinal inflammation (CD p < 0.001, UC p < 0.01) or IBS (p < 0.001 CD and UC). This mucosal IgG binding was shown on western blots and by enzyme linked immunosorbent assay (ELISA) to be principally directed against the bacterial cytoplasmic rather than the membrane proteins. Total mucosal IgA concentrations did not differ between IBD and controls, but the IgA titres against faecal bacteria were lower in UC than controls (p < 0.01). These experiments show that there is an exaggerated mucosal immune response particularly in active CD but also in UC directed against cytoplasmic proteins of bacteria within the intestinal lumen; this implies that in relapse of IBD there is a breakdown of tolerance to the normal commensal flora of the gut.