Immunopathogenesis Of Ulcerative Colitis Research Articles

Epigenetic regulation and therapeutic strategies in ulcerative colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease, and is characterized by the diffuse inflammation and ulceration in the colon and rectum mucosa, even extending to the caecum. Epigenetic modifications, including DNA methylations, histone modifications and non-coding RNAs, are implicated in the differentiation, maturation, and functional modulation of multiple immune and non-immune cell types, and are influenced and altered in various chronic inflammatory diseases, including UC. Here we review the relevant studies revealing the differential epigenetic features in UC, and summarize the current knowledge about the immunopathogenesis of UC through epigenetic regulation and inflammatory signaling networks, regarding DNA methylation, histone modification, miRNAs and lncRNAs. We also discuss the epigenetic-associated therapeutic strategies for the alleviation and treatment of UC, which will provide insights to intervene in the immunopathological process of UC in view of epigenetic regulation.

Immunopathogenesis and treatment of ulcerative colitis: from modern medicine to herbal medicines

Ulcerative colitis is one of the idiopathic inflammatory diseases of the large intestine with an unknown cause, which occurs in recurrent attacks of inflammation in the lining of the mucosa and below the intestinal mucosa. Impaired mucosal immune responses, the involvement of inflammatory cytokines such as IL-1, TNF-α, and IL-6, and other inflammatory mediators such as arachidonic acid metabolites play an important role in the immunopathogenesis of ulcerative colitis. Based on medical findings on the pathogenesis of the disease, new therapies have focused on the responses of the intestinal immune system and the inflammatory process. However, the widespread use of treatments such as aminosalicylates and corticosteroids continues. Most of these drugs have severe side effects. Some patients do not respond well to these treatments and sometimes have to undergo surgery and colectomy. Therefore, extensive studies are being conducted to control and prevent disease to use natural treatment methods such as the use of antioxidants with the approach of removing free radicals that prevent the destruction of cells and tissues in the body. Today, various studies have pointed to the effects of herbal medicines as a complementary treatment in inflammatory diseases. Their low cost and high effectiveness have attracted the attention of researchers in this field. The aim of the present study is a comprehensive review of modern and traditional treatments based on herbal medicines in the field of ulcerative colitis.

Цитокиновый профиль и иммунологический статус у пациентов с язвенным колитом

Objective. The increase in the incidence and prevalence of ulcerative colitis (UC) continues to be a worldwide trend. Both T-helpers and produced cytokines, as well as other cells of the immune system, are involved in the immunopathogenesis of UC. The aim of this study was to explore the immunological status and cytokine profile in patients with UC. Since there are significant gender differences in an immune response in inflammatory bowel disease (IBD), only men were included in this study. Patients and methods. 25 male patients with ulcerative colitis and 26 male healthy controls (HC) without IBD were enrolled in the study. T cell subsets were assessed by multicolor flow cytometry. Analysis of cytokines and chemokines in peripheral blood was performed by multiplex enzyme immunoassay. Results. The percentage of CD3+ T lymphocytes was significantly increased in UC patients compared with HC. In patients with UC, a decrease in the naive cytotoxic T lymphocytes (Tcyt) and central memory (CM) Tcyt was revealed with a significant increase in the CD3+CD8+ highly differentiated Tcyt TEMRA (terminally differentiated CD45RA-positive effector memory T-cells). CM regulatory T cells (Treg) subpopulations showed a significant negative correlation with the severity of UC, reproduced in the CD73+CD39+ Treg and CD73–CD39+ Treg subpopulations. The proportion of T follicular helper 2 cells (Tfh2) in patients with UC was significantly increased compared to НС. Analysis of the cytokine profile showed a significant increase in the concentrations of interleukins IL-5, IL-7, IL-12, IL-10, and chemokines CCL3/MIP-1α, CXCL8/IL-8, CXCL11/I-TAC, and CX3CL1/Fractalkine. Conclusion. New data were obtained on significant changes in peripheral blood T-lymphocytes and cytokine profile in male patients with UC, which turned out to be more characteristic of the Th2 response. Changes in the subpopulation composition of circulating follicular T-helpers in UC were associated with a significant increase in the percentage of Tfh2, which can switch the class of antibodies synthesized by B-cells from IgM to IgG and IgA. In addition, a significant increase in plasma concentrations of the cytokine IL-7 and the chemokine CXCL11/I-TAC was shown in patients with UC. Key words: inflammatory bowel disease, ulcerative colitis, T helper cell subsets, cytokines, chemokines

Targeting Immune Cell Wiring in Ulcerative Colitis

The cytokine TNF is thought to play a major role in the immunopathogenesis of ulcerative colitis, and anti-TNF antibodies are considered as cornerstones of clinical therapy. Two clinical trials published in The New England Journal of Medicine now challenge this paradigm and suggest new avenues for research.

Retraction Note: Cellular and molecular immunopathogenesis of ulcerative colitis

Ulcerative colitis (UC) is an inflammatory disease of the rectal and colonic mucosa and seems to result from a complex series of interactions between susceptibility genes, the environment and the immune system. Various components of the mucosal immune system are implicated in the immunopathogenesis of UC. Evidence from animal models also suggests that an altered immune response to the commensal microflora of the host plays a central role in the development of UC. So in this review, we elucidate the cells and molecules which are implicated in the immunopathogenesis of the disease from four aspects: antigens in the intestine, dendritic cells, toll like receptors and NF-kappaB in the UC.

Correlation of neutrophil and monocyte derived interleukin-1 receptor antagonist and interleukin-8 with colitis severity in the rabbit

Activated neutrophils and monocytes produce interleukin (IL)-8, a pro-inflammatory chemokine, but also IL-1 receptor antagonist (IL-1ra), which is an anti-inflammatory cytokine. We were interested to see the profiles of IL-8 and IL-1ra in the colonic tissue and in the peripheral blood leukocytes (PBL) during the development of immune complex induced colitis in rabbits. IL-1ra and IL-8 in PBL were measured in 26 rabbits at time 0h, 24h, and 48h after induction of colitis. The colons were removed at 48h for measuring myeloperoxidase (MPO), ulcer area, IL-1ra and IL-8. Epithelial damage, crypt abscess formation and leukocyte infiltration of the colonic tissue were major features of this colitis model. During the development of colitis, there was an increase in circulating neutrophils and monocytes (P<0.0001), but not lymphocytes. Likewise, elevated amounts of IL-1ra (P=0.0001) and IL-8 (P=0.0219) production by PBL were observed following induction of colitis. Flow cytometry revealed major source of IL-1ra was monocytes, while the main sources of IL-8 were neutrophils and monocytes. There was correlation between MPO and ulcer area (Rs=0.6327, P<0.0001). At 24h, PBL from MPOHigh group (n=11) showed increased IL-1ra (P=0.027) and IL-8 (P=0.0128) levels vs MPOLow group (n=15). IL-8 production by PBL showed correlation with tissue MPO (Rs=0.4273, P=0.0295). The colitis in this model was associated with an increase in circulating monocytes and neutrophils, which released increased amounts of IL-8 and IL-1ra. Further, IL-8 and IL-1ra showed correlation with the severity of colitis. These observations should significantly further understandings on the role of neutrophils and monocytes in the immunopathogenesis of ulcerative colitis.

Clcn5 knockout mice exhibit novel immunomodulatory effects and are more susceptible to dextran sulfate sodium-induced colitis.

Although the intracellular Cl(-)/H(+) exchanger Clc-5 is expressed in apical intestinal endocytic compartments, its pathophysiological role in the gastrointestinal tract is unknown. In light of recent findings that CLC-5 is downregulated in active ulcerative colitis (UC), we tested the hypothesis that loss of CLC-5 modulates the immune response, thereby inducing susceptibility to UC. Acute dextran sulfate sodium (DSS) colitis was induced in Clcn5 knockout (KO) and wild-type (WT) mice. Colitis, monitored by disease activity index, histological activity index, and myeloperoxidase activity were significantly elevated in DSS-induced Clcn5 KO mice compared with those in WT mice. Comprehensive serum multiplex cytokine profiling demonstrated a heightened Th1-Th17 profile (increased TNF-alpha, IL-6, and IL-17) in DSS-induced Clcn5 KO mice compared with that in WT DSS colitis mice. Interestingly, Clcn5 KO mice maintained on a high vitamin D diet attenuated DSS-induced colitis. Immunofluorescence and Western blot analyses of colonic mucosa validated the systemic cytokine patterns and further revealed enhanced activation of the NF-kappaB pathway in DSS-induced Clcn5 KO mice compared with those in WT mice. Intriguingly, high baseline levels of IL-6 and phospho-IkappaB were observed in Clcn5 KO mice, suggesting a novel immunopathogenic role for the functional defects that result from the loss of Clc-5. Our studies demonstrate that the loss of Clc-5 1) exhibits IL-6-mediated immunopathogenesis, 2) significantly exacerbated DSS-induced colitis, which is influenced by dietary factors, including vitamin D, and 3) portrays distinct NF-kappaB-modulated Th1-Th17 immune dysregulation, implying a role for CLC-5 in the immunopathogenesis of UC.

Adsorptive Depletion of α4 Integrinhi- and CX3CR1hi-Expressing Proinflammatory Monocytes in Patients with Ulcerative Colitis

Two main functionally distinct monocytes phenotypes are known: the CD14(hi)CD16(-) "classical" and the CD14(+)CD16(+) "proinflammatory" phenotypes. The latter phenotype is elevated in patients with ulcerative colitis (UC) and is suspected to have a major role in the immunopathogenesis of UC. To selectively deplete circulating proinflammatory CD14(+)CD16(+) monocyte phenotype. Seven corticosteroid-naïve patients with UC (clinical activity index = 8.7 +/- 1.3) and seven healthy subjects were included. In patients with UC, granulocyte/monocyte adsorption (GMA) was done with an Adacolumn that selectively adsorbs leucocytes of the myeloid lineage. Blood from all subjects at baseline and from the patients immediately after the first GMA session was processed. Isolated monocytes were subjected to fluorescence-activated cell sorter analyses. The seven UC patients achieved remission (CAI <or=4) after 5-10 GMA sessions. GMA induced a strong fall in the ratio (%) of CD14(+)CD16(+) to CD14(hi)CD16(-) monocytes, from 10.0 +/- 1.4 to 3.0 +/- 0.9. Further, expressions of alpha4 integrin (374.8 +/- 26.1 mean fluorescence intensity, MFI) and CX(3)CR1 (49.5 +/- 4.6 MFI) were significantly high on CD14(+)CD16(+)monocytes as compared with on CD14(hi)CD16(-) monocytes (169.2 +/- 17.2 and 33.2 +/- 3.6 MFI, respectively). Additionally, GMA significantly increased the ratio of the CD14(hi)CD16(-)CCR2(low) "immature" monocytes from 3.74 +/- 0.62 to 8.11 +/- 0.56 MFI. We found high expressions of alpha4 integrin and CX(3)CR1 on monocytes in patients with active UC, known to promote the extravasation of CD14(+)CD16(+) monocytes into the mucosa. GMA effectively depletes CD14(+)CD16(+) monocytes and concomitantly increases CD14(hi)CD16(-)CCR2(low) "immature" monocytes; thus GMA was associated with the emergence of less inflammatory monocyte phenotype in circulation.

Appendiceal Orifice Inflammation in Ulcerative Colitis

A 44-year-old man was diagnosed with distal ulcerative colitis (UC) when he had hematochezia at the age of 34. He had had a few relapses on maintenance oral mesalazine. He desired a total colonoscopy in the clinical remission. Physical examination showed no abnormalities and routine laboratory tests were normal. Colonoscopy disclosed the appendiceal orifice inflammation (AOI) with reddish and friable mucosa and mucopus (Fig. 1). The remaining colorectum showed no inflammation. He remains well during the follow-up. Since Cohen et al. first coined ‘‘ulcerative appendicitis’’ [1], AOI is uncommon but has increasingly been recognized in patients of distal UC. UC classically extends proximally from the rectum without skip lesions. Isolated AOI has been more frequently observed in patients with less extensive UC and is unlikely the result of patchy improvement due to treatments. The human appendix has long been recognized as a vestigial remnant. Although the pathogenesis of UC has not been fully clarified, clinical evidence has revealed the protective role of appendicectomy on onset and severity of UC [2, 3], indicating the appendix as a priming site for UC [4]. Experimental studies of murine models have also shown that the appendix may serve a central role in antigen sampling and immunological signaling [5]. Therefore, further studies of AOI may unveil not only its clinical implication but also the immunopathogenesis of UC. References

Bacterial superantigens and T cell receptor β-chain-bearing T cells in the immunopathogenesis of ulcerative colitis

Ulcerative colitis (UC) is a chronic relapsing-remitting inflammatory bowel disease (IBD) that affects the colon and the rectum producing debilitating symptoms, which impair ability to function and quality of life. The aetiology of IBD is incompletely understood, but within the lymphocyte population, specific T cell subsets are known to be major factors in the development of intestinal immune pathology while different subsets are essential regulators, controlling IBD. Hence, IBD is thought to reflect dysregulated T cell behaviour. This study was to investigate if the normal molecular configuration of the T cell receptor (TCR) repertoire is compromised in patients with UC. The percentage of T cell-bearing beta-chain 4 (TCRBV4) was high in patients with UC, and T cells showed polyclonal expansion in the presence of bacterial superantigens (SA) such as streptococcal mitogenic exotoxin Z-2 (SMEZ-2), indicating that bacterial SA promote specific TCRBV family expansion. Further, in patients with UC, the duration of UC was significantly longer in patients with skewed TCRBV4 compared with patients without TCRBV4 skewing, suggesting that long-term exposure to bacterial SA such as SMEZ-2 might promote systemic immune disorders like the remission-relapsing cycles seen in patients with UC. In conclusion, our observations in this study support the perception that the systemic activation of T cells by enteric bacterial SA might lead to a dysregulated, but exuberant immune activity causing the remission and flare-up cycle of mucosal inflammation in patients with UC. Future studies should strengthen our findings and increase understanding on the aetiology of IBD.

The central role of chemokines (chemotactic cytokines) in the immunopathogenesis of ulcerative colitis and Crohn's disease

The final composition of leukocytes present in a site of inflammation in response to chemokine stimulation and activation may depend on both the nature of the secreted chemokines as well as the relative expression of the multitude of specific chemokine cell surface receptors on many different cell types. Because related receptors with different affinities and cross-reactive binding capabilities are present on each type of leukocyte, relative differences in receptor distribution and receptor affinity for specific chemokines may significantly influence which cells are ultimately attracted to and activated by each individual chemokine. Production of IL-8, MCP-1, and ENA-78 by endothelial cells, LPMNC, and epithelial cells in IBD could establish a chemotactic gradient capable of influencing the increased migration of monocytes/macrophages, granulocytes, and lymphocytes from the blood stream through the endothelium into both the mucosa and submucosa during chronic IBD. The ability of chemokines to induce chemotaxis, leukocyte activation, granule exocytosis, increased production of metalloenzymes, and up-regulation of respiratory burst activity indicates that there may be a variety of different mechanisms by which chemokines could markedly increase chronic inflammation and chronic intestinal tissue destruction in IBD.

Autoimmunity against human tropomyosin isoforms in ulcerative colitis: Localization of specific human tropomyosin isoforms in the intestine and extraintestinal organs

Tropomyosins (TMs) are microfilament cytoskeletal proteins, and 5 major human TM isoforms (hTM1-5) are described. hTMs, particularly isoform 5 (hTM5), is capable of inducing autoantibodies and T-cell response in ulcerative colitis (UC). However, cellular localization of hTM isoforms in the colon and in extraintestinal organs commonly involved in UC is unknown. Using isoform-specific monoclonal antibodies, we localized hTMs through immunoperoxidase assay in normal colon (n = 12), small intestine (n = 14), esophagus (n = 10), skin (n = 19), eye (n = 12), gallbladder (n = 16), liver, including bile duct at the porta hepatis (n = 4), lungs (n = 4), and pancreas (n = 4). There is intense expression of hTM5, but not other isoforms, in the epithelium of the colon, gallbladder, and skin. In the eye, hTM5 is expressed only in the nonpigmented ciliary epithelium. Although extrahepatic and interlobar large ductal biliary epithelium was positive, bile canaliculi at the portal tract are negative. The immunoreactivity in epithelial cells from these organs is diffuse cytoplasmic and along the periphery. In colon epithelium, there is intense expression along basolateral areas and luminal (apical) surface. In the small intestinal epithelium, however, hTM5 expression is weak and distinctly different than in the colon. hTM5 was not detected in the squamous epithelium of the esophagus, although it was strongly positive in the skin. hTM1, hTM2, and hTM3 are localized predominantly in smooth muscle of the intestine and blood vessel wall but not the epithelium. HTM4 is localized in the endothelial cells and basement membrane of the colonic epithelium. hTM5 is the predominant isoform in the epithelium of colon and extraintestinal organs commonly involved in UC. The unique expression of hTM5 may allow its interaction with effector immune cells involved in the immunopathogenesis of UC and its extraintestinal manifestations.

The increased expression of an array of C-X-C and C-C chemokines in the colonic mucosa of patients with ulcerative colitis: regulation by corticosteroids

OBJECTIVE: To better understand the extent to which chemokines participate in the mucosal inflammatory response in patients with ulcerative colitis (UC), we assessed the expression of an array of chemokines in the colonic mucosa of UC patients and evaluated the effect of corticosteroids on their expression. METHODS: Colonic mucosal biopsy specimens were obtained from 15 patients with UC and 12 normal controls. Messenger RNA levels for 10 chemokines were quantitated by reverse transcription polymerase chain reaction using synthetic standard RNAs. The biopsy specimens were also cultured in the presence or absence of tumor necrosis factor α (TNFα) and/or dexamethasone, and secreted chemokines in culture supernatants were assayed by ELISA. RESULTS: The messenger RNA expression of C-X-C (interleukin 8, growth-related α [GROα], GROβ, GROγ, epithelial cell-derived neutrophil activator 78, and interferon-γ-inducible protein 10) and C-C (monocyte chemotactic protein 1, macrophage inflammatory protein 1β, and RANTES [regulated on activation, normal T-cell expressed and secreted]) but not C (lymphotactin) chemokines was significantly higher in the affected mucosa of UC patients than in the unaffected mucosa of UC patients or in the normal mucosa of normal controls. The degree of increased expression was more prominent in the C-X-C than in the C-C chemokines. Further, the secretion of interleukin 8, GROα, epithelial cell-derived neutrophil activator 78, and monocyte chemotactic protein 1 was higher in UC patients than in normal controls, induced significantly by TNFα, and downregulated by dexamethasone. Secretions of macrophage inflammatory protein 1β and RANTES also showed a trend toward an increase in UC, induction by TNFα, and downregulation by dexamethasone, but it did not reach statistical significance. CONCLUSIONS: The increased expression of a variety of chemokines in UC and their downregulation by dexamethasone suggest that chemokines may play an important role in the immunopathogenesis of UC.

Autoantibodies against the specific epitope of human tropomyosin(s) detected by a peptide based enzyme immunoassay in sera of patients with ulcerative colitis show antibody dependent cell mediated cytotoxicity against HLA-DPw9 transfected L cells

BACKGROUND AND AIMSRecent studies suggest that tropomyosin (TM) may act as a putative autoantigen in ulcerative colitis (UC). Recently, we identified, by computer homology analysis, a specific peptide (HIAEDADRK) in...

The central role of chemokines (chemotactic cytokines) in the immunopathogenesis of ulcerative colitis and Crohn's disease.

The final composition of leukocytes present in a site of inflammation in response to chemokine stimulation and activation may depend on both the nature of the secreted chemokines as well as the relative expression of the multitude of specific chemokine cell surface receptors on many different cell types. Because related receptors with different affinities and cross-reactive binding capabilities are present on each type of leukocyte, relative differences in receptor distribution and receptor affinity for specific chemokines may significantly influence which cells are ultimately attracted to and activated by each individual chemokine. Production of IL-8, MCP-1, and ENA-78 by endothelial cells, LPMNC, and epithelial cells in IBD could establish a chemotactic gradient capable of influencing the increased migration of monocytes/macrophages, granulocytes, and lymphocytes from the blood stream through the endothelium into both the mucosa and submucosa during chronic IBD. The ability of chemokines to induce chemotaxis, leukocyte activation, granule exocytosis, increased production of metalloenzymes, and up-regulation of respiratory burst activity indicates that there may be a variety of different mechanisms by which chemokines could markedly increase chronic inflammation and chronic intestinal tissue destruction in IBD.

Simultaneous appearance of a unique common epitope in fetal colon, skin, and biliary epithelial cells. A possible link for extracolonic manifestations in ulcerative colitis.

The tissue distribution of a previously identified M(r) 40 K epithelial autoantigen in ulcerative colitis was examined in situ in the fetal tissue by immunocytochemical method, using an immunoglobulin M (IgM) monoclonal antibody (7E12H12). Fetal-autopsy tissue from 9 to 19 weeks of development (11-21 gestational weeks) gestations, including specimens of colon (20 specimens), skin (19), small intestine (12), gallbladder (15), liver (20), spleen (20), kidney (3), urinary bladder (3), and umbilical cord/placenta (25) were examined. 7E12H12 reactive epitope appeared first in a few colonic epithelial cells at 10 weeks of gestation. By 11 weeks, 7E12H12 reactivity was clearly evident in most of the colonic epithelial cells. Goblet-cell reactivity was evident from 15 weeks of gestation. Enterocytes lining the small intestine from all the specimens were negative. In the skin, earliest immunoreactivity was evident in the basal layer of epidermis at 10 weeks of development, and by 11 weeks, the staining was intense and localized exclusively to squamous epithelial cells of the epidermis. The immunoreactivity in the fetal gallbladder mucosa was also evident earliest at 11 weeks of development. The staining was distinct in the mucosal epithelial cells, and localized along the periphery of the cells and in the apical areas. None of the other tissue specimens reacted with 7E12H12. These results demonstrate that the 7E12H12 reactive epitope is novel, is shared by colon, skin, and biliary epithelium, and appears more or less simultaneously in the three organs at 10 to 11 weeks of development of the fetus. A possible link of this crossreactive protein or proteins in the immunopathogenesis of ulcerative colitis, sclerosing cholangitis, and pyoderma gangrenosum is discussed.