Ulcerative Colitis: Strober W

Fuss IJ, Strober W. · Mucosal Immunity Section, Laboratory of Host Defenses, National Institutes of Health, Bethesda, Maryland, USA. · Mucosal Immunol. · Pubmed #19079225 No free full text.

Abstract: Recent studies that have evaluated the immunologic factors that mediate the development of the two forms of inflammatory bowel disease, namely Crohn's disease and ulcerative colitis (UC), have suggested that these diseases are because of disparate immune responses. Although Crohn's disease has been characterized as a dysregulation of the T helper (Th)1/Th17 pathways more recent evidence has emerged that UC pathogenesis is associated with a nonclassical NK (natural killer) T cell producing an atypical Th2 (interleukin (IL)-13) response. In the following review the insights gained from both animal models and human studies as to the function that IL-13 and NK T cells have in the pathogenesis of UC will be discussed.

Strober W, Fuss I, Mannon P. · Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA. · J Clin Invest. · Pubmed #17332878 links to  free full text

Abstract: Two broad hypotheses have arisen regarding the fundamental nature of the pathogenesis of inflammatory bowel diseases (IBDs, which include ulcerative colitis and Crohn disease). The first contends that primary dysregulation of the mucosal immune system leads to excessive immunologic responses to normal microflora. The second suggests that changes in the composition of gut microflora and/or deranged epithelial barrier function elicits pathologic responses from the normal mucosal immune system. Here we examine these hypotheses and conclude that IBD is indeed characterized by an abnormal mucosal immune response but that microbial factors and epithelial cell abnormalities can facilitate this response.

Bouma G, Strober W. · The Mucosal Immunity Section, National Institutes of Health, Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institutes of Allergy and Infectious Diseases, 10 Center Drive, Room 11N238, Bethesda, Maryland 20892, USA. · Nat Rev Immunol. · Pubmed #12876555 No free full text.

Abstract: The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Enormous progress has been made recently in understanding the pathogenesis of these diseases. Through the study of patients and mouse models, it has emerged that Crohn's disease is driven by the production of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma), whereas ulcerative colitis is probably driven by the production of IL-13. A second area of progress is in the identification of specific genetic abnormalities that are responsible for disease. The most important finding is the identification of mutations in the gene that encodes NOD2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease. Here, we discuss these recent findings and the implications for therapy.

Neurath M, Fuss I, Strober W. · Laboratory of Immunology, University of Mainz, Germany. · Int Rev Immunol. · Pubmed #10723677 No free full text.

Abstract: Disease states, such as the occurrence of gastrointestinal inflammation (Crohn's disease and ulcerative colitis), can be secondary to a host of determinants that act in conjunction to bring about pathologic change. The underlying factors that mediate the development of such mucosal inflammation has recently been brought to the forefront with the advent of animal models. The examination of these animal models have given researchers a better understanding of the mechanisms involved in the pathogenesis of inflammatory bowel disease. This review discusses one such model, TNBS-colitis, and the insights that it provides into the occurrence of IBD and its future treatment.

Fuss IJ, Becker C, Yang Z, Groden C, Hornung RL, Heller F, Neurath MF, Strober W, Mannon PJ. · Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 , USA. · Inflamm Bowel Dis. · Pubmed #16374252 No free full text.

Abstract: BACKGROUND: Interleukin (IL)-12p70 and IL-23 are key T helper-1 (TH1) cytokines that drive the inflammation seen in numerous models of intestinal inflammation. These molecules contain an identical p40 chain that is bound to a p35 chain in IL-12 and a p19 chain in IL-23, making both potentially susceptible to modulation by an anti-IL-12p40 monoclonal antibody (mAb). METHODS: In the present study, we sought to determine whether active inflammation in Crohn's disease (CD) is associated with the increased synthesis of both of these cytokines and whether patients treated with an anti-IL-12p40 mAb down-regulate IL-23 as well as IL-12p70 as previous reported. RESULTS: To this end we initially determined that IL-12p70 secretion by control and CD antigen-presenting cells (macrophages) in lamina propria mononuclear populations is optimized by stimulation with CD40L and interferon-gamma. In subsequent studies using these stimulation conditions we found that patients with CD manifested both increased IL-12p70 and IL-23 secretion before anti-IL-12p40 mAb treatment and normal levels of secretion of these cytokines following cessation of treatment. Antigen-presenting cells in lamina propria mononuclear cells from ulcerative colitis patients, in contrast, produced only baseline levels of IL-23. Finally, we found that IL-23-induced T cell production of IL-17 and IL-6 are also greatly reduced after antibody treatment. The latter data are parallel to those from previous studies showing that anti-IL-12p40 down-regulates IFN-gamma and tumor necrosis factor-alpha secretion. CONCLUSIONS: We conclude that CD but not ulcerative colitis is associated with high levels of both IL-12p70 and IL-23 secretion as well as the secretion of downstream effector cytokines, and that this cytokine production is down-regulated following administration of IL-12p40 mAb.

Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Bürgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD. · Department of Gastroenterology, Charité, Campus Benjamin Franklin, Berlin, Germany. · Gastroenterology. · Pubmed #16083712 No free full text.

Abstract: BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by a Th2 immune response with inflammation and epithelial barrier dysfunction. So far, Th2 cytokines have not been shown to directly influence epithelial barrier function. METHODS: Lamina propria mononuclear cells (LPMCs) were stimulated and interleukin (IL)-13 was measured by enzyme-linked immunosorbent assay. Functional IL-13 and IL-4 effects were studied on HT-29/B6 colonic epithelial cells in Ussing chambers and by conductance scanning. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. IL-13/IL-4 receptors were analyzed by reverse-transcription polymerase chain reaction and immunofluorescence. Western blotting combined with immunofluorescence was used to detect tight junction proteins. Furthermore, restitution velocity was measured. Finally, mucosal biopsy specimens from patients with UC were compared with cultured cells for these features. RESULTS: LPMCs from patients with UC produced large amounts of IL-13 (985 +/- 73 pg/mL), much more than from controls or patients with Crohn's disease. IL-13Ralpha1 and IL-4Ralpha receptors were present in HT-29/B6 cells and colonic epithelial cells of control patients and patients with UC. IL-13 had a dose-dependent effect on transepithelial resistance of HT-29/B6 monolayers (reduction to 60% +/- 4%), whereas IL-4 had no effect. This was due to an increased number of apoptotic cells (5.6-fold +/- 0.9-fold) and an increased expression of the pore-forming tight junction protein claudin-2 to 295% +/- 37%, both of which contributed equally. Finally, epithelial restitution velocity decreased from 15.1 +/- 0.6 to 10.6 +/- 0.5 microm/h after treatment with IL-13. Parallel changes were observed in human samples, with an increase in claudin-2 expression to 956% +/- 252%. CONCLUSIONS: IL-13 was identified as an important effector cytokine in UC that impairs epithelial barrier function by affecting epithelial apoptosis, tight junctions, and restitution velocity.

Fuss IJ, Heller F, Boirivant M, Leon F, Yoshida M, Fichtner-Feigl S, Yang Z, Exley M, Kitani A, Blumberg RS, Mannon P, Strober W. · Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda Maryland 20892, USA. · J Clin Invest. · Pubmed #15146247 links to  free full text

Abstract: While Crohn disease (CD) has been clearly identified as a Th1 inflammation, the immunopathogenesis of its counterpart inflammatory bowel disease, ulcerative colitis (UC), remains enigmatic. Here we show that lamina propria T (LPT) cells from UC patients produce significantly greater amounts of IL-13 (and IL-5) than control cells and little IFN-gamma, whereas comparable cells from CD patients produce large amounts of IFN-gamma and small amounts of IL-13. We then show that stimulation of UC LPT cells bearing an NK marker (CD161) with anti-CD2/anti-CD28 or with B cells expressing transfected CD1d induces substantial IL-13 production. While this provided firm evidence that the IL-13-producing cell is an NK T (NKT) cell, it became clear that this cell does not express invariant NKT cell receptors characteristic of most NKT cells since there was no increase in cells binding alpha-galactosylceramide-loaded tetramers, and alpha-galactosylceramide did not induce IL-13 secretion. Finally, we show that both human NKT cell lines as well as UC CD161(+) LPT cells are cytotoxic for HT-29 epithelial cells and that this cytotoxicity is augmented by IL-13. These studies show that UC is associated with an atypical Th2 response mediated by nonclassical NKT cells producing IL-13 and having cytotoxic potential for epithelial cells.

Heller F, Fuss IJ, Nieuwenhuis EE, Blumberg RS, Strober W. · Mucosal Immunity Section, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. · Immunity. · Pubmed #12433369 No free full text.

Abstract: Oxazolone colitis (OC) is an experimental colitis that has a histologic resemblance to human ulcerative colitis. Here we show that IL-13 production is a significant pathologic factor in OC since its neutralization by IL-13Ralpha2-Fc administration prevents colitis. We further show that OC is mediated by NK-T cells since it can be induced neither in mice depleted of NK-T cells nor in mice that cannot present antigen to NK-T cells and mice lacking an NK-T cell-associated TCR. Finally, we show that NK-T cells are the source of the IL-13, since they produce IL-13 upon stimulation by alpha-galactosylceramide, an NK-T cell-specific antigen. These data thus describe a cellular mechanism underlying an experimental colitis that may explain the pathogenesis of ulcerative colitis.

Bouma G, Kaushiva A, Strober W. · Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. · Gastroenterology. · Pubmed #12145808 No free full text.

Abstract: BACKGROUND & AIMS: Immunogenetic analysis of experimental colitis may contribute to the further unraveling of the complex genetic basis of the inflammatory bowel diseases, Crohn's disease and ulcerative colitis. METHODS: Genetic regions associated with susceptibility to trinitrobenzene sulfonic acid (TNBS)-induced colitis were identified in a genome-wide linkage analysis in F2 progeny of colitis-susceptible SJL/J and -resistant C57BL/6 mice. An immunogenetic approach was then used to further study the pathophysiologic role of one of the identified loci. RESULTS: We identified susceptibility loci on chromosomes 9 (Tnbs1) and 11 (Tnbs2). Tnbs2 harbors the interleukin (IL)-12 p40 gene, a likely candidate gene because IL-12 is a known central mediator for both experimental colitis and human Crohn's disease. We therefore tested the ability of colitis-susceptible and -resistant strains to mount IL-12 responses to lipopolysaccharide (LPS), a strong inducer of IL-12 that is abundantly present in the intestine. We observed a remarkably higher serum IL-12 response to LPS in susceptible SJL/J mice. Subsequently, we showed that the genetic region regulating the IL-12 response to LPS colocalizes with Tnbs2. CONCLUSIONS: These data strongly suggest that the tendency to mount a high LPS-induced IL-12 response and susceptibility to TNBS-induced colitis are related and that in fact a genetically determined high IL-12 response is involved in the immunologic basis of susceptibility to colitis.

Blumberg RS, Strober W. · Gastroenterology Division, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115, USA. · JAMA. · Pubmed #11176874 links to  free full text

Abstract: Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract that manifests as ulcerative colitis and Crohn disease. Both these clinical entities result from interrelated genetic and environmental factors that may be channeled through an abnormality in mucosal immune function, possibly due to dysregulated or excessive T helper cell (T(H))1 (Crohn disease) or T(H)2 (ulcerative colitis) responses. This article reviews current knowledge of the role of immune factors in inflammatory bowel disease and the potential therapeutic strategies that target the pathways of T(H)1- or T(H)2-induced inflammation.

Boirivant M, Marini M, Di Felice G, Pronio AM, Montesani C, Tersigni R, Strober W. · Laboratory of Immunology, Istituto Superiore di Sanità, Rome. · Gastroenterology. · Pubmed #10029614 No free full text.

Abstract: BACKGROUND & AIMS: Normal human lamina propria lymphocytes manifest increased unstimulated apoptosis compared with peripheral lymphocytes, which are enhanced after stimulation via the CD2 activation pathway. This activation-induced apoptosis down-regulates cell expansion and cytokine production. In previous studies, it was shown that lamina propria T cells from patients with Crohn's disease and ulcerative colitis manifest abnormal proliferation and cytokine production. It was therefore of interest to determine if such cells also showed abnormal patterns of apoptosis. METHODS: Apoptosis was evaluated by propidium iodide staining of cells followed by flow cytometric analysis. Fas expression and Bcl-2 levels in cells were evaluated by immunofluorescence. RESULTS: Lamina propria lymphocytes from patients with Crohn's disease and ulcerative colitis as well as from 2 patients with diverticulitis showed defective CD2 pathway-induced apoptosis. Studies of the mechanisms of this defect focusing on cells from patients with Crohn's disease showed that Crohn's disease lamina propria lymphocytes from inflamed tissues express the same amount of cell surface Fas but are less sensitive to Fas-mediated apoptosis than control cells. In addition, lamina propria lymphocytes from inflamed Crohn's disease tissues manifest increased expression of Bcl-2 after CD2 pathway stimulation and elevated Bcl-2 levels in cultures of unstimulated T cells. CONCLUSIONS: T cells isolated from areas of inflammation in Crohn's disease, ulcerative colitis, and other inflammatory states manifest decreased CD2 pathway-induced apoptosis. Studies of cells from inflamed Crohn's disease tissue indicate that this defect is accompanied by elevated Bcl-2 levels. These changes are probably caused by the chronic inflammation and may aggravate the underlying disease processes that are present.