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      Immunopathogenesis of IBD: current state of the art.

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          Abstract

          IBD is a chronic inflammatory condition of the gastrointestinal tract encompassing two main clinical entities: Crohn's disease and ulcerative colitis. Although Crohn's disease and ulcerative colitis have historically been studied together because they share common features (such as symptoms, structural damage and therapy), it is now clear that they represent two distinct pathophysiological entities. Both Crohn's disease and ulcerative colitis are associated with multiple pathogenic factors including environmental changes, an array of susceptibility gene variants, a qualitatively and quantitatively abnormal gut microbiota and a broadly dysregulated immune response. In spite of this realization and the identification of seemingly pertinent environmental, genetic, microbial and immune factors, a full understanding of IBD pathogenesis is still out of reach and, consequently, treatment is far from optimal. An important reason for this unsatisfactory situation is the currently limited comprehension of what are the truly relevant components of IBD immunopathogenesis. This article will comprehensively review current knowledge of the classic immune components and will expand the concept of IBD immunopathogenesis to include various cells, mediators and pathways that have not been traditionally associated with disease mechanisms, but that profoundly affect the overall intestinal inflammatory process.

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          Most cited references164

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          A microbial symbiosis factor prevents intestinal inflammatory disease.

          Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.
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            Recognition of microorganisms and activation of the immune response.

            The mammalian immune system has innate and adaptive components, which cooperate to protect the host against microbial infections. The innate immune system consists of functionally distinct 'modules' that evolved to provide different forms of protection against pathogens. It senses pathogens through pattern-recognition receptors, which trigger the activation of antimicrobial defences and stimulate the adaptive immune response. The adaptive immune system, in turn, activates innate effector mechanisms in an antigen-specific manner. The connections between the various immune components are not fully understood, but recent progress brings us closer to an integrated view of the immune system and its function in host defence.
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              A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group.

              Studies in animals and an open-label trial have suggested a role for antibodies to tumor necrosis factor alpha, specifically chimeric monoclonal antibody cA2, in the treatment of Crohn's disease. We conducted a 12-week multicenter, double-blind, placebo-controlled trial of cA2 in 108 patients with moderate-to-severe Crohn's disease that was resistant to treatment. All had scores on the Crohn's Disease Activity Index between 220 and 400 (scores can range from 0 to about 600, with higher scores indicating more severe illness). Patients were randomly assigned to receive a single two-hour intravenous infusion of either placebo or cA2 in a dose of 5 mg per kilogram of body weight, 10 mg per kilogram, or 20 mg per kilogram. Clinical response, the primary end point, was defined as a reduction of 70 or more points in the score on the Crohn's Disease Activity Index at four weeks that was not accompanied by a change in any concomitant medications. At four weeks, 81 percent of the patients given 5 mg of cA2 per kilogram (22 of 27 patients), 50 percent of those given 10 mg of cA2 per kilogram (14 of 28), and 64 percent of those given 20 mg of cA2 per kilogram (18 of 28) had had a clinical response, as compared with 17 percent of patients in the placebo group (4 of 24) (p<0.001 for the comparison of the cA2 group as a whole with placebo). Thirty-three percent of the patients given cA2 went into remission (defined as a score below 150 on the Crohn's Disease Activity Index), as compared with 4 percent of the patients given placebo (P=0.005). At 12 weeks, 41 percent of the cA2-treated patients (34 of 83) had had a clinical response, as compared with 12 percent of the patients in the placebo group (3 of 25) (P=0.008). The rates of adverse effects were similar in the groups. A single infusion of cA2 was an effective short-term treatment in many patients with moderate-to-severe, treatment-resistant Crohn's disease.
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                Author and article information

                Journal
                Nat Rev Gastroenterol Hepatol
                Nature reviews. Gastroenterology & hepatology
                1759-5053
                1759-5045
                Jan 2016
                : 13
                : 1
                Affiliations
                [1 ] Department of Gastroenterology &Multidisciplinary Research Laboratory, Federal University of Rio de Janeiro, Rio de Janeiro 21941-913, Brazil.
                [2 ] Department of Pathobiology, Lerner Research Institute, Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
                Article
                nrgastro.2015.186
                10.1038/nrgastro.2015.186
                26627550
                b1a95b3a-4aab-473a-b146-426273005c16
                History

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