Intramucosal bacteria in ileal pouch (original) (raw)
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Clinical & Experimental Immunology, 2008
SUMMARY The effect of macrophages on spontaneous immunoglobulin production by isolated human intestinal mononuclear cells (MNC) is unknown. Depietion of macrophages by adherence to fibronectin or by panning with macrophage-specific monoclonal antibody 3C10 lead to a significant reduction in IgA, IgG and lgM production by intestinal MNC from both normal (n= 10) and inflammatory bowel disease (IBD) (n= 13) mucosa. The reduction in immunoglobulin produced by macrophage-depleted intestinal MNC was greater in IBD patients than in normal controls. There was a significant correlation (r=0·816, P<0·001) between the percentage of macrophages depleted by panning with 3C10 and the reduction in IgG produced by macrophage-depleted intestinal MNC. Addition of either fibronectin-adherent cells or the supernatant from these macrophage-enriched cells enhanced immunoglobulin production in a dose-dependent fashion. A greater increase in IgG production by macrophage-depleted cells was seen when cult...
Editorial: Cytokines and Intestinal Mucosal Immunity
Frontiers in Immunology, 2021
Editorial on the Research Topic Cytokines and Intestinal Mucosal Immunity Since discovery of the prototypic cytokines, interleukin-1 (IL-1) and tumor necrosis factor-a (TNF), almost 50 years ago (1, 2), an explosion of information has followed regarding the biology of cytokines and their critical role(s) during health and disease. To date, 41 interleukins and more than 18 TNF superfamily (TNFSF) members have been described. Notably, in 1990, our group was one of the first to show that blockade of a single cytokine, i.e., IL-1, was effective in markedly reducing the severity of experimental colitis (3), laying the foundation to conceptualize that targeting of an individual cytokine could successfully impact the development and progression of a specific disease. The role of cytokines, in fact, has been particularly important in the gastrointestinal tract, both in maintaining homeostasis and during chronic inflammatory disorders, such as inflammatory bowel disease (IBD), wherein many cell types have the ability to both react to, and produce, cytokines in response to a variety of antigenic stimuli, dietary products, microbial components, and toxic agents. This wealth of new information has led to the approval of different anti-cytokine therapies, such as anti-TNF and anti-IL-12/23 monoclonal antibodies, for the treatment of both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD. In addition, novel small molecule inhibitors, such as those targeting the JAK/STAT pathway, and which possess broad anti-cytokine activity, are now available in the armamentarium of gastroenterologists to treat IBD. In this Research Topic, the role of canonical, and more novel, cytokines are discussed in the context of intestinal immunity and chronic gut inflammation. Three articles focus on the role(s) of TNFSF members (Li et al.; Valatas et al.; Giles et al.). Specifically, Li et al. and Valatas et al. report the importance of the TL1A (TNF-like ligand 1A, TNFSF15)/DR3 (death receptor 3,TNFRSF25) ligand-pair, for which increasing evidence suggests a critical role not only in the pathogenesis of IBD, but also in the development of gut fibrosis/fibrostenotic disease. These papers highlight TL1A/ DR3's pleiotropic functions in regulating the balance between T effector and T regulatory cells (Tregs), as well as innate lymphoid cells (ILCs), thereby serving as a vital rheostat during IBD. Notably, monoclonal antibodies against TL1A are currently in clinical trials for the treatment of CD and UC, and will shortly reveal the efficacy of anti-TL1A/DR3 strategies in IBD.
Le système immunitaire muqueux dans les maladies inflammatoires intestinales
Acta Endoscopica, 1991
Ľimmunité sécrétaire est la partie la mieux définie du système immunitaire muqueux. Ce mécanisme de défense humorale adapté dépend ďune coopération étroite entre ľépithélium sécrétoire et les plasmocytes locaux. Ces immunocytes produisent de préférence des diméres et de plus larges polyméres ďIgA. Les IgA polymériques (poly-IgA) et les pentaméres IgM, contiennent des chaînes J et peuvent pour cette raison, être liés au composant sécrétoire épithélial (CS). Son fonctionnement en tant que récepteur de transport poly-Ig est nécessaire à la production ďIgA sécrétoire (SIgA) et ďIgM sécrétoire (SIgM). Des faits multiples montrent que les anticorps SIgA et SIgM assurent ľexclusion immunitaire, ’opposant ainsi à la colonisation microbienne de la muqueuse et à la pénétration ďantigènes solubles. La production muqueuse de poly-IgA est déréglée de façon significative dans les maladies inflammatoires intestinales (Mil), ce dont témoigne la réduction drastique de ľexpression chaîne-J au niveau des immunocytes IgA muqueux. En outre, on observe une déviation significative des sous-classes IgA2 vers les IgAl, moins résistantes à la dégradation protéolytique. Ces modifications, associées à une activation des lymphocytes T et des macrophages, et à une augmentation importante des cellules productrices ďIgG, altèrent ľhoméostase immunitaire locale et menacent la défense muqueuse. Bien qu’un accroissement de la totalité de la population immunocytaire muqueuse puisse compenser la production relativement réduite de poly-IgA, la diminution de ľexpression CS au niveau de ľépithélium régénératif ou dysplasique, montre que le système SIgA n’est en aucun cas intact dans les Mil. Ľactivation du complément observée en relation avec des dépôts d'IgGl épithéliaux chez les patients atteints de recto-colite ulcéreuse, suggère que ľépithélium de surface est soumis à une agression immunitaire. Ces dépôts épithéliaux contiennent réguliérement des complexes terminaux du complément (CTC) et trés souvent du C3b, témoins ďune activation persistante. La comparaison entre des jumeaux univitellins mais différents du point de vue colite ulcéreuse, suggère qu’une réponse IgGl locale prononcée pourrait, en partie, être génétiquement déterminée ; une possibilité intéressante serait que ce phénomène représente une réponse autoimmune (anti-épithéliale). Néanmoins, ľévénement initial, déclenchant le mécanisme immunopathologique des MII demeure inconnu. La suppression de la tolérance orale aux antigènes endoluminaux a été suggérée comme un mécanisme ďautoentretien possible, probablement par interaction entre les lymphocytes T CD4b+ activés et les cellules épithéliales avec une expression HLA classe II exagérément intense. Secretory immunity is the best defined part of the mucosal immune system. This adaptive humoral defence mechanism depends on a fascinating cooperation between the secretory epithelium and the local plasma cells. These immunocytes produce preferentially dimers and larger polymers of IgA. Such polymeric IgA (poly-IgA), and also pentameric IgM, contain J chain and can therefore become bound to the epithelial secretory component (SC). Its function as a poly-Ig transport receptor is necessary for the generation of secretory IgA (SIgA) and secretory IgM (SIgM). There is abundant evidence that SIgA and SIgM antibodies perform immune exclusion, thereby counteracting microbial colonization and mucosal penetration of soluble antigens. The mucosal poly-IgA production is significantly down-regulated in inflammatory bowel disease (IBD), as revealed by a strikingly decreased J-chain expression in mucosal IgA immunocytes. There is moreover a significant shift from the IgA2 to the IgAl subclass, which is less resistant to proteolytic degradation. These changes, along with activation of T cells and macrophages and a dramatic increase of IgG-producing cells, will alter the local immunological homeostasis and jeopardize mucosal defence. Although the overall increase of the total mucosal immuno- cyte population may compensate for the relatively reduced poly-IgA production, decreased SC expression in regenerat- ing and dysplastic epithelium shows that the SIgA system is by no means intact in IBD. Complement activation observed in relation to epithelial IgGl deposits in
Immunobiology, 2011
Defects in macrophage function have been implicated in the establishment of Crohn's disease (CD). However, the response of macrophages from CD patients to live bacteria, particularly Mycobacterium avium subsp. paratuberculosis (MAP), has not been addressed. Considering MAP has long been associated to CD, our objective was to assess whether macrophages from CD patients showed impaired inflammatory response to infection by MAP comparing to M. avium subsp. avium (MA) and other live intestinal commensal bacteria. Human peripheral blood monocyte-derived macrophages were obtained from CD patients, ulcerative colitis (UC) patients and controls. Following in vitro infection with MAP, MA, Escherichia coli or Enterococcus faecalis, cytokine levels and cell surface receptor expression were evaluated at different time points. Macrophages from CD patients showed impaired TNF-␣ secretion in response to bacterial challenge, but augmented IL-23 secretion and preserved IL-12 secretion and CD-40 expression. In addition, CD macrophages showed low IL-10 secretion. Macrophages from IBD patients showed increased expression of TLR-2 and -4, unaffected by infection. Differences in cytokine secretion observed after bacterial challenge were not MAP-specific, as other bacteria (E. coli and MA) showed similar effects. Macrophages from UC patients showed a less compromised TNF-␣ synthesis in response to mycobacterial infection than CD macrophages, with increased constitutive IL-12 secretion, and preserved IL-10 secretion. The increased IL-23 levels in response to infection and decreased IL-10 production observed in macrophages from CD patients may contribute to the inflammatory exacerbation observed in those patients.
Immunobiology, 2011
Defects in macrophage function have been implicated in the establishment of Crohn's disease (CD). However, the response of macrophages from CD patients to live bacteria, particularly Mycobacterium avium subsp. paratuberculosis (MAP), has not been addressed. Considering MAP has long been associated to CD, our objective was to assess whether macrophages from CD patients showed impaired inflammatory response to infection by MAP comparing to M. avium subsp. avium (MA) and other live intestinal commensal bacteria. Human peripheral blood monocyte-derived macrophages were obtained from CD patients, ulcerative colitis (UC) patients and controls. Following in vitro infection with MAP, MA, Escherichia coli or Enterococcus faecalis, cytokine levels and cell surface receptor expression were evaluated at different time points. Macrophages from CD patients showed impaired TNF-␣ secretion in response to bacterial challenge, but augmented IL-23 secretion and preserved IL-12 secretion and CD-40 expression. In addition, CD macrophages showed low IL-10 secretion. Macrophages from IBD patients showed increased expression of TLR-2 and -4, unaffected by infection. Differences in cytokine secretion observed after bacterial challenge were not MAP-specific, as other bacteria (E. coli and MA) showed similar effects. Macrophages from UC patients showed a less compromised TNF-␣ synthesis in response to mycobacterial infection than CD macrophages, with increased constitutive IL-12 secretion, and preserved IL-10 secretion. The increased IL-23 levels in response to infection and decreased IL-10 production observed in macrophages from CD patients may contribute to the inflammatory exacerbation observed in those patients.
Scientific Reports
Crohn's disease (CD) is a chronic inflammatory disorder characterized by immune response dysregulation. Tumor necrosis factor-α (TNFα) is a key cytokine in the pathogenesis of CD, as indicated by the efficacy of anti-TNF-α therapy with infliximab (IFX). However, approximately 30-40% of CD patients fail to respond to IFX with still unclear underlying mechanisms. This study compares the inflammatory phenotype of monocytes from CD patients, who respond or non-respond to IFX. Under basal conditions, the mRNA for the cytokines TNFα, IL-23, IL-1β and the chemokines CXCL8/ IL-8, CCL5/RANTES and CCL2/MCP-1 was up-regulated in monocytes from non-responders than responders. The expression of the same cytokines and CCL2/MCP-1 was higher in non-responders also upon LPS treatment. Moreover, higher secretion of TNFα, IL-1β, IFNγ and IL-2 proteins occurred in the supernatants of LPS-treated non-responders cells. Resistance to IFX in CD may result from a transcriptional dysregulation of circulating monocytes, leading to hyperactivation of pro-inflammatory pathways. Monocytes' cytokine profile may thus represent a predictive marker of response to IFX. Monocytes were isolated from blood samples of 19 CD patients (11 responders, 8 nonresponders) and incubated with or without LPS. Cytokine profiles were assessed by RT-qPCR and, in the supernatants, by ELISA assay. Crohn's disease (CD) is a chronic inflammatory disorder potentially affecting the whole gastrointestinal tract, with segmental and transmural involvement of the gastrointestinal mucosa. Although the precise etiology of the disease is still controversial, there is a general consensus on a multifactorial pathogenesis, including genetic predisposition, environmental factors, and dysregulation of both innate and adaptive immune system responses against intestinal microflora 1. The hallmark of CD is a chronic inflammation promoted and sustained by hyperactivated effector immune cells through an increased production of proinflammatory cytokines, mainly tumor necrosis factor (TNF) 2. Lamina propria macrophages isolated from colonic biopsies of CD patients have been shown to spontaneously produce increased amounts of TNF, that correlate with the degree of tissue involvement and mucosal inflammation 3 , demonstrating their central role in the perpetuation of inflammation. TNF is synthesized as a membrane-bound protein (mTNF) which is released as soluble form (sTNF) after cleavage of the extracellular domain by TNF-converting enzyme (TACE) 4. The cytokine is endowed with different functions: by binding to the ubiquitous TNF receptor 1 (TNFR1), sTNF can alternatively activate caspase-dependent apoptosis, and promote proinflammatory cytokine expression through the activation of the
Scandinavian Journal of Gastroenterology, 2012
Objective. Mucosal cytokine profile determines T cell differentiation and may play an important role in the clinical course of inflammatory bowel disease (IBD). Cytokines from different T helper (Th) cell subsets are elevated in inflamed mucosa of patients with ulcerative colitis (UC), contributing to the inflammation. The aim of this study was to determine the predictive value of pre-treatment mucosal cytokine profile in response to therapy with the anti-TNF agent infliximab (IFX). Material and methods. The expression of Th1, Th17, Th2 and T-regulatory (Treg)-related cytokines was quantified by real-time PCR in mucosal biopsies from 74 UC patients before initiation of IFX induction therapy. Clinical and endoscopic effects were assessed after three infusions. Remission was defined as ulcerative colitis disease activity index (UCDAI) below 3. Results. Higher gene expression levels of IL-17A and IFN-g were significantly associated with remission after three IFX infusions (OR = 5.4, p = 0.013 and OR = 5.5, p = 0.011, respectively). IL-17A and IFN-g mRNA expression showed positive correlation. Th2 and Treg-related mediators were not significantly associated with clinical outcome, but were expressed at higher levels in UC patients compared with the controls. Immunohistochemistry (IHC) confirmed the presence of cells expressing both IL-17A and IFN-g. Conclusions. High expression of Th1-and Th17-related cytokines in the mucosa of UC patients can potentially predict a favorable outcome of IFX induction therapy. Th2 and Treg-related mediators do not appear useful as predictive markers.