Characteristics of Intestinal Dendritic Cells in Inflammatory Bowel Diseases

Hart, Ailsa; Al-Hassi, Hafid O.; Rigby, Rachael; Bell, Sally; Emmanuel, Anton; Knight, Stella C.; Kamm, Michael A.; Stagg, Andrew J.

doi:10.1053/j.gastro.2005.05.013

Cited by 472 publications

(390 citation statements)

References 69 publications

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“…It is now well established that DC play a central role in orchestrating intestinal immune responses through promotion of inflammatory pathways and the maintenance of tolerance [1][2][3]. Precisely, how DC mediate these diverse and opposing functions is not known.…”

Section: Introductionmentioning

confidence: 99%

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Laffont¹,

Siddiqui²,

2010

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Intestinal CD103 1 DC promote the differentiation of Foxp3 1 Treg from naïve CD4 1 T cells through mechanisms involving TGF-b and the dietary metabolite, retinoic acid (RA). In this study, we have analysed whether the specialised features of CD103 1 DC are conserved in colitis. Our results show that inflammation dampens the tolerogenic properties of MLN CD103 1 DC, which is associated with lower expression of tgfb2 and aldh1a2. Accordingly, CD103 1 DC taken from colitic mice are impaired in their ability to induce Foxp3 1 Treg and instead favour the emergence of IFN-c-producing CD4 1 T cells compared with their steady-state counterparts. BrdU-labelling studies and analysis of ontogeny markers show that CD103 1 DC from steady-state and colitic settings retain similar subset composition and developmental pathways. These results indicate that MLN CD103 1 DC are not hard-wired to promote tolerance but can adapt to environmental conditions. The inflammatory properties of MLN CD103 1 DC in colitic mice may reflect defective gut tolerogenic conditioning or altered migratory pathways and raise the possibility that migratory DC populations contribute to the pathogenesis of inflammatory bowel disease.Key words: Colitis . DC . Intestinal immunity . Ontogeny . Treg IntroductionThe intestinal immune system must maintain a fine balance between harmless responses to food and commensal bacteria and protective immunity to invading pathogens. It is now well established that DC play a central role in orchestrating intestinal immune responses through promotion of inflammatory pathways and the maintenance of tolerance [1][2][3]. Precisely, how DC mediate these diverse and opposing functions is not known. One possibility is that these activities are mediated by distinct DC populations and indeed many subtypes of DC have been identified in the gut [4]. It has been proposed that resident gutconditioned DC may favour tolerogenic responses, whereas newly recruited inflammatory DC may drive host protective immunity.Alternatively, tissue-resident DC may adopt distinct functions under homeostatic and inflammatory conditions [4,5].We and others [6][7][8][9] have identified and characterised a specialised population of MLN DC that express the integrin a E chain, CD103. CD103 1 DC represent a sentinel DC population in the small intestine (SI) and can migrate to the MLN to initiate adaptive immune responses [10]. Under homeostatic conditions, CD103 1 DC in MLN promote the development of Foxp3 1 Treg. By contrast, the reciprocal CD103 À MLN DC population displays a more pro-inflammatory phenotype and appears to represent a developmentally distinct DC population [9].In intestinal inflammation, immune regulatory pathways that normally promote tolerance in the intestine break down. Whether this is attributable to changes in DC populations or their function in the MLN is not known. Here, we show that in colitic mice, the tolerogenic properties of CD103 1 MLN DC are lost and that this APC population now drives inflammatory T-cell responses that may c...

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Section: Introductionmentioning

confidence: 99%

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Laffont¹,

Siddiqui²,

2010

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“…Intestinal DCs control immune tolerance in the gastrointestinal tract [8][9][10]. DCs also maintain immune responses localized to specific tissues, since they imprint specific tissue-homing profiles on stimulated T cells [11].…”

Section: Introductionmentioning

confidence: 99%

“…1A), assessing cytokine secretion by DCs is not a feasible approach. Therefore, we studied their natural ongoing intracellular cytokine production, in the absence of any external challenge [8,26], following conditioning with intestinal microenvironments.None of the assayed cytokines in the culture SNs correlated with the ongoing cytokine production of DCs following SN conditioning (data not shown). When exposed to a noninflamed microenvironment, DCs decreased ongoing production of proinflammatory cytokines IL-12 and IL-6, and increased regulatory cytokine IL-10, when compared with DCs exposed to paired inflamed areas (Fig.…”

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confidence: 99%

IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

et al. 2012

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Dendritic cells (DCs) control the type and location of immune responses. Ulcerative colitis (UC) is considered a Th2 disease mediated by IL-13 where up to one third of patients can develop extraintestinal manifestations. Colonic biopsies from inflamed and noninflamed areas of UC patients were cultured in vitro and their supernatants were used to condition human blood enriched DCs from healthy controls. Levels of IL-13 in the culture supernatants were below the detection limit in most cases and the cytokine profile suggested a mixed profile rather than a Th2 cytokine profile. IL-6 was the predominant cytokine found in inflamed areas from UC patients and its concentration correlated with the Mayo endoscopic score for severity of disease. DCs conditioned with noninflamed culture supernatants acquired a regulatory phenotype with decreased stimulatory capacity. However, DCs conditioned with inflamed culture supernatants acquired a proinflammatory phenotype with increased expression of the skin-homing chemokine CCR8. These DCs did not have decreased T-cell stimulatory capacity and primed T cells with the skin-homing CLA molecule in an IL-6-dependent mechanism. Our results highlight the role of IL-6 in UC and question the concept of UC as a Th2 disease and the relevance of IL-13 in its etiology.Keywords: Dendritic cells r IL-6 r Mucosal immunity r Intestinal immunity r Ulcerative colitis Correspondence: Prof. Stella C. Knight e-mail: s.knight@imperial.ac.uk IntroductionThe gastrointestinal tract is in contact with a wide variety of commensal microbiota and diverse pathogens, and therefore C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 1338 David Bernardo et al. Eur. J. Immunol. 2012. 42: 1337-1353 requires a balance to be maintained between immunity and immune tolerance; the lack of immune responses against food antigens and/or the commensal microbiota is essential to maintain the homeostasis of the gastrointestinal tract [1]. Ulcerative colitis (UC) is a form of inflammatory bowel disease (IBD), traditionally related to a Th2 cytokine profile mediated by 3], where immune homeostasis of the gastrointestinal tract is compromised. Up to 1/3rd of UC patients can develop extraintestinal manifestations with the skin being one of such tissues [4,5].Dendritic cells (DCs) are the most potent antigen presenting cells and determine the nature and type of immune responses [6,7]. Intestinal DCs control immune tolerance in the gastrointestinal tract [8][9][10]. DCs also maintain immune responses localized to specific tissues, since they imprint specific tissue-homing profiles on stimulated T cells [11]. Retinoic acid (RA), the active form of vitamin A following dehydrogenization by the RALDH2 enzyme controls some of the mechanisms of immune homeostasis of the gut [12][13][14]. RA-producing DCs mediate the IgA switching of B cells [15], the generation of T cells with a regulatory phenotype [10], and the imprinting of gut-homing markers on B and T cells [16,17], thereby keeping tolerogenic immune responses com...

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“…7,31 In patients with CD, but not UC, dendritic cells from inflamed tissue express significantly higher levels of maturation and activation markers CD80/CD86 and CD40. 32 The apoptosis-preventing effect of CD40 ligation has been related to upregulation of the anti-apoptotic proteins Bcl-2 and Bcl-XL, which counter-balance the apoptotic property of various maturation stimuli in dendritic cells. 33 Moreover, blocking of CD40/CD154 ligation is an effective means to ameliorate autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

CD44v7 ligation downregulates the inflammatory immune response in Crohn's disease patients by apoptosis induction in mononuclear cells from the lamina propria

et al. 2007

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Deletion of exon CD44v7 abrogates experimental colitis by apoptosis induction in intestinal mononuclear cells. Here we show that CD44v7 expression was upregulated upon CD40 ligation in human mononuclear cells, and examined whether ligation of CD44v7 also affects activation and apoptosis in lamina propria mononuclear cells (LPMC) from Crohn's disease (CD) patients. Thirty five patients with chronic inflammatory bowel disease (IBD), fourteen controls and four patients with diverticulitis were evaluated. CD44v7 was upregulated predominantly in the inflamed mucosa of CD patients. Furthermore, incubation with an antiCD44v7 antibody induced apoptosis in LPMC isolated from inflamed mucosa of CD patients, but not from non-inflamed mucosa, from patients with ulcerative colitis (UC) or from normal controls. CD40 ligation and simultaneous incubation with anti-CD44v7 significantly downregulated CD80 in dendritic cells, thus inhibiting a critical second signal for naive T-cell activation. The apoptotic signal was mediated via the intrinsic mitochondrial pathway with decreased Bcl-2 and increased 7A6 (a mitochondrial membrane protein) expression. It was Fas independent and required caspases-3 and -9 activation. The process is highly specific for macrophage activation via CD40. These findings point to a novel mechanism of apoptosis induction in CD patients mediated by CD44v7 ligation.

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Characteristics of Intestinal Dendritic Cells in Inflammatory Bowel Diseases

Cited by 472 publications

References 69 publications

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

CD44v7 ligation downregulates the inflammatory immune response in Crohn's disease patients by apoptosis induction in mononuclear cells from the lamina propria

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Characteristics of Intestinal Dendritic Cells in Inflammatory Bowel Diseases

Cited by 472 publications

References 69 publications

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103+ dendritic cells

IL‐6 promotes immune responses in human ulcerative colitis and induces a skin‐homing phenotype in the dendritic cells and Tcells they stimulate

CD44v7 ligation downregulates the inflammatory immune response in Crohn's disease patients by apoptosis induction in mononuclear cells from the lamina propria

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Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells

Intestinal inflammation abrogates the tolerogenic properties of MLN CD103⁺ dendritic cells