IL-23/IL-17 immunity as a hallmark of Crohnʼs disease

Hölttä, Veera; Klemetti, Paula; Sipponen, Taina; Westerholm-Ormio, Mia; Kociubinski, Guillermo; Salo, Harri M.; Räsänen, Laura; Kolho, Kaija‐Leena; Färkkilä, Martti; Savilahti, Erkki; Vaarala, Outi

doi:10.1002/ibd.20475

Cited by 165 publications

(90 citation statements)

References 33 publications

(42 reference statements)

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“…2B and C). This is consistent with previous studies pointing to the mucosa as a privileged site for Th17-cell development due to elevated secretion of specific polarizing mediators such as IL-6 and TGF-b1 [25]. Moreover, while the frequency of IFN-g-secreting CD4…”

Section: Cd25supporting

confidence: 92%

“…T cells in colonic biopsies of CD patients [25]. Furthermore, our results demonstrate that both CD4 1 and gd T cells from mucosal tissues of recipient mice are more activated as they display a higher proliferation rate and secrete more pro-inflammatory cytokines compared to cells from LNs.…”

mentioning

confidence: 54%

“…1F and G Studies show that a prominent role for Th1, and in particular Th17, polarized immune responses in autoimmunity and IBD-like disorders in humans and in mouse models [44,45]. In particular, IL-17-secreting T cells are found in lesions of patients with CD [4,22,25], and genome-wide association studies of CD and ulcerative colitis patients indicate the importance of Th17-promoting factors, including IL-23, in IBD [46,47]. We then sought to characterize the inflammatory nature of the mucosal inflammation.…”

Section: Foxp3mentioning

confidence: 99%

“…More specifically, it has been shown that gd T cells readily accumulate in inflamed tissues of IBD patients [22][23][24][25], although, in murine studies, gd T cells have been shown to either potently reduce [26][27][28] or exacerbate inflammation [29][30][31][32][33]. Some studies also identify gd T cells as a source of rapidly activated T cells with Th17-like effector properties providing the first line of defense against pathogens [34][35][36].…”

mentioning

confidence: 99%

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CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

2011

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Foxp31 regulatory T (T REG ) cells are critical mediators of peripheral immune tolerance, and abrogation of their function provokes a variety of autoimmune and inflammatory states including inflammatory bowel disease. In this study, we investigate the functional dynamics of T REG -cell responses in a CD4) hosts to gain insights into the mechanism and cellular targets of suppression in vivo. We show that CD4 1 T effector cell transfer into T-cell-deficient mice rapidly induces mucosal inflammation and colitis development, which is associated with prominent Th1 and Th17 responses. Interestingly, we unveil a prominent role for resident cd T cells in mucosal inflammation as they promote Th1 and particularly Th17 responses in the early phase of inflammation, thus exacerbating colitis development. We further demonstrate that CD4

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Section: Cd25supporting

confidence: 92%

mentioning

confidence: 54%

Section: Foxp3mentioning

confidence: 99%

mentioning

confidence: 99%

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CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

2011

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“…Indeed, Th17 immunity is considered a crucial element in the mucosal immune protection against bacterial and fungal pathogens (6). Its activation is also seen in autoimmune conditions and inflammatory bowel disease (6,12). In autoimmune diabetes, the lymphocytes in the inflamed islets show mucosal homing properties as demonstrated both in animal models and human T1D (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

IL-17 Immunity in Human Type 1 Diabetes

Honkanen

Nieminen

Gao

et al. 2010

The Journal of Immunology

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258

209

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Th17 immunity has been shown to regulate autoimmune diabetes in mice. IL-17 neutralization prevented development of diabetes when given postinitiation of insulitis but not earlier, suggesting interference with the effector phase of the disease. Islet-cell Ag-specific Th17 cells converted into IFN-γ–secreting Th1-like cells and caused diabetes in mice recipients. The role of IL-17 in human type 1 diabetes (T1D) is, however, not established. In this study, we show upregulation of Th17 immunity in peripheral blood T cells from children with T1D. This was characterized by increased IL-17 secretion and expression of IL-17, IL-22, and retinoic acid-related orphan receptor C isoform 2, but also FOXP3 transcripts upon T cell activation in vitro. Also, circulating memory CD4 cells from children with T1D showed the same pattern of IL-17, IL-22 and FOXP3 mRNA upregulation, indicating IL-17 pathway activation in vivo. IL-17–positive T cells appeared to be CD4+ cells expressing TCR-αβ and CCR6, and a subpopulation showed coproduction of IFN-γ. Given the Th17 immunity in T1D, we demonstrated that IL-17 had detrimental effects on human islet cells in vitro; it potentiated both inflammatory and proapoptotic responses. Our findings highlight the role of IL-17 immunity in the pathogenesis of human T1D and point to a potential therapeutic strategy.

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Interleukin‐23 Mediates the Intestinal Response to Microbial β‐1,3‐Glucan and the Development of Spondyloarthritis Pathology in SKG Mice

Benham

Rehaume

Hasnain

et al. 2014

Arthritis & Rheumatology

179

125

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Results. In curdlan-treated SKG mice, arthritis, enthesitis, and ileitis were IL-23 dependent. Enthesitis was specifically dependent on IL-17A and IL-22. IL-23 was induced in the ileum, where it amplified ER stress, goblet cell dysfunction, and proinflammatory cytokine production. IL-17A was pathogenic, while IL-22 was protective against ileitis. IL-22؉CD3؊ innate-like cells were increased in lamina propria mononuclear cells of ileitis-resistant BALB/c mice, which developed ileitis after curdlan injection and anti-IL-22.Conclusion. In response to systemic ␤-1,3-glucan, intestinal IL-23 provokes local mucosal dysregulation and cytokines driving the SpA syndrome, including IL-17/IL-22-dependent enthesitis. Innate IL-22 production promotes ileal tolerance.

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IL-23/IL-17 immunity as a hallmark of Crohnʼs disease

Abstract: Our findings suggest that activation of the IL-23/IL-17 axis is fundamentally connected to the etiology of CD and may represent the basis for the relapsing nature of the disease by increasing the sensitivity of epithelium to microbial LPS.

Cited by 165 publications

References 33 publications

CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

IL-17 Immunity in Human Type 1 Diabetes

Interleukin‐23 Mediates the Intestinal Response to Microbial β‐1,3‐Glucan and the Development of Spondyloarthritis Pathology in SKG Mice

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IL-23/IL-17 immunity as a hallmark of Crohnʼs disease

Abstract: Our findings suggest that activation of the IL-23/IL-17 axis is fundamentally connected to the etiology of CD and may represent the basis for the relapsing nature of the disease by increasing the sensitivity of epithelium to microbial LPS.

Cited by 165 publications

References 33 publications

CD4+Foxp3+ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

CD4+Foxp3+ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

IL-17 Immunity in Human Type 1 Diabetes

Interleukin‐23 Mediates the Intestinal Response to Microbial β‐1,3‐Glucan and the Development of Spondyloarthritis Pathology in SKG Mice

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CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation

CD4⁺Foxp3⁺ regulatory T cells suppress γδ T‐cell effector functions in a model of T‐cell‐induced mucosal inflammation