Potential role of Th17 cells in the pathogenesis of type 2 autoimmune pancreatitis

Loos, Michaela; Lauffer, Felix; Schlitter, Anna Melissa; Kleeff, Jörg; Friess, Helmut; Klöppel, Günter; Espósito, Irene

doi:10.1007/s00428-015-1850-4

Cited by 19 publications

(15 citation statements)

References 61 publications

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“…3A). No difference in the expression of Th17 cytokines was observed, supporting the hypothesis that Th17 cells are not involved in type 1 AIP pathogenesis (19). Although the TF Rorgt is upregulated in Tg(Ela1-Lta,b) mice, this TF is also expressed by lymphoid tissue inducer cells and lymphoid tissue inducer-like cells (20).…”

Section: Inhibition Of Ltbr Signaling Moderates Local Inflammatory Resupporting

confidence: 52%

Amelioration of Murine Autoimmune Pancreatitis by Targeted LTβR Inhibition and Anti-CD20 Treatment

et al. 2020

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Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis, for which treatment options, especially the long-term management, are limited. The only therapy that has been established and accepted so far is corticosteroids, but the relapse rate is significant. In the current study, we discern the effector mechanisms of targeted LTbR pathway inhibition using LTbR-Ig. Furthermore, the efficacy of LTbR-Ig therapy is compared with the depletion of immune cell subsets (CD4 + and CD20 +), which are suggested to play a pathological role in AIP development. Three well-established mouse models of AIP were used to examine treatment efficacies and mechanisms. Tg(Ela1-Lta,b) mice represent a genetic model, in which AIP develops spontaneously. In MRL/Mp and IL-10 2/2 mice, AIP is induced by repeated polyinosinic:polycytidylic acid injection. Mice with AIP were treated with anti-CD20, anti-CD4 mAbs, or targeted LTbR-Ig. LTbR-Ig and anti-CD20 treatment led to significant improvement of AIP, including a decrease in autoantibody production and pancreatic inflammation in Tg(Ela1-Lta,b) and IL-10 2/2 mice. The molecular mechanism of this beneficial effect possibly involves the downregulation of Stat3 and noncanonical NF-kb activation. Anti-CD4 treatment reduced Th1 and Th2 signature but did not alleviate AIP. Additionally, in contrast to anti-CD20 or anti-CD4 treatments, blocking LTbR signaling disrupted tertiary lymphoid organs in all three models. We demonstrate that treatment with LTbR-Ig or anti-CD20 Ab alleviated murine AIP. LTbR-Ig treatment for AIP was effective in both lymphotoxin-dependent and lymphotoxin-independent AIP models, possibly because of its dual anti-inflammatory and antiautoimmune mechanisms. ImmunoHorizons, 2020, 4: 688-700.

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Section: Inhibition Of Ltbr Signaling Moderates Local Inflammatory Resupporting

confidence: 52%

Amelioration of Murine Autoimmune Pancreatitis by Targeted LTβR Inhibition and Anti-CD20 Treatment

et al. 2020

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“…It has been reported that Th17 may be involved in the pathogenesis of type 2 AIP, especially in cases leading to the formation of granulocytic epithelial lesions. However, a comprehensive immune‐related gene expression profile was not analysed in this study . We performed a comprehensive analysis of the immune‐related gene expression profile of follicular pancreatitis compared to that of IgG4‐related AIP.…”

Section: Discussionmentioning

confidence: 99%

“…However, a comprehensive immune-related gene expression profile was not analysed in this study. 24 We performed a comprehensive analysis of the immune-related gene expression profile of follicular pancreatitis compared to that of IgG4related AIP. The findings clearly demonstrated that dendritic cells and lymphoid follicle markers and regulatory factors of Th17 are significantly up-regulated in cases of follicular pancreatitis.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological and immunological features of follicular pancreatitis – a distinct disease entity characterised by Th17 activation

et al. 2019

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Aim Follicular pancreatitis is a recently recognised, distinct clinicopathological entity characterised by the presence of many intrapancreatic lymphoid follicles with reactive germinal centres. However, the clinicopathological and immunological features and causes have not yet been established. We assessed the clinicopathological and immunological profiles of patients with follicular pancreatitis who underwent surgery. Methods and results This study included three patients with pancreatic masses (age range = 62–75 years; women:men: 1:2). A histopathological study of the resected pancreatic masses revealed abundant lymphoid follicles with reactive germinal centres in both periductal regions and diffusely within the parenchyma. No storiform fibrosis, obliterative phlebitis or granulocytic epithelial lesions were observed. The immunohistochemical examination revealed an IgG4/IgG‐positive plasma cell ratio <30% in all patients. Podoplanin (Th17 marker)‐expressing lymphocytes were present in the lymphoid follicles of those with follicular pancreatitis, whereas these were absent in normal lymph nodes and in lymphoid follicles of those with IgG4‐related autoimmune pancreatitis (AIP). An RNA digital counting assay clearly demonstrated that the expression counts of 20 genes, including dendritic cells and lymphoid follicles markers, and related cytokines were significantly higher in follicular pancreatitis than in IgG4‐related AIP (P < 0.01). The expressions of CCR6 and IL23A, which are genes related to Th17, were high. Conclusions This study shows that follicular pancreatitis is a histopathologically and immunologically distinct disease entity of pancreatitis and is characterised by upregulated Th17 expression.

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“…It is known that elevated numbers of Th-17 cells and IL-17 levels, found in the periductal compartiments, are linked to the destruction of the pancreatic duct epithelium in AIP-2 [43]. Supporting the deleterious behavior of IL-17 it has been shown that IL-17 intensifies the effects of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 [44], thus orchestrating the formation of neutrophil extracellular traps (NETs) and the occlusion of pancreatic ducts leading to pancreatic inflammation [45].…”

Section: Discussionmentioning

confidence: 99%

Distinct pathophysiological cytokine profiles for discrimination between autoimmune pancreatitis, chronic pancreatitis, and pancreatic ductal adenocarcinoma

et al. 2017

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BackgroundDiscriminating between autoimmune pancreatitis (AIP), chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC) can be challenging. In this retrospective study, levels of serum and tissue cytokines were analyzed as part of the clinical strategy for the preoperative differentiation between AIP and PDAC. The identification of differential cytokine profiles may help to prevent unnecessary surgical resection and allow optimal treatment of these pathologies.MethodsTo compare the cytokine profiles of AIP, CP, and PDAC patients, serum and pancreatic tissue homogenates were subjected to multiplex analysis of 17 inflammatory mediators. In total, serum from 73 patients, composed of 29 AIP (14 AIP-1 and 15 AIP-2), 17 CP, and 27 PDAC, and pancreatic tissue from 36 patients, including 12 AIP (six AIP-1 and six AIP-2), 12 CP, and 12 PDAC, were analyzed.ResultsComparing AIP and PDAC patients’ serum, significantly higher concentrations were found in AIP for interleukins IL-1β, IL-7, IL-13, and granulocyte colony-stimulating factor (G-CSF). G-CSF also allowed discrimination of AIP from CP. Furthermore, once AIP was divided into subtypes, significantly higher serum levels for IL-7 and G-CSF were measured in both subtypes of AIP and in AIP-2 for IL-1β when compared to PDAC. G-CSF and TNF-α were also significantly differentially expressed in tissue homogenates between AIP-2 and PDAC.ConclusionsThe cytokines IL-1β, IL-7, and G-CSF can be routinely measured in patients’ serum, providing an elegant and non-invasive approach for differential diagnosis. G-CSF is a good candidate to supplement the currently known serum markers in predictive tests for AIP and represents a basis for a combined blood test to differentiate AIP and particularly AIP-2 from PDAC, enhancing the possibility of appropriate treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-017-1227-3) contains supplementary material, which is available to authorized users.

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Potential role of Th17 cells in the pathogenesis of type 2 autoimmune pancreatitis

Cited by 19 publications

References 61 publications

Amelioration of Murine Autoimmune Pancreatitis by Targeted LTβR Inhibition and Anti-CD20 Treatment

Amelioration of Murine Autoimmune Pancreatitis by Targeted LTβR Inhibition and Anti-CD20 Treatment

Clinicopathological and immunological features of follicular pancreatitis – a distinct disease entity characterised by Th17 activation

Distinct pathophysiological cytokine profiles for discrimination between autoimmune pancreatitis, chronic pancreatitis, and pancreatic ductal adenocarcinoma

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