Endoscopic methods are increasingly used in the diagnosis of cystic lesions of the pancreas. The two major endoscopic approaches are endoscopic ultrasonography (EUS) and transpapillary diagnosis. ...EUS‐guided fine‐needle aspiration cytology and EUS‐guided fine needle‐based confocal laser endomicroscopy have been used in the differential diagnosis of mucinous and non‐mucinous pancreatic cysts. EUS is the most sensitive modality for detecting mural nodules (MN) in intraductal papillary mucinous neoplasms (IPMN). Contrast‐enhanced harmonic EUS (CH‐EUS), as an add‐on to EUS, is useful for identifying and characterizing MN. Recent studies show that CH‐EUS has a sensitivity of 60–100% and a specificity of 75–92.9% for diagnosing malignant cysts. Intraductal ultrasonography and peroral pancreatoscopy are especially useful for detecting MN and IPMN. A recent meta‐analysis showed that cytological assessment of pancreatic juice using a transpapillary approach had a pooled sensitivity, specificity, and accuracy of 35.1%, 97.2%, and 92.9%, respectively, for diagnosing malignant IPMN. Further studies are warranted to determine the indications for each of these novel techniques in assessing cystic lesions of the pancreas.
Abstract
Previous studies have shown that inhibition of receptor-interacting serine/threonine kinase (RICK) (also known as RIP2) results in amelioration of experimental colitis. This role has largely ...been attributed to nucleotide-binding oligomerization domain 2 (NOD2) signaling since the latter is considered a major inducer of RICK activation. In this study, we explored the molecular mechanisms accounting for RICK-mediated inhibition of inflammatory bowel disease (IBD). In an initial series of studies focused on trinitrobenzene sulfonic acid (TNBS)-colitis and dextran sodium sulfate (DSS)-colitis we showed that down-regulation of intestinal RICK expression in NOD2-intact mice by intra-rectal administration of a plasmid expressing RICK-specific siRNA was accompanied by down-regulation of pro-inflammatory cytokine responses in the colon and protection of the mice from experimental colitis. Somewhat surprisingly, intra-rectal administration of RICK-siRNA also inhibited TNBS-colitis and DSS-colitis in NOD2-deficient and in NOD1/NOD2-double deficient mice. In complementary studies of humans with IBD we found that expression of RICK, cellular inhibitor of apoptosis protein 2 (cIAP2) and downstream signaling partners were markedly increased in inflamed tissue of IBD compared to controls without marked elevations of NOD1 or NOD2 expression. In addition, the increase in RICK expression correlated with disease activity and pro-inflammatory cytokine responses. These studies thus suggest that NOD1- or NOD2-independenent activation of RICK plays a major role in both murine experimental colitis and human IBD.
RICK/RIP2 can mediate NOD2-independent gut inflammation
Inflammatory bowel diseases (IBDs) are becoming more frequent worldwide. A significant fraction of patients with IBD are refractory to various types of therapeutic biologics and small molecules. ...Therefore, identification of novel therapeutic targets in IBD is required. Receptor-interacting serine/threonine kinase 2 (RIPK2), also known as receptor-interacting protein 2 (RIP2), is a downstream signaling molecule for nucleotide-binding oligomerization domain 1 (NOD1), NOD2, and Toll-like receptors (TLRs). RIPK2 is expressed in antigen-presenting cells, such as dendritic cells and macrophages. Recognition of microbe-associated molecular patterns by NOD1, NOD2, and TLRs leads to the interaction between RIPK2 and these innate immune receptors, followed by the release of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-12/23p40 through the activation of nuclear factor kappa B and mitogen-activated protein kinases. Thus, activation of RIPK2 plays a critical role in host defense against microbial infections. Recent experimental and clinical studies have provided evidence that activation of RIPK2 is involved in the development of autoimmune diseases, especially IBDs. In addition, the colonic mucosa of patients with IBD exhibits enhanced expression of RIPK2 and associated signaling molecules. Furthermore, the blockage of RIPK2 activation ameliorates the development of experimental murine colitis. Thus, activation of RIPK2 underlies IBD immunopathogenesis. In this review, we attempt to clarify the roles played by RIPK2 in the development of IBD by focusing on its associated signaling pathways. We also discuss the possibility of using RIPK2 as a new therapeutic target in IBD.
Autoimmune pancreatitis (AIP) is now considered a pancreatic manifestation of a newly proposed disease condition, IgG4-related disease (IgG4-RD). IgG4-RD is characterized by enhanced IgG4 antibody ...responses and multiple organ involvements. Recent epidemiological studies have addressed the incidence of cancer in patients with AIP and/or IgG4-RD. Surprisingly, a significant number of AIP patients were detected with cancer at or within one year of the diagnosis of AIP. Furthermore, around 50% of all cancers detected in AIP patients comprised mainly 3 types (gastric, lung, and prostate cancer). Thus, AIP appears to be associated with cancer of other organs rather than the pancreas itself, which suggests that AIP is not a pre-cancerous condition of the pancreas. Moreover, the simultaneous occurrence of cancer and AIP in many patients has led to the establishment of an attractive concept that AIP might sometimes arise from co-existing cancers as a paraneoplastic syndrome.
Dysbiosis contributes to the development of autoimmune pancreatitis
Abstract
Autoimmune pancreatitis (AIP) is a pancreatic manifestation of a newly proposed disease entity, IgG4-related disease ...(IgG4-RD), characterized by enhanced IgG4 antibody responses and involvement of multiple organs. We have previously reported that innate immune activation contributes to the development of AIP and IgG4-RD, as these diseases are characterized by the production of IFN-α and IL-33 by plasmacytoid dendritic cells (pDCs) that mediate chronic fibroinflammatory responses. In this study, we investigated the roles played by innate immunity against intestinal microflora in experimental AIP induced in MRL/MpJ mice by repeated administrations of 100 µg of polyinosinic-polycytidylic acid poly (I:C). Bowel sterilization with a broad spectrum of antibiotics inhibited pancreatic accumulation of pDCs producing IFN-α and IL-33, and thereby suppressed the development of AIP. Mice treated with 10 µg of poly (I:C) developed severe AIP equivalent to that induced by 100 µg of poly (I:C) upon co-housing with mice treated with 100 µg of poly (I:C). Fecal microbiota transplantation (FMT) from donor mice treated with 100 µg of poly (I:C) led to the development of severe AIP in the recipient mice upon injection with 10 µg of poly (I:C). Induction of severe AIP in mice with 10 µg of poly (I:C) was associated with pancreatic accumulation of pDCs producing IFN-α and IL-33 in the co-housing and FMT experiments. These data collectively suggest that innate immune responses against intestinal microflora are involved in the development of experimental AIP, and that intestinal dysbiosis increases sensitivity to experimental AIP via activation of pDCs.
Abstract
Polymorphisms in the autophagy-related protein 16 like 1 (ATG16L1) and nucleotide-binding oligomerization domain 2 (NOD2) genes are associated with Crohn’s disease (CD). Impaired interaction ...between ATG16L1 and NOD2 underlies CD immunopathogenesis. Although activation of the receptor-interacting serine–threonine kinase (RICK, also known as RIP2), a downstream signaling molecule for NOD2 and multiple toll-like receptors (TLRs), plays a pathogenic role in the development of inflammatory bowel disease, the molecular interaction between ATG16L1 and RICK/RIP2 remains poorly understood. In this study, we examined the physical interaction between ATG16L1 and RICK/RIP2 in human embryonic kidney 293 cells and human monocyte-derived dendritic cells (DCs) expressing excessive and endogenous levels of these proteins, respectively. We established that ATG16L1 binds to RICK/RIP2 kinase domain and negatively regulates TLR2-mediated nuclear factor-kappa B (NF-κB) activation and pro-inflammatory cytokine responses by inhibiting the interaction between TLR2 and RICK/RIP2. Binding of ATG16L1 to RICK/RIP2 suppressed NF-κB activation by down-regulating RICK/RIP2 polyubiquitination. Notably, the percentage of colonic DCs expressing ATG16L1 inversely correlated with IL-6 and TNF-α expression levels in the colon of CD patients. These data suggest that the interaction between ATG16L1 and RICK/RIP2 maintains intestinal homeostasis via the down-regulation of TLR-mediated pro-inflammatory cytokine responses.
ATG16L1 inhibits RICK-TLR2 interactions and intestinal inflammation
Most hepatocellular carcinomas (HCC) develop as a result of chronic liver inflammation. We have shown that the oncoprotein gankyrin is critical for inflammation‐induced tumorigenesis in the colon. ...Although the in vitro function of gankyrin is well known, its role in vivo remains to be elucidated. We investigated the effect of gankyrin in the tumor microenvironment of mice with liver parenchymal cell‐specific gankyrin ablation (Alb‐Cre;gankyrinf/f) and gankyrin deletion both in liver parenchymal and non‐parenchymal cells (Mx1‐Cre;gankyrinf/f). Gankyrin upregulates vascular endothelial growth factor expression in tumor cells. Gankyrin binds to Src homology 2 domain‐containing protein tyrosine phosphatase‐1 (SHP‐1), mainly expressed in liver non‐parenchymal cells, resulting in phosphorylation and activation of signal transducer and activator of transcription 3 (STAT3). Gankyrin deficiency in non‐parenchymal cells, but not in parenchymal cells, reduced STAT3 activity, interleukin (IL)‐6 production, and cancer stem cell marker (Bmi1 and epithelial cell adhesion molecule EpCAM) expression, leading to attenuated tumorigenic potential. Chronic inflammation enhances gankyrin expression in the human liver. Gankyrin expression in the tumor microenvironment is negatively correlated with progression‐free survival in patients undergoing sorafenib treatment for HCC. Thus, gankyrin appears to play a critical oncogenic function in tumor microenvironment and may be a potential target for developing therapeutic and preventive strategies against HCC.
Gankyrin activates STAT3 by binding to SHP‐1, leading to enhanced IL‐6 production in tumors. The augmented inflammatory response would activate STAT3 and upregulate stem cell markers, which eventually promote the development of hepatocellular cancer. Gankyrin expression in the tumour microenvironment is negatively correlated with the therapeutic response to sorafenib and overall survival in patients with HCC.
Contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS), a novel technology, visualizes parenchymal perfusion in the pancreas. This study prospectively evaluated how accurately CH-EUS ...characterizes pancreatic lesions and compared its diagnostic ability with that of contrast-enhanced multidetector-row computed tomography (MDCT) and endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA).
A total of 277 consecutive patients with pancreatic solid lesions that were detected by conventional EUS underwent CH-EUS for evaluation of vascularity. After infusing an ultrasound contrast, CH-EUS was performed by using an echoendoscope and a specific mode for contrast harmonic imaging. On the basis of the intensity of enhancement, the lesions were categorized into four patterns: nonenhancement, hypoenhancement, isoenhancement, and hyperenhancement. For comparison, all patients underwent MDCT. The ability of CH-EUS to differentiate ductal carcinomas from the other solid tumors, particularly small lesions (≤2 cm in diameter) was assessed, and compared with the differentiating abilities of MDCT and EUS-FNA.
In terms of reading the CH-EUS images, the κ-coefficient of the interobserver agreement test was 0.94 (P<0.001). CH-EUS-depicted hypoenhancement diagnosed ductal carcinomas with a sensitivity and specificity of 95.1% (95% confidence interval (CI) 92.7-96.7%) and 89.0% (95% CI 83.0-93.1%), respectively. For diagnosing small carcinomas by CH-EUS, the sensitivity and specificity were 91.2 % (95% CI 82.5-95.1%) and 94.4% (95% CI 86.2-98.1%), respectively. CH-EUS-depicted hypervascular enhancement diagnosed neuroendocrine tumors with a sensitivity and specificity of 78.9% (95% CI 61.4-89.7%) and 98.7% (95% CI 96.7-98.8%), respectively. Although CH-EUS and MDCT did not differ significantly in diagnostic ability with regard to all lesions, CH-EUS was superior to MDCT in diagnosing small (≤2 cm) carcinomas (P<0.05). In 12 neoplasms that MDCT failed to detect, 7 ductal carcinomas and 2 neuroendocrine tumors had hypoenhancement and hyperenhancement on CH-EUS, respectively. When CH-EUS was combined with EUS-FNA, the sensitivity of EUS-FNA increased from 92.2 to 100%.
CH-EUS is useful for characterizing conventional EUS-detected solid pancreatic lesions. EUS equipped with contrast harmonic imaging may play an important role in the characterization of small tumors that other imaging methods fail to depict and may improve the diagnostic yield of EUS-FNA.
Efficient protection against coronavirus disease 2019 (COVID-19) has been achieved by immunization with mRNA-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ...However, efficient immune responses against this novel virus by vaccination are accompanied by a wide variety of side effects. Indeed, flares or new-onset of autoimmune disorders have been reported soon after the COVID-19 vaccination. Although pro-inflammatory cytokine responses play pathogenic roles in the development of autoimmunity, cytokines charactering COVID-19 vaccination-related autoimmune responses have been poorly understood. Given that mRNA derived from COVID-19 vaccine is a potent inducer for pro-inflammatory cytokine responses, these cytokines might mediate autoimmune responses after COVID-19 vaccination. Here we report a case with new-onset rheumatoid arthritis (RA) following COVID-19 vaccination. Serum concentrations not only of arthrogenic cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), but also of type I interferon (IFN) were elevated at the active phase in this case. Induction of remission by methotrexate and tocilizumab was accompanied by a marked reduction in serum concentrations of type I IFN, IL-6, and TNF-α. These results suggest that production of type I IFN, IL-6, and TNF-α induced by COVID-19 vaccination might be involved in this case with new-onset RA.
Mutations in nucleotide-binding oligomerization domain 2 (NOD2) are associated with Crohn's disease (CD). Although NOD2 activation contributes to the maintenance of intestinal homeostasis through the ...negative regulation of pro-inflammatory cytokine responses mediated by Toll-like receptors (TLRs), the effects of NOD2 activation on interferon (IFN)-α responses induced by TLR9 have been poorly defined. To explore the cross-talk between NOD2 and TLR9, human monocytes or dendritic cells (DCs) were stimulated with NOD2 and/or TLR9 ligands to measure IFN-α production. The severity of dextran sodium sulfate (DSS)-induced colitis was compared in mice treated with NOD2 and/or TLR9 ligands. Expression of IFN-α and IFN-stimulated genes (ISGs) was examined in the colonic mucosa of patients with inflammatory bowel disease (IBD). NOD2 activation reduced TLR9-induced IFN-α production by monocytes and DCs in a deubiquitinating enzyme A (DUBA)-dependent manner. Activation of DUBA induced by the co-stimulation of TLR9 and NOD2 inhibited Lys63-linked polyubiquitination of TRAF3 and suppressed TLR9-mediated IFN-α production. NOD2 activation in hematopoietic cells protected mice from TLR9-induced exacerbation of DSS-induced colitis by down-regulating IFN-α responses and up-regulating DUBA expression. Colonic mucosa of patients with active and remitted IBD phases was characterized by the enhanced and reduced expression of ISGs, respectively. Expression levels of IFN-α and IL-6 positively correlated in the active colonic mucosa of patients with ulcerative colitis and CD, whereas DUBA expression inversely correlated with that of IFN-α in patients with CD. Collectively, these data suggest that DUBA-dependent negative effect of NOD2 on TLR9-mediated IFN-α responses contributes to the maintenance of intestinal homeostasis.
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