Dysbiosis contributes to the development of autoimmune pancreatitis

IgG4-related disease (IgG4-RD) is a multi-organ autoimmune disease characterized by elevated serum IgG4 concentration. Although serum IgG4 concentration is widely used as a biomarker for IgG4-RD and type 1 autoimmune pancreatitis (AIP), a pancreatic manifestation of IgG4-RD, a significant number of patients have normal serum IgG4 levels, even in the active phase of the disease. Recently, we reported that the development of experimental AIP and human type 1 AIP is associated with increased expression of IFN-α and IL-33 in the pancreas. In this study, we assessed the utility of serum IFN-α and IL-33 levels as biomarkers for type 1 AIP and IgG4-RD. Serum IFN-α and IL-33 concentrations in patients who met the diagnostic criteria for definite type 1 AIP and/or IgG4-RD were significantly higher than in those with chronic pancreatitis or in healthy controls. Strong correlations between serum IFN-α, IL-33, and IgG4 concentrations were observed. Diagnostic performance of serum IFN-α and IL-33 concentrations as markers of type 1 AIP and/or IgG4-RD was comparable to that of serum IgG4 concentration, as calculated by the receiver operating characteristic curve analysis. Induction of remission by prednisolone treatment markedly decreased the serum concentration of these cytokines. We conclude that serum IFN-α and IL-33 concentrations can be useful as biomarkers for type 1 AIP and IgG4-RD.

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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Background and Aims Pancreatic neuroendocrine neoplasms (PanNENs), including Grade 1 (G1) or G2 tumors, can have a poor prognosis. This study investigated the value of contrast‐enhanced harmonic endoscopic ultrasonography (CH‐EUS) for predicting the prognosis of PanNENs. Methods This single‐center, retrospective study included 47 consecutive patients who underwent CH‐EUS and were diagnosed with PanNEN by surgical resection or EUS‐guided fine needle aspiration between December 2011 and February 2016. Patients were divided into aggressive and non‐aggressive groups according to the degree of clinical malignancy. CH‐EUS was assessed regarding its capacity for diagnosing aggressive PanNEN, the correspondence between contrast patterns and pathological features, and its ability to predict the prognosis of PanNEN. Results There were 19 cases of aggressive PanNEN and 28 cases of non‐aggressive PanNEN. The aggressive group included three G1, four G2, three G3 tumors, three mixed neuroendocrine non‐neuroendocrine neoplasms, and six neuroendocrine carcinomas. CH‐EUS was superior to contrast‐enhanced computed tomography for the diagnosis of aggressive PanNEN (P < 0.001): hypo‐enhancement on CH‐EUS was an indicator of aggressive PanNEN, with sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 94.7%, 100%, 100%, 96.6%, and 97.9%, respectively. Among G1/G2 PanNENs, cases with hypo‐enhancement on CH‐EUS had a poorer prognosis than those with hyper/iso‐enhancement (P = 0.0009). Assessment of 36 resected specimens showed that hypo‐enhancement on CH‐EUS was associated with smaller and fewer vessels and greater degree of fibrosis. Conclusion Contrast‐enhanced harmonic endoscopic ultrasonography may be useful for predicting the prognosis of PanNENs.