Katsutoshi Kuriyama

Risk of Cancer in Patients With Autoimmune Pancreatitis

OBJECTIVES:Although simultaneous occurrences of autoimmune pancreatitis (AIP) and cancer are occasionally observed, it remains largely unknown whether cancer and AIP occur independently or these disorders are interrelated. The aim of this study was to examine the relationship between AIP and cancer.METHODS:We conducted a multicenter, retrospective cohort study. One hundred and eight patients who met the Asian diagnostic criteria for AIP were included in the study. We calculated the proportion, standardized incidence ratio (SIR), relative risk, and time course of cancer development in patients with AIP. We also analyzed the clinicopathological characteristics of AIP patients with cancer in comparison with those without cancer.RESULTS:Of the 108 AIP patients, 18 cancers were found in 15 patients (13.9%) during the median follow-up period of 3.3 years. The SIR of cancer was 2.7 (95% confidence interval (CI) 1.4–3.9), which was stratified into the first year (6.1 (95% CI 2.3–9.9)) and subsequent years (1.5 (95% CI 0.3–2.8)) after AIP diagnosis. Relative risk of cancer among AIP patients at the time of AIP diagnosis was 4.9 (95% CI 1.7–14.9). In six of eight patients whose cancer lesions could be assessed before corticosteroid therapy for AIP, abundant IgG4-positive plasma cell infiltration was observed in the cancer stroma. These six patients experienced no AIP relapse after successful cancer treatment.CONCLUSIONS:Patients with AIP are at high risk of having various cancers. The highest risk for cancer in the first year after AIP diagnosis and absence of AIP relapse after successful treatment of the coexisting cancers suggest that AIP may develop as a paraneoplastic syndrome in some patients.

Pathogenicity of IgG in patients with IgG4-related disease

Objective IgG4-related disease (IgG4-RD) is a systemic disease characterised by elevated serum IgG4 and IgG4-positive lymphoplasmacytic infiltration in the affected tissues. The pathogenic role of IgGs, including IgG4, in patients with IgG4-RD, however, is unknown. Design We examined the pathogenic activity of circulating IgGs in patients with IgG4-RD by injecting their IgGs into neonatal male Balb/c mice. Binding of patient IgGs to pancreatic tissue was also analysed in an ex vivo mouse organ culture model and in tissue samples from patients with autoimmune pancreatitis (AIP). Results Subcutaneous injection of patient IgG, but not control IgG, resulted in pancreatic and salivary gland injuries. Pancreatic injury was also induced by injecting patient IgG1 or IgG4, with more destructive changes induced by IgG1 than by IgG4. The potent pathogenic activity of patient IgG1 was significantly inhibited by simultaneous injection of patient IgG4. Binding of patient IgG, especially IgG1 and IgG4, to pancreatic tissue was confirmed in both the mouse model and AIP tissue samples. Conclusions IgG1 and IgG4 from patients with IgG4-RD have pathogenic activities through binding affected tissues in neonatal mice.

Plasmacytoid Dendritic Cell Activation and IFN-α Production Are Prominent Features of Murine Autoimmune Pancreatitis and Human IgG4-Related Autoimmune Pancreatitis

The abnormal immune response accompanying IgG4-related autoimmune pancreatitis (AIP) is presently unclear. In this study, we examined the role of plasmacytoid dendritic cell (pDC) activation and IFN-α production in this disease as well as in a murine model of AIP (MRL/Mp mice treated with polyinosinic-polycytidylic acid). We found that the development of AIP in treated MRL/Mp mice occurred in parallel with pancreatic accumulation of pDCs producing IFN-α, and with pDC depletion and IFN-α-blocking studies, we showed that such accumulation was necessary for AIP induction. In addition, we found that the pancreas of treated MRL/Mp mice contained neutrophil extracellular traps (NETs) shown previously to stimulate pDCs to produce IFN-α. Consistent with these findings, we found that patients with IgG4-related AIP also exhibited pancreatic tissue localization of IFN-α–expressing pDCs and had significantly higher serum IFN-α levels than healthy controls. In addition, the inflamed pancreas of these patients but not controls also contained NETs that were shown to be capable of pDC activation. More importantly, patient pDCs cultured in the presence of NETs produced greatly increased levels of IFN-α and induced control B cells to produce IgG4 (but not IgG1) as compared with control pDCs. These data suggest that pDC activation and production of IFN-α is a major cause of murine AIP; in addition, the increased pDC production of IFN-α and its relation to IgG4 production observed in IgG4-related AIP suggest that this mechanism also plays a role in the human disease.

Impact of EUS-FNA for preoperative para-aortic lymph node staging in patients with pancreatobiliary cancer

BACKGROUND AND AIMS In patients with pancreatobiliary cancer, para-aortic lymph node (PALN) metastasis is considered to be the involvement beyond the regional lymph nodes, namely, distant metastasis. Effective methods for preoperative PALN staging, however, are not established. This study aimed to compare the diagnostic capability for PALN metastasis between EUS-FNA and (18)F-fluorodeoxyglucose positron emission tomography with CT (PET/CT). METHODS We performed a prospective, nonrandomized, single-center trial. Between December 2010 and March 2014, 208 patients with pancreatobiliary cancer without apparent distant metastasis except for PALNs were assessed for study eligibility before surgery. Among them, 52 consecutive patients with PALN enlargement were enrolled in the study. (18)F-Fluorodeoxyglucose PET/CT and EUS-FNA were performed sequentially as a single combined procedure to evaluate PALN metastases. The primary outcome was to compare the diagnostic capability of EUS-FNA and PET/CT for PALN metastasis. RESULTS Of 71 enlarged PALNs in the 52 patients, 30 (42.3%) were finally diagnosed as metastases in 21 patients (40.4%). Of the 21 patients with PALN metastases, preoperative EUS-FNA or PET/CT made a correct diagnosis in 20 (95.2%) or 12 (57.1%), respectively. EUS-FNA had higher sensitivity and specificity for the diagnosis of PALN metastasis (sensitivity, 96.7% [29/30]; 95% confidence interval, 82.2%-99.9%; specificity, 100% [39/39]; 95% confidence interval, 91.0%-100%) than PET/CT. CONCLUSIONS EUS-FNA is superior to PET/CT for preoperative PALN staging in patients with pancreatobiliary cancer. Because of the clinical benefit of EUS-FNA to reduce unnecessary surgery, it should be part of the standard preoperative examination for patients with pancreatobiliary cancer. (UMIN clinical trials registry number: 000006408.).

Chemokine CXCL16 mediates acinar cell necrosis in cerulein induced acute pancreatitis in mice

Severe acute pancreatitis is a lethal inflammatory disease frequently accompanied by pancreatic necrosis. We aimed to identify a key regulator in the development of pancreatic necrosis. A cytokine/chemokine array using sera from patients with acute pancreatitis (AP) revealed that serum CXCL16 levels were elevated according to the severity of pancreatitis. In a mouse model of AP, Cxcl16 expression was induced in pancreatic acini in the late phase with the development of pancreatic necrosis. Cxcl16−/− mice revealed similar sensitivity as wild-type (WT) mice to the onset of pancreatitis, but better resisted development of acinar cell necrosis with attenuated neutrophil infiltration. A cytokine array and immunohistochemistry revealed lower expression of Ccl9, a neutrophil chemoattractant, in the pancreatic acini of Cxcl16−/− mice than WT mice. Ccl9 mRNA expression was induced by stimulation with Cxcl16 protein in pancreatic acinar cells in vitro, suggesting a Cxcl16/Ccl9 cascade. Neutralizing antibody against Cxcl16 ameliorated pancreatic injury in the mouse AP model with decreased Ccl9 expression and less neutrophil accumulation. In conclusion, Cxcl16 expressed in pancreatic acini contributes to the development of acinar cell necrosis through the induction of Ccl9 and subsequent neutrophil infiltration. CXCL16 could be a new therapeutic target in AP.

Laminin 511 is a target antigen in autoimmune pancreatitis

The extracellular matrix protein laminin 511 is an autoantigen involved in the pathophysiology of autoimmune pancreatitis. Pancreatic perturbation Autoimmune pancreatitis (AIP) is difficult to diagnose and can sometimes be confused with pancreatic cancer, which presents with similar symptoms. AIP is an inflammatory disease involving elevated IgG4, but the target autoantigen(s) is unidentified. This group’s previous work pointed to the extracellular matrix, and now, Shiokawa et al. show that a truncated form of laminin 511 may be a major autoantigen in AIP. They observed that half of AIP patients they analyzed had anti–laminin 511 antibodies, which were absent in healthy controls. Patient pancreatic tissues were positive for laminin 511, and immunization of mice with this protein induced AIP-like symptoms. These results reveal an autoimmune target in this disease and one day may aid AIP diagnosis. Autoimmune pancreatitis (AIP), a major manifestation of immunoglobulin G4–related disease (IgG4-RD), is an immune-mediated disorder, but the target autoantigens are still unknown. We previously reported that IgG in patients with AIP induces pancreatic injuries in mice by binding the extracellular matrix (ECM). In the current study, we identified an autoantibody against laminin 511-E8, a truncated laminin 511, one of the ECM proteins, in patients with AIP. Anti–laminin 511-E8 IgG was present in 26 of 51 AIP patients (51.0%), but only in 2 of 122 controls (1.6%), by enzyme-linked immunosorbent assay. Because truncated forms of other laminin family members in other organs have been reported, we confirmed that truncated forms of laminin 511 also exist in human and mouse pancreas. Histologic studies with patient pancreatic tissues showed colocalization of patient IgG and laminin 511. Immunization of mice with human laminin 511-E8 induced antibodies and pancreatic injury, fulfilling the pathologic criteria for human AIP. Four of 25 AIP patients without laminin 511-E8 antibodies had antibodies against integrin α6β1, a laminin 511 ligand. AIP patients with laminin 511-E8 antibodies exhibited distinctive clinical features, as the frequencies of malignancies or allergic diseases were significantly lower in patients with laminin 511-E8 antibodies than in those without. The discovery of these autoantibodies should aid in the understanding of AIP pathophysiology and possibly improve the diagnosis of AIP.