Purpose: Autoimmune pancreatitis is a unique form of chronic pancreatitis characterized by high serum IgG4 concentrations and abundant IgG4 bearing plasma cell infiltration in the pancreatic lesion, and has been reported to be associated with a variety of extra-pancreatic lesions, leading us to postulate the concept of systemic inflammatory disease. To confirm this, we attempted to clarify the exact distribution of and provide a panoramic view of these extra-pancreatic lesions. Methods: The frequency, distribution, clinical characteristics, and pathology of five extra-pancreatic lesions were determined in 64 patients with autoimmune pancreatitis by examining clinical and laboratory findings. Results The most frequent extra-pancreatic lesion was hilar lymphadenopathy (80.4%), followed by extra-pancreatic bile duct lesions (73.9%), lachrymal and salivary gland lesions (39.1%), hypothyroidism (22.2%), and retroperitoneal fibrosis (12.5%). No patients had all of five lesions. Patients with hilar lymphadenopathy or lachrymal and salivary gland lesions were found to have significantly higher IgG4 levels than those without (p=0.0042, 0.0227, respectively). Patients with 3 lesions were found to have significantly higher IgG4 levels than those with no lesion, suggesting that patients with multiple extra-pancreatic lesions represent an active state of the disease. Similar to pancreatic lesions, extra-pancreatic lesions have a characteristic histological finding of abundant IgG4 bearing plasma cell infiltration, and they respond favorably to corticosteroid therapy. Conclusion: Autoimmune pancreatitis can be recognized as systemic inflammatory disease. Furthermore, recognition of these characteristic findings will aid in correct diagnosis of this disease.

Uremic toxins induce free radical production by renal tubular cells and activate NF-kappaB which, in turn, up-regulates PAI-1 expression. Thus, progression of chronic renal failure may be promoted by PAI-1 up-regulation induced by uremic toxins.

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IgG4‐related sclerosing cholangitis (IgG4‐ SC ) is a distinct type of cholangitis frequently associated with autoimmune pancreatitis and currently recognized as a biliary manifestation of IgG4‐related disease. Although clinical diagnostic criteria of IgG4‐ SC were established in 2012, differential diagnosis from primary sclerosing cholangitis and cholangiocarcinoma is sometimes difficult. Furthermore, no practical guidelines for IgG4‐ SC are available. Because the evidence level of most articles retrieved through searching the PubMed, Cochrane Library, and Igaku Chuo Zasshi databases was below C based on the systematic review evaluation system of clinical practice guidelines MINDS 2014, we developed consensus guidelines using the modified Delphi approach. Three committees (a guideline creating committee, an expert panelist committee for rating statements according to the modified Delphi method, and an evaluating committee) were organized. Eighteen clinical questions ( CQ s) with clinical statements were developed regarding diagnosis (14 CQ s) and treatment (4 CQ s). Recommendation levels for clinical statements were set using the modified Delphi approach. The guidelines explain methods for accurate diagnosis, and safe and appropriate treatment of IgG4‐ SC .

Gastric gland mucin secreted from the lower portion of the gastric mucosa contains unique O-linked oligosaccharides (O-glycans) having terminal α1,4-linked N-acetylglucosamine residues (αGlcNAc). Previously, we identified human α1,4-N-acetylglucosaminyltransferase (α4GnT), which is responsible for the O-glycan biosynthesis and characterized αGlcNAc function in suppressing Helicobacter pylori in vitro. In the present study, we engineered A4gnt -/-mice to better understand its role in vivo. A4gnt -/-mice showed complete lack of αGlcNAc expression in gastric gland mucin. Surprisingly, all the mutant mice developed gastric adenocarcinoma through a hyperplasia-dysplasia-carcinoma sequence in the absence of H. pylori infection. Microarray and quantitative RT-PCR analysis revealed upregulation of genes encoding inflammatory chemokine ligands, proinflammatory cytokines, and growth factors, such as Ccl2, Il-11, and Hgf in the gastric mucosa of A4gnt -/-mice. Further supporting an important role for this O-glycan in cancer progression, we also observed significantly reduced αGlcNAc in human gastric adenocarcinoma and adenoma. Our results demonstrate that the absence of αGlcNAc triggers gastric tumorigenesis through inflammation-associated pathways in vivo. Thus, αGlcNAc-terminated gastric mucin plays dual roles in preventing gastric cancer by inhibiting H. pylori infection and also suppressing tumor-promoting inflammation.

Objective.Because it is uncertain whether immunoglobulin G4–related disease (IgG4-RD) is associated with malignancy, we evaluated the incidence of cancer development in a large cohort of patients with IgG4-RD.Methods.The study enrolled 158 patients diagnosed as having IgG4-RD between 1992 and 2012. We calculated the standardized incidence ratio (SIR) and cumulative rate of malignancies in this group and searched for risk factors associated with the occurrence of tumors.Results.A total of 34 malignancies were observed in the patients with IgG4-RD over a mean followup period of 5.95 ± 4.48 years. The overall SIR of malignancies was 2.01 (95% CI 1.34–2.69). The SIR of patients who exhibited a tumor within 1 year after IgG4-RD diagnosis was 3.53 (95% CI 1.23–5.83), while that of subjects forming a malignancy in subsequent years was 1.48 (95% CI 0.99–1.98). The cumulative rate of malignancy development was significantly higher in patients with IgG4-RD within 12 years after diagnosis than in the Japanese general population. Comparable results were obtained for an autoimmune pancreatitis subgroup. The serum concentrations of several disease activity markers at diagnosis were significantly higher in patients with malignancies than in those without.Conclusion.We identified a close association between IgG4-RD and malignancy formation within 12 years after diagnosis, particularly during the first year. An active IgG4-RD state is presumed to be a strong risk factor for malignancy development.

Contrary to previous reports, we observed both relapse and pancreatic stone formation in some patients with autoimmune pancreatitis, which suggests that autoimmune pancreatitis has the potential to be a progressive disease with pancreatic stones.

Objectives: Autoimmune pancreatitis (AIP) is characterized by high serum IgG4 concentrations, lymphoplasmacytic inflammation, and a favorable response to corticosteroid treatment. Although the HLA DRB1*0405-DQB1*0401 haplotype and Fc receptor-like 3 polymorphisms have been associated with AIP, the role of other genetic factors is largely unknown. As cytotoxic T lymphocyte antigen 4 (CTLA4) polymorphisms have recently been linked with several autoimmune diseases, we sought to determine if CTLA4 polymorphisms and serum sCTLA4 levels were associated with AIP as well. Methods: Five CTLA4 polymorphisms, located at -1722, -658, and -318 in the promoter, +49 in exon 1, and +6230 in the 3' untranslated region, were genotyped in 59 patients with AIP and 102 healthy subjects. Serum sCTLA4 levels were also determined in cohorts of 52 patients and 32 controls. Results: Compared with healthy subjects, we found a significant increase in the +6230 G/G genotype (64% vs. 42%, odds ratio [OR], 2.48; P = 0.011) in AIP patients. Haplotype 2, which had the +6230A, was associated with AIP resistance (OR, 0.49; P = 0.011). The +49A/A and +6230A/A genotypes were associated with an enhanced risk of relapse (OR, 5.45; P = 0.038 and OR, 12.66; P = 0.022). Additionally, median serum sCTLA4 levels were significantly higher in patients with AIP (8.9 ng/mL) compared with healthy subjects (2.9 ng/mL; P < 0.001). The +6230G/A polymorphism did not influence sCTLA4 levels in AIP patients. Conclusions: Our findings suggest that AIP is associated with a genetic polymorphism in CTLA4 and is positively correlated with serum sCTLA4 levels.