Sclerosing Esophagitis with IgG4-positive Plasma Cell Infiltration.

The patient was a 76-year-old woman who had noticed slight difficulty in swallowing in the 3 years prior to this presentation. Her dysphagia progressed while she was hospitalized following cervical cancer surgery. Esophagogastroduodenoscopy and an esophagram showed circumferential erosion and a stricture of the thoracic esophagus. Esophageal resection was performed; the resected specimens showed a stricture and wall thickening. Histologically, transmural hyperplasia, which consisted of inflammatory granulation tissue with the abundant infiltration of IgG4-positive plasma cells and lymphocytes, was observed. The patient was diagnosed with probable IgG4-related disease. IgG4-related esophageal disease presenting as esophageal lesions alone is a very rare condition.

The role of CD19+ CD24high CD38high and CD19+ CD24high CD27+ regulatory B cells in patients with type 1 autoimmune pancreatitis.

BACKGROUND: Patients with type 1 autoimmune pancreatitis (AIP) have several immunologic and histologic abnormalities. It is known that depletion of B cells by rituximab is effective for treatment of IgG4-related disease (IgG4-RD) such as type 1 AIP, suggesting that B cells may be a key player in IgG4-RD. However, the role of regulatory B cells (Bregs) in type 1 AIP is unclear, and the objective of this paper is to clarify the role of Bregs in the pathophysiology of type 1 AIP by analyzing circulating Bregs. METHOD: We recruited 21 patients with type 1 AIP as determined by the International Consensus Diagnostic Criteria for AIP (ICDC). No patients received corticosteroid treatments. For comparison, we recruited 14 patients with chronic pancreatitis (CP), 20 patients with pancreatic cancer, and 25 healthy subjects as controls. We analyzed Bregs as CD19+ CD24high CD38high and CD19+ CD24high CD27+ from peripheral blood by flow cytometry. RESULTS: In peripheral blood, CD19+ CD24high CD38high Bregs were significantly increased in type 1 AIP patients compared with CP, pancreatic cancer, and healthy controls. Although not significant different, CD19+ CD24high CD27+ Bregs of type 1 AIP were decreased compared to those of other groups. IL-10(+) B cells were not significantly different from type 1 AIP patients and healthy controls. In untreated type 1 AIP patients, the number of CD19+ CD24high CD38high Bregs and IgG4 were not correlated. CONCLUSIONS: Our data suggested that CD19+ CD24high CD38high Bregs seemed to increase reactively to suppress the disease activity, and are consistent with the hypothesis that CD19+ CD24high CD27+ Bregs might be involved in the development of type 1 AIP, although it still remains unclear whether the decrease of CD19+ CD24high CD27+ cells is cause or effect of AIP.

Transcutaneous monitoring of partial pressure of carbon dioxide during endoscopic retrograde cholangiopancreatography using a double-balloon endoscope with carbon dioxide insufflation under conscious sedation.

BACKGROUND AND AIM: A double-balloon (DB) endoscope can be selectively inserted into the afferent loop to carry out endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically altered anatomy, allowing various types of endoscopic treatments for pancreaticobiliary diseases to be successfully carried out. In order to make such a lengthy procedure more comfortable and safe, sedatives and carbon dioxide (CO2 ) insufflation are widely used for gastrointestinal endoscopy. However, these techniques can increase the risk of CO2 retention. Recently, a new sensor for transcutaneous measurement of partial pressure of carbon dioxide (PCO2 ) has been introduced. The aim of the present study was to evaluate the changes in transcutaneous PCO2 (PtcCO2 ) during DB-ERCP with CO2 insufflation under conscious sedation and assess any complications related to sedation and CO2 insufflation. METHODS: A total of 312 patients underwent DB-ERCP with CO2 insufflation at our hospital between March 2009 and December 2012. The patients were moderately sedated using midazolam with or without pentazocine. PtcCO2 was measured by a non-invasive sensor throughout DB-ERCP in all patients. RESULTS: The mean peak PtcCO2 during the procedure was significantly higher than the mean PtcCO2 value before and after DB-ERCP. Body mass index, procedure time and dose of pentazocine were significantly higher in the CO2 retention group (peak PtcCO2 ≥ 50 mmHg). CO2 narcosis was observed in one case. CONCLUSIONS: DB-ERCP with CO2 insufflation under conscious sedation might have the potential to increase the risk of CO2 retention. Hence, non-invasive and continuous PtcCO2 measurement is useful for early detection of hypercapnia.

Possible Involvement of Foxp3(+) Regulatory T Cells in the Development of Immune-Mediated Pancreatitis in MRL/Mp Mice Treated with Polyinosinic:Polycytidylic Acid.

Objectives. This study was conducted to clarify whether or not Tregs are involved in the development of immune-mediated pancreatitis in MRL/Mp mice as an AIP (autoimmune pancreatitis) model, in order to understand more clearly the pathogenic mechanism of AIP. Methods. We compared the immunohistochemical features of pancreatic forkhead box P3 (Foxp3) in the administration of poly I:C in MRL/Mp mice and two types of control mice (BALB/c and C57BL/6). As a contrast, we analyzed three mouse models of pancreatitis without autoimmune mechanism (Cerulein-, Ligation-, and Ligation + Cerulein-treated mice). After staining these specimens, we compared the ratios of Foxp3-positive cells to infiltrated mononuclear cells (Foxp3/Mono). Results. Our immunohistochemical study of Foxp3 revealed that the infiltration of Foxp3-positive cells increased in poly I:C-treated MRL/Mp mice. The histopathological score of pancreatitis showed no difference among poly I:C-treated MRL/Mp, Ligation-, and Ligation + Cerulein-treated mice; however, the Foxp3/Mono ratio in poly I:C-treated MRL/Mp mice was significantly increased compared with Ligation- and Ligation + Cerulein-treated mice. Conclusions. MRL/Mp mice treated with poly I:C showed early development of pancreatitis with abundant infiltration of Foxp3-positive cells. There may be a possibility that Tregs are involved in the development of pancreatitis in these mice.

A proposal of a diagnostic algorithm with validation of International Consensus Diagnostic Criteria for autoimmune pancreatitis in a Japanese cohort.

BACKGROUND: Among many diagnostic criteria for autoimmune pancreatitis (AIP), the International Consensus Diagnostic Criteria (ICDC) first enabled us to diagnose and compare type 1 and type 2 AIP, which permitted tailoring individual diagnostic algorithms depending on local expertise. We compared them and validated ICDC with special reference to levels 1 and 2, and proposed a diagnostic algorithm for AIP in Japan. METHODS: The diagnostic sensitivity of 5 major criteria (ICDC, Korean, Japanese-2011, Asian, and HISORt criteria) was compared, using 61 patients with AIP. Fifty six patients with pancreatic cancer served as a control. Pancreas imaging on computed tomography (CT) and endoscopic retrograde pancreatography (ERP) were independently evaluated by 3 pancreatologists (5, 10, and 20 years of career experience) and each diagnostic criterion of ICDC was validated with special reference to levels 1 and 2. RESULTS: The sensitivities of 5 major criteria were 95.1% (ICDC), 90.2% (Korean), 86.9% (Japanese), 83.6% (Asian), and 83.6% (HISORt) with 100% of specificity in each. In the evaluation of pancreas imaging, diagnostic sensitivities of combination with CT and ERP in segmental/focal type AIP were significantly higher than single imaging (26% in CT (P < 0.01) or 35% in ERP (P < 0.05) vs 63% in CT + ERP), but not significantly different in the diffuse type. CONCLUSIONS: Of the 5 criteria, ICDC is the most sensitive and useful for diagnosing AIP. We have proposed a diagnostic algorithm with CT for the diffuse type of AIP, and combination with CT + ERP followed by EUS-FNA for the segmental/focal type.

The similarity of Type 1 autoimmune pancreatitis to pancreatic ductal adenocarcinoma with significant IgG4-positive plasma cell infiltration.

BACKGROUND: High serum immunoglobulin G4 (IgG4) levels and infiltration of IgG4-positive cells are characteristic of Type 1 autoimmune pancreatitis (AIP). We previously reported that increased regulatory T cells (Tregs) may regulate IgG4 production in AIP. Although an increased serum IgG4 concentration is observed in some patients with pancreatic ductal adenocarcinoma (PDA), clarification is still necessary. We have therefore studied the correlations between IgG4-positive cells and Tregs in patients with PDA. SUBJECTS AND METHODS: A total of 21 PDA and nine AIP patients were enrolled in our study. The numbers and ratios of Tregs, IgG4-positive, and IgG-positive cells immunohistochemically stained with anti-Foxp3, IgG4, and IgG antibodies, respectively, were counted in three areas of resected pancreata in PDA, peritumoral pancreatitis (PT), and obstructive pancreatitis (OP). RESULTS: In PDA, PT, OP area, the number of IgG4-Positive cells (5.183 ± 1.061, 2.250 ± 0.431, 4.033 ± 1.018, respectively; p < 0.05) and the ratio of IgG4/IgG (0.391 ± 0.045, 0.259 ± 0.054, 0.210 ± 0.048, respectively; p < 0.05) were significantly lower than those in AIP (21.667 ± 2.436 and 0.306 ± 0.052, respectively). The numbers of IgG4-positive cells did not differ significantly among the three areas of resected pancreata examined. However, the IgG4/IgG (0.391 ± 0.045) and Foxp3/monocyte (0.051 ± 0.008) ratios in PDA area were significantly (p < 0.05) higher than those in OP area (IgG4/IgG: 0.210 ± 0.048; oxp3/monocyte: 0.0332 ± 0.005), but not in PT area. Of the 21 cases of PDA, the ratio of IgG4/IgG was >40 % in nine (43%), six (29%) and three (14%) cases in PDA, PT and OP area, respectively. Foxp3 and IgG4 were positively correlated in OP area, but not in PDA and PT area. CONCLUSIONS: Clinicians should be careful when basing a differential diagnosis of PDA and AIP on the numbers of IgG4-positive cells and the ratio of IgG4/IgG, especially when determined using a small biopsied sample.

A case of IgG4-related disease associated with diffuse large B cell lymphoma.

In June 2008, a 74-year-old male was diagnosed with IgG4-related disease including histologically proven IgG4-related prostatitis, and then followed as an outpatient. In July 2011, cervical, chest, and abdominal computed tomography (CT) revealed right parotid gland swelling and lymph node enlargement of the supraclavicular, mediastinal, left hilar, porta hepatis, and para-aorta. A biopsy of the right parotid gland was performed, and we diagnosed diffuse large B-cell lymphoma (DLBCL). As malignancies are possible complications for patients with IgG4-related disease, we must be careful in the follow-up of IgG4-related disease patients.

Autoimmune pancreatitis with histologically proven lymphoplasmacytic sclerosing pancreatitis with granulocytic epithelial lesions.

Recent histological and clinical studies have suggested the existence of 2 distinct types of autoimmune pancreatitis (AIP): type 1 AIP related to IgG4, exhibiting lymphoplasmacytic sclerosing pancreatitis (LPSP), and type 2 AIP related to granulocyte epithelial lesions (GELs), exhibiting idiopathic duct-centric chronic pancreatitis (IDCP). We herein present a case of type 1 AIP with histologically proven LPSP with GELs. This patient had neither serum IgG4 elevation nor MPD narrowing. In this case, the clinically and histologically atypical findings for type 1 AIP are intriguing.

Regulatory T cells in type 1 autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) is a newly recognized pancreatic disorder. Recently, International Consensus Diagnostic Criteria for AIP (ICDC) was published. In this ICDC, AIP was classified into Type 1 and Type 2. Patients with Type 1 AIP have several immunologic and histologic abnormalities specific to the disease, including increased levels of serum IgG4 and storiform fibrosis with infiltration of lymphocytes and IgG4-positive plasmacytes in the involved organs. Among the involved organs showing extrapancreatic lesions, the bile duct is the most common, exhibiting sclerosing cholangitis (IgG4-SC). However, the role of IgG4 is unclear. Recently, it has been reported that regulatory T cells (Tregs) are involved in both the development of various autoimmune diseases and the shift of B cells toward IgG4, producing plasmacytes. Our study showed that Tregs were increased in the pancreas with Type 1 AIP and IgG4-SC compared with control. In the patients with Type 1 AIP and IgG4-SC, the numbers of infiltrated Tregs were significantly positively correlated with IgG4-positive plasma cells. In Type 1 AIP, inducible costimulatory molecule (ICOS)(+) and IL-10(+) Tregs significantly increased compared with control groups. Our data suggest that increased quantities of ICOS(+) Tregs may influence IgG4 production via IL-10 in Type 1 AIP.

Involvement of inducible costimulator- and interleukin 10-positive regulatory T cells in the development of IgG4-related autoimmune pancreatitis.

OBJECTIVES: Immunoglobulin G4 (IgG4)-related autoimmune pancreatitis (AIP) is a new clinical entity of pancreatic disorder. There are immunologic and histological abnormalities, including increased serum IgG4 levels and the infiltration of IgG4-positive plasmacytes. However, the role of IgG4 is unclear. Recently, regulatory T cells (Tregs) were reported to contribute to the development of various autoimmune diseases as well as in B-cell shifting to IgG4-producing plasmacytes. We studied Tregs in the pancreas and peripheral blood. METHODS: We recruited 44 patients with IgG4-related AIP. For comparison, we recruited 37 patients with other pancreatic diseases and 27 healthy subjects as controls. We studied infiltrating cells in the pancreas by immunohistochemistry and analyzed inducible costimulator-positive Tregs and interleukin 10-positive Tregs in the peripheral blood by flow cytometry. RESULTS: The ratio of Foxp3-positive cells to infiltrated mononuclear cells (Foxp3/Mono) in AIP patients was significantly higher than in patients with alcoholic chronic pancreatitis. In AIP, Foxp3/Mono and IgG4/Mono were positively correlated. Inducible costimulator-positive Tregs were significantly higher in AIP patients than in the patients with other pancreatic diseases and the healthy control group. Interleukin 10-positive Tregs were significantly higher in AIP patients than in the healthy control group. CONCLUSIONS: Increased quantities of inducible costimulator-positive Tregs may influence IgG4 production in IgG4-related AIP.

The specific linker phosphorylation of Smad2/3 indicates epithelial stem cells in stomach; particularly increasing in mucosae of Helicobacter-associated gastritis.

BACKGROUND: The gastric corpus and antrum are believed to contain epithelial stem cells in the isthmus. However, the lack of useful markers has hindered studies of their origin. We explored whether Smad2/3, phosphorylated at specific linker threonine residues (pSmad2/3L-Thr), could serve as a marker for stem cells. METHODS: Stomachs, small intestines, and colons from Helicobacter felis-infected and noninfected C57BL/6 mice were examined. Double immunofluorescent staining of pSmad2/3L-Thr with Ki67, cytokeratin 8, or doublecortin and calcium/calmodulin-dependent protein kinase-like-1 (DCAMKL1) was performed, and pSmad2/3L-Thr immunostaining-positive cells were counted. After immunofluorescent staining, we stained the same sections with hematoxylin-eosin and observed these cells under a light microscope. RESULTS: In infected mice, pSmad2/3L-Thr immunostaining-positive cells were significantly increased in the corpus and antrum compared with those of noninfected mice (p < 0.0001). The number of Ki67 immunostaining-positive cells in the corpus and antrum of infected mice was also much greater than in the noninfected mice. Although pSmad2/3L-Thr immunostaining-positive cells were detected among the Ki67 cells, immunohistochemical co-localization of pSmad2/3L-Thr with Ki67 was never observed. pSmad2/3L-Thr immunostaining-positive cells showed immunohistochemical co-localization with cytokeratin 8, but some of them showed co-localization or adjacent localization with DCAMKL1 immunostaining-positive cells. Under a light microscope, pSmad2/3L-Thr immunostaining-positive cells indicated undifferentiated morphological features and were confirmed in the isthmus. In small intestines and colons, pSmad2/3L-Thr immunostaining-positive cells were detected in specific epithelial cells around crypt bases, where the respective putative stem cells are thought to exist. CONCLUSIONS: We have identified the significant expression of pSmad2/3L-Thr in specific epithelial cells of the murine stomach and have suggested these cells to be epithelial stem cells.

The effective therapy of cyclosporine A with drug delivery system in experimental colitis.

Cyclosporine A (CyA) is a useful immunosuppressive agent for steroid-dependent or steroid-refractory ulcerative colitis. However, side effects have been reported in clinical trials of ulcerative colitis treated with CyA. Biodegradable microspheres (MS) have been investigated as drug delivery system. We evaluated the effect of a drug delivery system with poly(d,l-lactic acid)-MS containing CyA. Colitis was induced in C57BL/6 mice by 3% dextran sulfate sodium (DSS). Mice with DSS-induced colitis were treated with oral administration of CyA or CyA-MS: CyA (0.2 mg/kg/day)-MS; CyA (2 mg/kg/kg)-MS). Serum levels of CyA were significantly less elevated after oral administration of CyA (2 mg/kg/day)-MS compared with CyA (2 mg/kg/day) (CyA (2 mg/kg/day), 44.7 ± 0.8 ng/ml; CyA (2 mg/kg/day)-MS, 7.7 ± 1.3 ng/ml). The body weight at day 10 was significantly recovered in the mice treated with CyA (0.2 mg/kg/day)-MS and CyA (2 mg/kg/day)-MS compared with CyA (0). The histological score and myeloperoxidase activity in the mice treated with CyA-MS was significantly lower than CyA (0). Gene expressions of interleukin-1ß (IL-1ß), IL-6, and CXCL1 in the mice treated with CyA (0.2 mg/kg/day)-MS and CyA (2 mg/kg/day)-MS were downregulated compared with CyA (0)-MS. CyA-MS might be possible to treat ulcerative colitis effectively by decreasing the total dosage without the elevation of the serum level or the side effects of CyA.

Idiopathic duct-centric pancreatitis (IDCP) with immunological studies.

A 65-year-old woman with elevated serum levels of pancreatic enzymes was referred to our hospital for further examinations. Abdominal US and contrast-enhanced CT demonstrated swelling of the pancreas body and tail. MRCP and ERCP revealed abrupt ending of the MPD in the pancreas body. Under the suspicion of malignancy, distal pancreatectomy and splenectomy were performed. The histopathological findings showed idiopathic duct-centric pancreatitis (IDCP) with granulocytic epithelial lesions (GEL). As most cases of Japanese autoimmune pancreatitis (AIP) are lymphoplasmacytic sclerosing pancreatitis (LPSP), the present case seems to be helpful to clarify the clinical findings of IDCP in Japan.

Primary sclerosing cholangitis with elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells.

Immunoglobin G4-related sclerosing cholangitis (IgG4-SC) is recognized as one of the systemic sclerosing diseases characterized by abundant IgG4-positive plasma cells with effective steroid therapy. On the other hand, primary sclerosing cholangitis (PSC), recognized as a sclerosing cholangitis of unknown origin without steroid efficacy, has been often clinically confused with IgG4-SC. To date, the prognosis of IgG4-SC is unclear, while the prognosis of PSC is well known to be poor. Therefore, it is clinically very important to be able to distinguish IgG4-SC from PSC. However, at the present time it still remains unclear whether PSC may sometimes be misdiagnosed as IgG4-SC or not. Herein, we report three rare cases of PSC with elevated serum IgG4 levels and/or an infiltration of abundant IgG4-positive plasma cells in the liver: a young male with ulcerative colitis (UC), and elderly female and a young female, each with elevated serum IgG4 levels. The first two patients showed infiltration of abundant IgG4-positive plasma cells in the portal area of the liver without response to steroid therapy. From our experiences, we emphasize that some patients with PSC, who do not respond to steroid therapy, show elevated serum IgG4 levels and/or infiltration of abundant IgG4-positive plasma cells, although the mechanism still remains unclear.

Xanthogranulomatous inflammation of the peripancreatic region mimicking pancreatic cystic neoplasm.

Xanthogranulomatous inflammation (XGI) is histopathologically characterized by a marked proliferative fibrosis, parenchymal destruction, and infiltration of foamy histiocytes intermixed with other inflammatory cells. Herein, we report a case of a 73-year-old man without symptoms who was initially diagnosed with a pancreatic cystic tumor but later with XGI in the peripancreatic region. Although XGI has been reported to occur in various organs or tissues, such as the gallbladder, kidney, bone, stomach, colon, appendix, lymph nodes, and soft tissues, XGI involving the pancreas or its surrounding tissues is extremely rare. When a pancreatic cystic lesion does not have typical clinicoradiological features of common pancreatic cystic neoplasms, this pathologic condition should be considered in the differential diagnosis.

Long-term outcome of autoimmune pancreatitis.

PURPOSE: Autoimmune pancreatitis (AIP) is a unique form of pancreatitis and can be complicated with various extrapancreatic lesions. Little is known about the long-term clinical course of AIP. Here we aimed to document the clinical course of AIP. METHODS: For this study, we recruited 21 patients, averaging 66.5 years in age (range, 19-84 years) and observed them at a mean interval of 40.8 months (range, 18-130 months). Three of the patients were also diagnosed with retroperitoneal fibrosis, 3 had sialoadenitis, 2 had chronic thyroiditis, 1 had interstitial nephritis, and 1 had interstitial pneumonia. Three of the patients underwent surgical therapy, 12 patients received methylprednisolone (PSL) treatment, and the 6 remaining patients received no treatment. RESULTS: Enlargement of the pancreas was attenuated in all the PSL-treated patients. Seven of the 21 patients showed pancreatic atrophy, of whom 2 were non-PSL-treated patients. Three patients developed chronic pancreatitis. One patient was diagnosed with pancreatic cancer after 50 months of PSL therapy. CONCLUSIONS: As with chronic pancreatitis patients, AIP patients should be observed closely for abnormality in pancreatic function.

"Proton-pump inhibitor-first" strategy versus "step-up" strategy for the acute treatment of reflux esophagitis: a cost-effectiveness analysis in Japan.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common condition, and acid-suppressing agents are the mainstays of treatment. For the acute medical management of GERD, two different strategies can be proposed: either the most effective therapy, i.e., proton-pump inhibitors (PPIs), can be given first, or histamine H2-receptor antagonists (H2RAs) can be attempted first (the "step-up" approach). METHODS: A clinical decision analysis comparing the PPI-first strategy and the H2RA-first "step-up" strategy for the acute treatment of reflux esophagitis in Japan was performed, using a Markov chain approach. RESULTS: The PPI-first strategy was consistently superior to the step-up strategy with regard to clinical outcomes for the patient and with regard to cost-effectiveness (direct cost per patient to achieve clinical success). This superiority was robust within the plausible range of probabilities according to the sensitivity analyses. CONCLUSIONS: The PPI-first strategy is superior to the H2RA-first "step-up" strategy with regard to both efficacy and cost-effectiveness and therefore, the PPI-first strategy is the preferred therapeutic approach for the acute medical treatment of reflux esophagitis.