[Show abstract][Hide abstract] ABSTRACT: Quiescent (slow-cycling) and active (rapid-cycling) stem cells are demonstrated in small intestines. We have identified significant expression of Smad2/3, phosphorylated at specific linker threonine residues (pSmad2/3L-Thr), in murine stomach, and suggested these cells are epithelial stem cells.
Digestive Diseases and Sciences 09/2014; · 2.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
Ordinary chronic pancreatitis (CP), such as alcoholic CP, is well established to have the increased risk for pancreatic cancer (PaC), nevertheless an association between autoimmune pancreatitis (AIP) and PaC is still unknown. The aims of this study are to examine the frequency of patients who developed PaC during follow-up after being diagnosed with type 1 AIP and to compare the incidence rate of PaC between patients with type 1 AIP and CP.
Sixty-three patients with type 1 AIP and 41 patients with CP were enrolled. We examined development of PaC during follow-up from their clinical records.
The mean follow-up period was 62.4 months in AIP group and 49.2 months in CP group. The occurrence of PaC was observed in 3 patients with AIP during the mean follow-up period of 94.7 months (range, 31-186), whereas a single CP patient developed PaC 38 months after CP diagnosis. The incident rate of PaC during follow-up was comparable between the 2 groups [4.8% (3/63) in type 1 AIP group vs. 2.4% (1/41) in CP group]. In all of 3 AIP patients who developed accompanying PaC, the clinical remission of AIP was achieved with maintenance steroid therapy, when tumors were discovered. In the histological examination of one surgical patient with PaC, lymphoplasmacytic infiltration in storiform fibrosis with abundant IgG4-positive cell infiltration was observed around the PaC area.
Similar to patients with ordinary CP, surveillance for development of PaC is needed at regular interval during follow-up in AIP patients.
[Show abstract][Hide abstract] ABSTRACT: The stem cell compartment in the esophageal epithelium is possibly located in the basal layer. We have identified significant expression of Smad2/3, phosphorylated at specific linker threonine residues (pSmad2/3L-Thr), in the epithelial cells of murine stomach and intestine, and have suggested that these cells are epithelial stem cells. In this study, we explore whether pSmad2/3L-Thr could serve as a biomarker for esophageal stem cells. We examined esophageal tissues from normal C57BL/6 mice and those with esophagitis. Double immunofluorescent staining of pSmad2/3L-Thr with Ki67, CDK4, p63, or CK14 was performed. After immunofluorescent staining, we stained the same sections with hematoxylin–eosin and observed these cells under a light microscope. We used the 5-bromo-2-deoxyuridine (BrdU) labeling assay to examine label retention of pSmad2/3L-Thr immunostaining-positive cells. We collected specimens 5, 10, 15, and 20 days after repeated BrdU administrations and observed double immunofluorescent staining of pSmad2/3L-Thr with BrdU. In the esophagus, pSmad2/3L-Thr immunostaining-positive cells were detected in the basal layer. These cells were detected between Ki67 immunostaining-positive cells, but they were not co-localized with Ki67. pSmad2/3L-Thr immunostaining-positive cells showed co-localization with CDK4, p63, and CK14. Under a light microscope, pSmad2/3L-Thr immunostaining-positive cells indicated undifferentiated morphological features. Until 20 days follow-up period, pSmad2/3L-Thr immunostaining-positive cells were co-localized with BrdU. pSmad2/3L-Thr immunostaining-positive cells significantly increased in the regeneration phase of esophagitis mucosae, as compared with control mice (esophagitis vs. control : 6.889 ± 0.676/cm vs. 4.293 ± 0.659/cm; P < 0.001). We have identified significant expression of pSmad2/3L-Thr in the specific epithelial cells of murine esophagi. We suggest that these cells are slow-cycling epithelial stem-like cells before re-entry to the cell cycle.
Diseases of the Esophagus 09/2014; · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, autoimmune pancreatitis has been classified into two subtypes. Type 1 is related to immunoglobulin G4 and type 2 is related to granulocytic epithelial lesions, but pathogenetic mechanisms in both still remain unclear. Apart from type 2 autoimmune pancreatitis, the pathological features of type 1 autoimmune pancreatitis with increased serum immunoglobulin G4/immunoglobulin E levels, abundant infiltration of immunoglobulin G4+plasmacytes and lymphocytes, fibrosis, and steroid responsiveness are suggestive of abnormal immunity such as allergy or autoimmunity. Although pathophysiological conditions seem to be different in each, both respond well to steroid drugs. After remission, the patients with type 1 autoimmune pancreatitis show high relapse rates (30-50% within 6-12 months), whereas those with type 2 autoimmune pancreatitis seldom relapse. After remission, the steroid maintenance therapy and therapeutic strategy for relapsing patients with type 1 is different among local expertise. In this paper, recent advances in pathogenesis and clinical guidance for therapy are discussed.
Therapeutic advances in chronic disease. 05/2014; 5(3):104-111.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Recent studies suggested the existence of two subtypes of autoimmune pancreatitis (AIP): type 1 related with IgG4 as the pancreatic manifestation of IgG4-related disease (IgG4-RD), and type 2 related with a granulocytic epithelial lesion. Apart from type 2 AIP, the characteristic features of type 1 AIP are increased serum IgG4 levels, lymphoplasmacytic sclerosing pancreatitis (abundant infiltration of IgG4+plasmacytes and lymphocytes, storiform fibrosis, and obliterative phlebitis), extra-pancreatic manifestations of IgG4-RD (eg. sclerosing cholangitis, sclerosing sialadenitis, retroperitoneal fibrosis), and steroid responsiveness. Although the way how to diagnose IgG4-RD has not been established yet, the Comprehensive Diagnostic Criteria (CDC) for IgG4-RD for general use, and several organ specific criteria for AIP have been proposed; the International Consensus Diagnostic Criteria (ICDC) and the revised clinical diagnostic criteria in 2011 by Japan Pancreas Society (JPS-2011) for type1 AIP. In cases of probable or possible IgG4-RD diagnosed by the CDC, organ specific diagnostic criteria should be concurrently used according to an algorhythm of diagnosis for IgG4-RD with referring to the specialist.
[Show abstract][Hide abstract] ABSTRACT: 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.
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+CD24highCD38high and CD19+CD24highCD27+ from peripheral blood by flow cytometry.
In peripheral blood, CD19+CD24highCD38high Bregs were significantly increased in type 1 AIP patients compared with CP, pancreatic cancer, and healthy controls. Although not significant different, CD19+CD24highCD27+ Bregs of type 1 AIP were decreased compared to those of other groups. IL-10+ B cells were not significantly different from type1 AIP patients and healthy controls. In untreated type 1 AIP patients, the number of CD19+CD24highCD38high Bregs and IgG4 were not correlated.
Our data suggested that CD19+CD24highCD38high Bregs seemed to increase reactively to suppress the disease activity, and are consistent with the hypothesis that CD19+CD24highCD27+ Bregs might be involved in the development of type 1 AIP, although it still remains unclear whether the decrease of CD19+CD24highCD27+ cells is cause or effect of AIP.
[Show abstract][Hide abstract] ABSTRACT: Recently, autoimmune pancreatitis (AIP) has been classified into two subtypes: type 1 as a pancreatic manifestation of IgG4-related disease (IgG4-RD), and type 2 related with a granulocytic epithelial lesion (GEL). Different from type 2 AIP, T helper type 2 (Th2) immune response is predominant over Th1 in type1/IgG4-RD. Recent human and experimental animal studies have suggested a possible involvement of innate immunity in addition to acquired immunity, such as genetic background, bacterial/viral infections, complement activation via classical pathway, or IgG4-production of monocytes/basophils with TLR/NOD stimulation. Based on these findings, we have proposed a hypothesis for the development of type1 AIP, one of the IgG4-RD.
Japanese Journal of Clinical Immunology 01/2014; 37(1):11-8.
[Show abstract][Hide abstract] ABSTRACT: 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.
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 midazolamwith or without pentazocine. PtcCO2 was measured by a non-invasive sensor throughout DB-ERCP in all patients.
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.
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.
[Show abstract][Hide abstract] ABSTRACT: Endoscopic retrograde cholangiopancreatography (ERCP) using a double-balloon enteroscope (DBE) in patients with bowel reconstruction due to a previous abdominal surgery is now widely accepted. In particular, a short DBE, which has a 2.8-mm working channel and 152-cm working length, is useful for ERCP because of its good rotational and straightening ability and the availability of various conventional ERCP accessories through the working channel. Herein we report a case of intrahepatic cholangiocarcinoma via ERCP with a short DBE. This is the first report in which the pre-cutting and the brush cytological examination were performed successfully under a DBE to diagnose intrahepatic cholangiocarcinoma pathologically. The short DBE allowed us to perform all diagnostic and therapeutic procedures accepted in conventional ERCP in patients with surgically altered anatomies.
World Journal of Gastroenterology 07/2013; 19(27):4427-31. · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
International Journal of Rheumatology 01/2013; 2013:367325.
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Gastroenterology 10/2012; · 4.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
International Journal of Rheumatology 01/2012; 2012:795026.
[Show abstract][Hide abstract] ABSTRACT: 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.
Internal Medicine 01/2012; 51(7):733-7. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Internal Medicine 01/2009; 48(21):1881-4. · 0.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.