Norimasa Fukata

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.

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.

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-1β (IL-1β), 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.

A comparison of the resection rate for cold and hot snare polypectomy for 4–9 mm colorectal polyps: a multicentre randomised controlled trial (CRESCENT study)

Objective To investigate the success rate of cold snare polypectomy (CSP) for complete resection of 4–9 mm colorectal adenomatous polyps compared with that of hot snare polypectomy (HSP). Design A prospective, multicentre, randomised controlled, parallel, non-inferiority trial conducted in 12 Japanese endoscopy units. Endoscopically diagnosed sessile adenomatous polyps, 4–9 mm in size, were randomly assigned to the CSP or HSP group. After complete removal of the polyp using the allocated technique, biopsy specimens from the resection margin after polypectomy were obtained. The primary endpoint was the complete resection rate, defined as no evidence of adenomatous tissue in the biopsied specimens, among all pathologically confirmed adenomatous polyps. Results A total of 796 eligible polyps were detected in 538 of 912 patients screened for eligibility between September 2015 and August 2016. The complete resection rate for CSP was 98.2% compared with 97.4% for HSP. The non-inferiority of CSP for complete resection compared with HSP was confirmed by the +0.8% (90% CI −1.0 to 2.7) complete resection rate (non-inferiority p<0.0001). Postoperative bleeding requiring endoscopic haemostasis occurred only in the HSP group (0.5%, 2 of 402 polyps). Conclusions The complete resection rate for CSP is not inferior to that for HSP. CSP can be one of the standard techniques for 4–9 mm colorectal polyps. (Study registration: UMIN000018328)

Utility of newly developed short type double balloon endoscopy for endoscopic retrograde cholangiography in postoperative patients

The utility of conventional short‐type double‐balloon endoscopy (DBE) for pancreatobiliary disease in patients with postoperative anatomy had been widely acknowledged and accepted. However, some technical difficulties yet remained. In an attempt to solve these problems, the new short‐type DBE (N‐short DBE) was uniquely designed for therapeutic endoscopic retrograde cholangiography (ERC) in postoperative patients. The aim of this study was to evaluate the usefulness of N‐short DBE for ERC in postoperative patients.

Endoscopic removal of large gastric lipomas: En bloc resection with submucosal dissection or partial resection with unroofing technique?

have a coiled caudal extremity. Females are slightly larger at approximately 30–50 mm in length, and have an uncoiled posterior extremity. The females may shed 3000–20 000 eggs per day, and have a lifespan of 3 years. Diagnosis is usually made after detecting the eggs in feces; however, colonoscopy may be useful in cases where stool samples are negative, but disease is suspected. Trichuris trichiura must be on a clinician’s differential when dealing with a patient from or with a recent travel history to an endemic area.

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.

Short double-balloon enteroscope for previously failed colonoscopy

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

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.

Peri-Appendiceal Red Patch and Pathogenesis of the Appendix in Ulcerative Colitis

To the Editor,We read with interest the article by Rubin and Roth [1]on the peri-appendiceal red patch (PARP) in ulcerativecolitis (UC). In 367 UC patients with distal colitis, 29(7.9%) patients had PARP. In the 29 patients, 23 (79%)were male, none had prior appendectomy, 20 of 30 (67%)biopsy findings showed that the parallel histologic activityin the PARP and the distal colitis, and 11 of 21 patients(52%) with endoscopic follow-up progressed to moreextensive disease. We believe that the pathogenesis of theappendix in UC patients should be highlighted.Although UC is characterized by continuous and diffuseinflammation extending proximally from the rectum, PARPhas been increasingly recognized in 48–86% patients withdistal UC [2–4], as in the study of Rubin and Rothe [1].Patients with PARP experience a more aggressive andrelapsing disease courses compared with patients withoutPARP [3]. Many case–control studies suggest that previousappendectomy is rare in UC patients [2, 3]. Patients withprevious appendectomy have a delayed onset of UC, areduced need for immunomodulators and proctocolectomy,and a reduced relapse rate and extent of UC [5]. Moreover,we and several investigators have reported the improve-ment of UC after appendectomy, especially in youngpatients with PARP [2, 6].The pathogenesis of UC has not been determined, but anabnormal mucosal immune response plays a major role inthe occurrence and pathophysiology of UC [2, 4]. Extensiveinfiltration of lymphocytes, especially CD4? T cells, hasbeen observed in the inflamed mucosa of UC patients.Activated CD4? T cells exhibit increased cytotoxic activityand secrete cytokines that enhance the inflammatory state,resulting in tissue injury. We have disclosed that the pro-portion of CD4? early-but-not-mature-activated T cells issignificantly increased in the appendix of UC patients [4, 7],and suspect that the appendix may be a priming site in theoccurrence of UC. We therefore believe that the appendixshould no longer be considered an evolutionary redundancy,especially in UC patients with PARP.References