Yuki Yamauchi

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.

Hypoglycemia Unawareness in Insulinoma Revealed with Flash Glucose Monitoring Systems

The delayed diagnosis of insulinoma remains a clinical issue. One of the main causes of such a delay is hypoglycemia unawareness. A 53-year-old woman fell unconscious during postprandial exercises. Flash glucose monitoring (FGM) systems revealed glucose profiles with fasting hypoglycemia, which facilitated the clinical diagnosis of insulinoma even though she was unaware of her hypoglycemia. The preoperative comparison of the blood glucose values provided by FGM with those obtained from capillary blood were consistent. Thus, FGM may have potential utility in revealing the presence of insulinoma-induced hypoglycemia.

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.

Successful endoscopic removal of fractured guidewire fragments from a peripheral bile duct using a biliary stent delivery system and biopsy forceps

A 61-year-old man with sclerosing cholangitis was referred to our hospital. Blood tests on admission suggested he had acute cholangitis. An abdominal radiograph revealed, in addition to two plastic biliary stents, a foreign body in the upper abdominal area, which appeared to be a fractured guidewire fragment in a peripheral bile duct that had remained after endoscopic retrograde cholangiopancreatography (ERCP) performed at the previous hospital (▶Fig. 1). A further ERCP was performed in our facility for acute cholangitis and removal of the fragments. Cholangiography revealed a biliary stricture from the hilar to peripheral bile ducts, in which guidewire fragments were identified (▶Fig. 2). After the duct had been dilated with a 7-Fr dilator (Soehendra dilation catheter; Cook Japan, Japan), the introducer tube and pusher tube of a biliary stent delivery system (Gadelius Medical, Japan) (▶Fig. 3) were inserted. Once the tip of the pusher tube reached the fragments, the introducer tube was withdrawn and the guidewire fragments were removed through the pusher tube with biopsy forceps (Radial Jaw 4 Pediatric Biopsy Forceps; Boston Scientific Japan, Japan) (▶Fig. 4 and ▶Fig. 5; ▶Video1). Finally, endoscopic nasobiliary drainage tubes were placed in the bilateral hepatic ducts. The patient’s acute cholangitis improved following this procedure. Although there are several reports of fractured guidewires being present in the bile ducts, removal of guidewire fragments from a peripheral bile duct has not previously been reported [1 –4]. To remove the fragments, we modified the previously reported method for a “mapping biopsy” of the bile duct using a Soehendra dilation catheter and biopsy E-Videos