Hereditary pancreatitis is caused by gene mutations resulting in increased trypsin activity. Persistent trypsin activity due to degradation defects and compromised trypsin inhibitor function are good examples, and also contribute to idiopathic chronic pancreatitis. In addition to increased trypsin activity, gene mutations leading to endoplasmic reticulum stress also cause pancreatitis. Next generation sequencing, which progressed rapidly over the last decade, largely contributed to the genetic analysis of pancreatitis-related genes. Panels of known gene mutations related to pancreatitis can be analyzed by targeted resequencing as a screening test. Identification of novel pancreatitis-related genes by whole-exome or whole-genome sequencing will delineate the detailed genetic background of pancreatitis.

The characteristic pathological change of chronic pancreatitis is fibrosis. It is known that pancreatic stellate cells (PSCs) and pancreatic myofibroblasts, which are activated pancreatic stellate cells, play a central role in the fibrosis of pancreas. Once PSCs are activated by etiological factors such as ethanol, ethanol metabolites, and ROS, PSCs produce cytokines and chemokines. Platelet-derived growth factor facilitates the proliferation and the migration of myofibroblasts, and transforming growth factor-β stimulates the production of extracellular matrix, leading to the fibrosis of pancreas. Furthermore, it has been reported that pancreatic myofibroblasts produce various kinds of inflammatory mediators by stimulation of endogenous cytokines and chemokines, resulting in the persistence of inflammation and the development of fibrosis. In this article, we introduce the function of the novel cytokine IL-36 on pancreatic myofibroblasts and describe the role of inflammatory cytokines in pancreatic fibrosis.

Pancreatic acinar cells synthesize a variety of digestive enzymes and secrete them into the pancreatic duct. Intracellular vesicle transport mechanisms play important roles in maintaining these functions. Exocytosis, autophagy and endocytosis are representative of intracellular vesicle trafficking in pancreatic acinar cells. These intracellular vesicular trafficking systems are mediated by soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, autophagy-related genes and the Ras-related GTP-binding protein Rab family. Recent studies demonstrated that defects in intracellular vesicular trafficking systems including exocytosis, autophagy and endocytosis are involved in the onset and progression of acute pancreatitis. These intracellular trafficking pathways are closely related to each other. Therefore, in order to elucidate the pathophysiological mechanisms of acute pancreatitis, it is important to investigate the interactions as well as the participation of each pathway in the onset and progression of acute pancreatitis.

Severe acute pancreatitis (SAP) is a lethal inflammatory disease frequently accompanied by pancreatic necrosis. To improve the outcomes of patients with SAP, it is necessary to understand the molecular mechanisms distinguishing necrotizing pancreatitis from edematous pancreatitis. Immune cells are believed to play a pivotal role in the development of pancreatic necrosis. There are some reports showing the importance of chemokines that recruit leukocytes into pancreatic tissue in the early phase of AP. However, the key chemokine responses in the progression of necrotizing pancreatitis, especially in the late phase, have not yet been identified. CXCL16, a CXC chemokine, was recently reported to be an indicator of necrotizing pancreatitis. Here we provide the evidence that the chemokine CXCL16 is related to the progression of human necrotizing pancreatitis. Using a mouse model, we found that CXCL16 is produced by pancreatic acinar cells in the late phase of AP and then accelerates inflammatory cascades through the induction of Ccl9 and subsequent neutrophil infiltration. We also propose a potential treatment approach for AP by inhibiting Cxcl16-mediated signaling pathways.

Chronic fibro-inflammatory disorders of the pancreas are classified into chronic pancreatitis (CP) and autoimmune pancreatitis (AIP). Both CP and AIP are characterized by infiltration of immune cells and tissue fibrosis. Although adaptive and innate immunity are involved in the generation of chronic fibro-inflammatory responses of the pancreas, recent studies highlight the importance of innate immunity over adaptive immunity in the pathogenesis of CP and AIP. CP and AIP share characteristic innate immune responses in that excessive production of type I interferon (IFN) and IL-33 underly their immuno-pathogenesis. Pancreatic acinar cells and plasmacytoid dendritic cells produce large amounts of type I IFN and IL-33 in CP and AIP, respectively. Development of chronic inflammation and fibrosis depends upon type I IFN and IL-33 in CP and AIP. The type I IFN-IL-33 axis might be a new therapeutic target for CP and AIP.

The pathophysiology of immunoglobulin G4 (IgG4)-related disease (IgG4-RD) remain unknown.

To understand the role of immunoglobulin G (IgG) in the pathogenesis of IgG4-RD, we injected IgGs (control) into neonatal Balb/c mice. We also examined the activity of IgG1, IgG2, IgG3, and IgG4 in patients with IgG4-RD by injecting their IgGs into neonatal Balb/c mice. The subcutaneous injection of patients' IgG, but not control IgG, induced pathologic changes in the pancreas and salivary glands. Interestingly, pancreatic injury was also induced by injecting patients' IgG1 or IgG4, with more destructive change induced by IgG1 than by IgG4. The binding of patients' IgG to the pancreatic extracellular matrix was confirmed in both the mouse model and AIP tissue samples.

To reveal whether the antibodies in patients with IgG4-RD have also pathological effects on humans, the nature of the antigen, and whether the pathophysiology in IgG4-RD is antigen-antibody disease, more studies are needed.

Autoimmune pancreatitis (AIP) is classified into type 1 and type 2. Type 1 AIP is recognized as the pancreatic manifestation of IgG4-related disease (IgG4-RD). The role of IgG4 in IgG4-RD is still unclear. However, inducible co-stimulatory (ICOS) molecule positive regulatory T cells are considered to be involved in the production of IgG4 via IL-10. It is also reported that innate immunity (basophils and monocytes) plays an important role of the production of IgG4. Recently, innate immune mechanisms are known to be necessary for the development of several immune-related diseases. We reviewed the involvement of the innate immune system including basophils in the pathophysiology of type 1 AIP.

Autoimmune pancreatitis type 1 involves both innate and acquired immunity. Although the actual etiology remains to be defined, immune-related genetic factors and environmental factors seem to be the cause of AIP. Microorganisms, especially symbiotic bacteria, may contribute to sustaining the stimuli in the pathogenesis of AIP. Underlying mechanisms caused by the microbes may involve activation of innate immunity through pattern-recognition receptors, activation of auto-reactive T cells through induction of inflammatory cytokines, and molecular mimicry of self-antigens released from tissue damaged at the time of infection. Structural details of the microbial components sensing topical pancreatic autoimmunity may lead to new diagnostic and therapeutic measures against AIP using bacteriologic approaches.

A 75-year-old female presented with a high fever and left-sided abdominal pain. Abdominal computed tomography (CT) scan revealed multiple tumors in the pancreatic tail and both lobes of the liver. The leukocyte count and serum C-reactive protein (CRP) levels were elevated. Endoscopic ultrasonography-guided fine-needle aspiration biopsy showed moderate to poorly differentiated adenocarcinoma. Although we planned chemotherapy, the fever, leukocyte count and serum CRP levels worsened. Despite a thorough physical examination, blood cultures and whole-body CT scan, there was no obvious source of infection. Antibiotics did not resolve the fever. Therefore, we suspected her of having a granulocyte colony-stimulating factor (G-CSF)-producing adenocarcinoma and nab-paclitaxel plus gemcitabine (nab-PTX+GEM) chemotherapy was given. The fever resolved, and the leukocyte count and serum CRP levels decreased. The serum G-CSF level was elevated before chemotherapy, and immunohistochemical staining was positive for G-CSF. This is a rare case of G-CSF-producing pancreatic adenocarcinoma treated with nab-PTX+GEM chemotherapy. We report this patient along with a review of the pertinent literature.

A 70-year-old woman presented with worsening diabetes mellitus, and was found to have pancreatic cancer. The tumor was an unresectable locally advanced pancreatic cancer in contact with and invading more than 180 degrees of the superior mesenteric artery. Combined therapy with gemcitabine hydrochloride and nanoparticle albumin-bound paclitaxel (GEM+nab-PTX) was administered with measurable antitumor effects. After granting informed consent, subtotal pylorus-preserving pancreatoduodenectomy and portal vein resection were performed. Histopathologic findings showed that the effect of chemotherapy was grade 2 (Grading of histological response to preoperative therapy), and the surgical margins were histologically negative. Two years postoperatively, the patient is alive without recurrence. These findings suggest that the GEM+nab-PTX therapy for locally advanced pancreatic cancer enables radical resection of a previously unresectable tumor.