Kazushige Uchida

In 1995, Yoshida et al. proposed first the concept of “autoimmune pancreatitis” (AIP). Since then, AIP has been accepted as a new pancreatic inflammatory disease and is now divided two subtypes. Type 1 AIP affected immunoglobulin G4 (IgG4) and implicates the pancreatic manifestation of IgG4-related disease, while type 2 is characterized by neutrophil infiltration and granulocytic epithelial lesions (GEL). Recent research has clarified the clinical and pathophysiological aspects of type 1 AIP, which is more than type 2 among the Japanese population. However, many details remain unclear about the pathogenesis and progression of this disease. In this review, we discuss the current knowledge and recent advances relating to type 1 AIP.

IgG4-related disease (RD) is a proposed concept of systemic inflammatory condition from Japanese researchers. Patients with IgG4-RD manifest several immunological and histological characterizations in the organs involved, including elevated levels of serum IgG4 and lympho-plasmacytic infiltration, storiform fibrosis, IgG4-positive plasma cells infiltration, and obstructive phlebitis. Nevertheless, the pathogenesis of IgG4-RD still remains unclear. It has been made clear that several immune cells with regulatory function play a vital part in several diseases. In particular, abnormalities in the function and proportion of regulatory T cells (Tregs) are implicated in several diseases, and their part in IgG4-RD has been investigated. This review offers an overview of the research in IgG4-RD related to Tregs. Herein, the basic information of Tregs, knowledge gained from animal models involving Tregs, and the role of IgG4-RD has been provided. We also included the immunological mechanisms of IgG4-RD based on the data accumulated so far in our hypothesis.

Background Stimulation of Toll-like receptor 3 (TLR3) induces autoimmune-mediated pancreatitis in susceptible mice, whereas stimulation of TLR4 causes nonautoimmune-mediated pancreatitis. However, the effects of TLR2 stimulation on the pancreas are unknown. Aims We investigated the role of TLR2 stimulation on pancreatic damage by repeatedly stimulating mice with TLR2 ligands. Methods Wild-type (WT) and interleukin 10-deficient (IL-10-knockout (KO)) mice were administered zymosan and lipoteichoic acid (LTA) intraperitoneally at various doses twice weekly for 4 weeks. Syngeneic T-cell-deficient mice, B-cell-deficient mice, recombination activating gene 2-deficient (RAG2–KO) mice and RAG2–KO mice that had been reconstituted with CD4⁺ or CD8⁺ T cells isolated from WT mice were treated with zymosan similarly. Mice were killed, the severity of pancreatitis was graded histologically, and serum cytokine levels were measured. Results Repeated administration of zymosan induced pancreatitis dose dependently in both WT and IL-10–KO mice. Administration of LTA induced pancreatitis only in IL-10–KO mice. Adoptive transfer of splenocytes obtained from IL-10–KO mice with pancreatitis did not cause pancreatitis in recipient RAG2–KO mice. Pancreatitis was scarcely observed in RAG2–KO mice and was attenuated in T-cell-deficient and B-cell-deficient mice compared with WT mice. A single administration of zymosan significantly increased the serum level of monocyte chemoattractant protein 1 (MCP-1) in WT mice. Conclusions Repeated stimulation of TLR2 and dectin-1 induced nonautoimmune-mediated pancreatitis in mice. Participation of acquired immunity seems to play an important role in the pathogenesis of pancreatitis in association with the increase in serum MCP-1 level.

The characteristic finding of sausage-shaped pancreas or capsule-like rim facilitates the diagnosis of autoimmune pancreatitis. We herein report a case of a 67-year-old man showing a sausage-shaped, enlarged pancreas with a capsule-like rim on computed tomography. Furthermore, endoscopic retrograde cholangiopancreatography demonstrated diffuse narrowing of the main pancreatic duct, in addition to stenosis of the lower bile duct. Finally, we were able to diagnose pancreatic cancer in this patient by an endoscopic ultrasound-guided fine-needle aspiration biopsy following peroral cholangioscopy and bile cytology. This report emphasizes the significance of pathological confirmation before starting treatment, even in cases with diffuse pancreatic enlargement.