Autoimmune Pancreatitis: Expression and Cellular Source of Profibrotic Cytokines and Their Receptors

Abstract

Chronic pancreatitis is a fibrogenic disease. In autoimmune pancreatitis (AIP), a lymphoplasmacytic infiltration is followed by fibrosis. In vitro it has been shown that pancreatic stellate cells are transformed into proliferating myofibroblasts mainly by transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF). We studied the expression of these profibrotic cytokines, their receptors, and their cellular sources in AIP. Pancreatic tissues from 21 patients with AIP of different grades of severity were selected from a series of 52 AIP cases. Myofibroblasts (ie, activated pancreatic stellate cells), macrophages, lymphocytes, plasma cells, and the cytokines latency-associated peptide, a TGF-beta1 propeptide, TGF-beta receptor II (TGF-beta-RII), PDGF-B, and the alpha and beta isoforms of the PDGF receptor (PDGF-R alpha and PDGF-R beta) were identified immunohistochemically. Their expression and cellular distribution were related to the severity of AIP. In grade 1 and 2 AIP, macrophages and myofibroblasts expressing profibrotic cytokines and their receptors were found in periductal areas showing lymphoplasmacytic inflammation. In grade 3 AIP, there were numerous macrophages, myofibroblasts, and epithelial cells which were positive for latency-associated peptide, PDGF-B, TGF-beta-RII, PDGF-R alpha, and PDGF-R beta not only in periductal, but also in interlobular and intralobular areas. In grade 4 AIP, which is characterized by advanced fibrosis, cellularity and expression of cytokines and their receptors were greatly reduced. Our data indicate that in AIP the occurrence of myofibroblasts is intimately related to the presence of macrophages and lymphoplasmacytic cells. These cells and adjacent epithelial cells express profibrotic cytokines and their receptors, which are probably responsible for the initiation and maintenance of the fibrogenic process.

Interleukin-32 Expression in the Pancreas

“…The primary role of the pancreatic duct cells is to secrete water plus various electrolytes, but several lines of evidence have suggested that the pancreatic epithelial cells may also serve as active participants in various immunologic functions. For example, the expression of transforming growth factor-␤1 has been detected in these cells in vivo (38,39). In this study, we demonstrated that IL-32 is expressed by pancreatic duct cells and that it was increased in chronic pancreatitis.…”

Immunoglobulin G4-Associated Cholangitis: One Variant of Immunoglobulin G4-Related Systemic Disease

“…Interestingly, IL-4 and IL-10 may direct B-cells to produce IgG4 [19, 38]. In addition, TGF-β is a powerful fibrogenic cytokine [14, 19, 39] possibly mediating IgG4-positive plasma cell infiltration and periductal fibrosis/sclerosis, two of the most prominent pathological findings in ISD. It remains to be mentioned that an earlier study had shown increased IFN-γ levels in ISD patients, more indicative of an autoimmune Th1-predominant immune response [40].…”

Immunoglobulin G4-related Lung Disease Accompanied by Organizing Pneumonia

“…It has been reported that these factors may be associated with the pathogenesis of IgG4-RD (14,15). Organizing pneumonia is a frequently observed response pattern that is attributed to post-respiratory infection changes, drug-related tissue damage, radiation therapy, organ transplantation, occupational and environmental factors and rheumatological or connective tissue diseases, and that is also associated with underlying lung diseases, such as pulmonary abscess and lung cancer.…”