BACKGROUND & AIMS: IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis (IgG4-SC/AIP) are characterized by massive lymphoplasmacytic infiltration including Th2 and regulatory T cells (Tregs). This study was conducted to address which chemotactic factors are involved in this condition. METHODS: Chemokine expression profiles in tissue were examined in IgG4-SC/AIP (n=17), classical primary sclerosing cholangitis (IgG4(low) PSC, n=17), PSC with elevated serum/tissue IgG4 levels (IgG4(high) PSC, n=5), and primary biliary cirrhosis (n=7). We focused on five chemotactic factors/receptors (CCL1-CCR8, CCL17/CCL22-CCR4), given that CCR4 and CCR8 are predominantly expressed in both Th2 and Tregs. RESULTS: In conjunction with higher expression levels of IL-4 and IL-10, expression values of CCL1 and CCR8 transcripts were significantly higher in IgG4-SC/AIP than in IgG4(low) PSC (p=0.002) and IgG4(high) PSC (p=0.023). CCL1 and CCR8 were also overexpressed in IgG4(high) PSC than in IgG4(low) PSC (p=0.023). No difference was seen for CCL17, CCL22, and CCR4. In situ hybridization revealed CCL1 to be predominantly expressed in the pancreatic duct epithelium, peribiliary glands, and vascular endothelial cells including the ones involved in obliterative phlebitis in IgG4-SC/AIP, in contrast to IgG4(high) PSC where this chemotactic factor was positive in several infiltrating lymphocytes. These CCL1-expressing sites were infiltrated by CCR8(+) lymphocytes. On immunohistochemistry, GATA3(+) Th2 lymphocytes and FOXP3(+) Tregs were significantly larger in number in IgG4-SC/AIP, with the GATA3(+)/T-bet(+) cell ratio to be shifted in favour of Th2 in periductal and perivascular areas. CONCLUSIONS: CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4-SC/AIP, leading to duct-centred inflammation and obliterative phlebitis.
BACKGROUND & AIMS: IgG4-related sclerosing cholangitis and type 1 autoimmune pancreatitis (IgG4-SC/AIP) are characterized by massive lymphoplasmacytic infiltration including Th2 and regulatory T cells (Tregs). This study was conducted to address which chemotactic factors are involved in this condition. METHODS: Chemokine expression profiles in tissue were examined in IgG4-SC/AIP (n=17), classical primary sclerosing cholangitis (IgG4(low) PSC, n=17), PSC with elevated serum/tissue IgG4 levels (IgG4(high) PSC, n=5), and primary biliary cirrhosis (n=7). We focused on five chemotactic factors/receptors (CCL1-CCR8, CCL17/CCL22-CCR4), given that CCR4 and CCR8 are predominantly expressed in both Th2 and Tregs. RESULTS: In conjunction with higher expression levels of IL-4 and IL-10, expression values of CCL1 and CCR8 transcripts were significantly higher in IgG4-SC/AIP than in IgG4(low) PSC (p=0.002) and IgG4(high) PSC (p=0.023). CCL1 and CCR8 were also overexpressed in IgG4(high) PSC than in IgG4(low) PSC (p=0.023). No difference was seen for CCL17, CCL22, and CCR4. In situ hybridization revealed CCL1 to be predominantly expressed in the pancreatic duct epithelium, peribiliary glands, and vascular endothelial cells including the ones involved in obliterative phlebitis in IgG4-SC/AIP, in contrast to IgG4(high) PSC where this chemotactic factor was positive in several infiltrating lymphocytes. These CCL1-expressing sites were infiltrated by CCR8(+) lymphocytes. On immunohistochemistry, GATA3(+) Th2 lymphocytes and FOXP3(+) Tregs were significantly larger in number in IgG4-SC/AIP, with the GATA3(+)/T-bet(+) cell ratio to be shifted in favour of Th2 in periductal and perivascular areas. CONCLUSIONS: CCL1-CCR8 interaction may play a critical role in lymphocytic recruitment in IgG4-SC/AIP, leading to duct-centred inflammation and obliterative phlebitis.
Authors: Xiaoming Xing; Thomas J Flotte; Mark E Law; Anthony J Blahnik; Wee-Joo Chng; Gaofeng Huang; Ryan A Knudson; Rhett P Ketterling; Julie C Porcher; Stephen M Ansell; Jagmohan Sidhu; Ahmet Dogan; Andrew L Feldman Journal: Appl Immunohistochem Mol Morphol Date: 2015-09