Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4-related sclerosing cholangitis

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.