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Previous studies have evaluated the roles of T and B cells in the pathogenesis of Sjögren’s syndrome (SS); however, their relationships with age-dependent and metabolic abnormalities remain unclear. We examined the impacts of changes associated with aging or metabolic abnormalities on populations of T and B cells and SS disease severity. We detected increased populations of IL-17-producing T and B cells, which regulate inflammation, in the salivary glands of NOD/ShiLtJ mice. Inflammation-induced human submandibular gland cell death, determined based on p-MLKL and RIPK3 expression levels, was significantly increased by IL-17 treatment. Among IL-17-expressing cells in the salivary gland, peripheral blood, and spleen, the α4β7 (gut-homing integrin)-negative population was significantly increased in aged NOD/ShiLtJ mice. The α4β7-positive population markedly increased in the intestines of aged NOD/ShiLtJ mice following retinoic acid (RA) treatment. A significant increase in α4β7-negative IL-17-expressing cells in salivary glands may be involved in the onset and progression of SS. These results suggest the potential therapeutic utility of RA in SS treatment.

Introduction: The co-occurrence of inflammatory bowel disease (IBD) in up to 80% of patients with primary sclerosing cholangitis (PSC) suggests a relation between the gut and the liver in patients with both PSC and IBD. One hypothesis suggests that aberrantly expressed homing molecules in the liver drive infiltration of gut-homing memory T-cells that are originally primed in intestinal environment. One of the main findings supporting this hypothesis is the expression of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in PSC livers. Expression of homing molecules in early PSC remains unclear. The aim of this study was to investigate expression patterns of homing chemokines and adhesion molecules in PSC-IBD colons and livers, and to study whether changes are already present in early stages of PSC. Methods: Needle biopsies from livers of 20 PSC patients with short-term PSC (PSC-IBDST) as well as explant liver biopsies of 8 patients with long-term PSC (PSC-IBDLT) were collected (median disease duration 0 and 22 years, respectively). Only patients with concomitant IBD were included (89% ulcerative colitis and 11% Crohn’s disease). Expression and distribution of MAdCAM-1, VAP-1, integrin β7, CCL25, CCL28, CXCL12, αE (CD103) and E-cadherin were assessed in both liver and colon tissue. Liver tissue collected from obstructive cholangitis in resection specimens for Klatskin tumors or resection specimens from hepatic metastasis, liver tissue of patients with hepatitis C virus (HCV) and of patients with primary biliary cholangitis (PBC) served as controls. Results: MAdCAM-1 expression in livers of PSC-IBDLT patients was increased compared to controls. The proportion of CD3+ T-cells expressing integrin β7 did not differ between PSC-IBDST and control groups, but was higher in liver tissue of PSC-IBDLT patients. There was no difference in αE+ T-cells between PSC-IBDLT and control groups. The chemokine CCL28 was highly expressed in biliary epithelial cells. This intense staining pattern was more pronounced in PSC-IBDST, but overall did not significantly differ from controls. Conclusions: We confirm that aberrant gut lymphocyte homing to the liver exists in PSC, linking gut and liver disease pathology in PSC-IBD. Our data suggests that this phenomenon increases over time in later stages of the disease, worsening ongoing inflammation.