The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid‐Derived Suppressor Cell Activation in Immunoglobulin G4–Related Sclerosing Cholangitis

Abstract

The primary function of myeloid-derived suppressor cells (MDSCs) is reflected in their immune modulatory role in several immune-mediated diseases. In immunoglobulin G4 (IgG4)-related disease (IgG4-RD), it has been hypothesized that there are selective regulatory defects that lead to a T helper 2 (Th2) bias immune response. Herein we have taken advantage of a large cohort of patients with IgG4-related sclerosing cholangitis (IgG4-SC), the most common extrapancreatic involvement of IgG4-RD, as well as controls consisting of primary sclerosing cholangitis, autoimmune hepatitis, and healthy volunteers, to study MDSCs. We report dramatically increased levels of receptor activator for nuclear factor kappa B ligand (RANKL) expression in serum and liver from patients with IgG4-SC compared to both liver-disease and healthy controls. Moreover, in IgG4-SC liver, RANKL-secreting cells specifically colocalized with cluster of differentiation 38-positive plasma cells and MDSCs, particularly monocytic MDSCs, and express the RANKL receptor in liver. Similarly, the frequency and number of peripheral blood MDSCs were significantly increased. Importantly, serum expression levels of RANKL were inversely correlated with the serum level of gamma-glutamyltransferase but significantly positively correlated with the frequency of MDSCs. Moreover, we confirmed that RANKL induced the expansion and activation of MDSCs through the RANKL/RANK/nuclear factor kappa B signal pathway. Of note, RANKL-treated MDSCs suppressed T-cell proliferation and induced Th2 differentiation. Conclusion: Our data suggest that plasma cell-derived RANKL induces the expansion and activation of MDSCs, which suppress T-cell proliferation and contribute to the Th2-type response characteristic of IgG4-SC.

Treatment With Endothelin-A Receptor Antagonist BQ123 Attenuates Acute Inflammation in Mice Through T-Cell-Dependent Polymorphonuclear Myeloid-Derived Suppressor Cell Activation

“…Our previous studies have indicated that targeting T-cells is key to alleviating inflammatory diseases (24,44,58). Other studies have also suggested that MDSCs suppress inflammation by inhibiting the over-activation of T-cells (61,62). Consistent with the published literature, we also demonstrated that adoptive transfer with BQ123-induced PMN-MDSCs can alleviate acute inflammation in the presence of T-cells.…”

The Clinical Significance of Hepatic CD69+CD103+CD8+ Resident‐Memory T Cells in Autoimmune Hepatitis

“…Confocal laser scanning microscopy was used for co‐staining detection of two primary antibodies, as previously described. ( 29 ) After antigen retrieval, liver samples were incubated with two primary antibodies together overnight at 4°C. Primary antibodies included CD103 (ab238010), CD8 (ab93278, ab17147), CD69 (ab233396), granzyme B (ab255598), IFN‐γ (ab231036), CCR7 (ab227768), CD62L (ab264045), E‐cadherin (ab40772), and CK8‐18 (ab17139) (all from Abcam).…”

MutT Homolog 1 Inhibitor Karonudib Attenuates Autoimmune Hepatitis by Inhibiting DNA Repair in Activated T Cells

“…Confocal laser scanning microscopy was used for the detection of costaining markers, as described. ( 24 ) Briefly, after antigen retrieval, liver samples were incubated with donkey serum for 30 minutes before being incubated with primary antibodies MTH1 (ab200832; Abcam), CD3 (60181‐1‐Ig; Proteintech), CD4 (ab67001; Abcam), and CD8 (ab17147; Abcam) at 4°C overnight. After three washes with PBS, the slides were incubated with fluorochrome‐conjugated secondary antibodies (1:200; Invitrogen) at room temperature for 30 minutes.…”