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

Min Lian, Qixia Wang, Xiang Jiang, Jun Zhang, Yiran Wei, Yanmei Li, Bo Li, Weihua Chen, Haiyan Zhang, Qi Miao, Yanshen Peng, Xiao Xiao, Li Sheng, Weici Zhang, Jingyuan Fang, Ruqi Tang, M. Eric Gershwin, Xiong Ma

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1922-1936
Number of pages15
JournalHepatology
Volume68
Issue number5
DOIs
StatePublished - Nov 1 2018

Fingerprint

RANK Ligand
Sclerosing Cholangitis
Immunoglobulins
Liver
Serum
Cell Proliferation
T-Lymphocytes
Myeloid-Derived Suppressor Cells
Autoimmune Hepatitis
gamma-Glutamyltransferase
NF-kappa B
Immune System Diseases
Plasma Cells
Liver Diseases
Signal Transduction
Blood Cells
Healthy Volunteers

ASJC Scopus subject areas

  • Hepatology

Cite this

The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid-Derived Suppressor Cell Activation in Immunoglobulin G4–Related Sclerosing Cholangitis. / Lian, Min; Wang, Qixia; Jiang, Xiang; Zhang, Jun; Wei, Yiran; Li, Yanmei; Li, Bo; Chen, Weihua; Zhang, Haiyan; Miao, Qi; Peng, Yanshen; Xiao, Xiao; Sheng, Li; Zhang, Weici; Fang, Jingyuan; Tang, Ruqi; Gershwin, M. Eric; Ma, Xiong.

In: Hepatology, Vol. 68, No. 5, 01.11.2018, p. 1922-1936.

Research output: Contribution to journalArticle

Lian, M, Wang, Q, Jiang, X, Zhang, J, Wei, Y, Li, Y, Li, B, Chen, W, Zhang, H, Miao, Q, Peng, Y, Xiao, X, Sheng, L, Zhang, W, Fang, J, Tang, R, Gershwin, ME & Ma, X 2018, 'The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid-Derived Suppressor Cell Activation in Immunoglobulin G4–Related Sclerosing Cholangitis', Hepatology, vol. 68, no. 5, pp. 1922-1936. https://doi.org/10.1002/hep.30095
Lian, Min ; Wang, Qixia ; Jiang, Xiang ; Zhang, Jun ; Wei, Yiran ; Li, Yanmei ; Li, Bo ; Chen, Weihua ; Zhang, Haiyan ; Miao, Qi ; Peng, Yanshen ; Xiao, Xiao ; Sheng, Li ; Zhang, Weici ; Fang, Jingyuan ; Tang, Ruqi ; Gershwin, M. Eric ; Ma, Xiong. / The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid-Derived Suppressor Cell Activation in Immunoglobulin G4–Related Sclerosing Cholangitis. In: Hepatology. 2018 ; Vol. 68, No. 5. pp. 1922-1936.
@article{3900f79f3ddc480b907f022859744536,
title = "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.",
author = "Min Lian and Qixia Wang and Xiang Jiang and Jun Zhang and Yiran Wei and Yanmei Li and Bo Li and Weihua Chen and Haiyan Zhang and Qi Miao and Yanshen Peng and Xiao Xiao and Li Sheng and Weici Zhang and Jingyuan Fang and Ruqi Tang and Gershwin, {M. Eric} and Xiong Ma",
year = "2018",
month = "11",
day = "1",
doi = "10.1002/hep.30095",
language = "English (US)",
volume = "68",
pages = "1922--1936",
journal = "Hepatology",
issn = "0270-9139",
publisher = "John Wiley and Sons Ltd",
number = "5",

}

TY - JOUR

T1 - The Immunobiology of Receptor Activator for Nuclear Factor Kappa B Ligand and Myeloid-Derived Suppressor Cell Activation in Immunoglobulin G4–Related Sclerosing Cholangitis

AU - Lian, Min

AU - Wang, Qixia

AU - Jiang, Xiang

AU - Zhang, Jun

AU - Wei, Yiran

AU - Li, Yanmei

AU - Li, Bo

AU - Chen, Weihua

AU - Zhang, Haiyan

AU - Miao, Qi

AU - Peng, Yanshen

AU - Xiao, Xiao

AU - Sheng, Li

AU - Zhang, Weici

AU - Fang, Jingyuan

AU - Tang, Ruqi

AU - Gershwin, M. Eric

AU - Ma, Xiong

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85054562189&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054562189&partnerID=8YFLogxK

U2 - 10.1002/hep.30095

DO - 10.1002/hep.30095

M3 - Article

C2 - 29774578

AN - SCOPUS:85054562189

VL - 68

SP - 1922

EP - 1936

JO - Hepatology

JF - Hepatology

SN - 0270-9139

IS - 5

ER -