Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease

Hiroto Tsuboi, Mana Iizuka-Koga, Hiromitsu Asashima, Hiroyuki Takahashi, Hanae Kudo, Yuko Ono, Fumika Honda, Akira Iizuka, Seiji Segawa, Saori Abe, Mizuki Yagishita, Masahiro Yokosawa, Yuya Kondo, Masafumi Moriyama, Isao Matsumoto, Seiji Nakamura, Takayuki Sumida

Research output: Contribution to journalArticle

Abstract

Objectives: To determine the protein expression level, expressing cell types, and pathogenic roles of chemokine (C-C motif) ligand 18 (CCL18) and its receptor chemokine (C-C motif) receptor 8 (CCR8) in affected tissues of patients with IgG4-related disease (IgG4-RD). Methods: The protein expression levels of CCL18 in labial salivary glands (LSGs) assessed by immunofluorescence (IF) staining were compared among patients with IgG4-RD (n = 3), primary Sjögren’s syndrome (pSS; n = 4), and control subjects (n = 5). CCL18 expression levels in macrophages, CD11c+ cells, B cells, and plasmacytes in LSGs were examined by double IF staining. The protein expression levels of CCR8 and expressing cells (T, B cells, and plasmacytes) in LSGs were also compared among patients with IgG4-RD, pSS, and control subjects by double IF staining. The effects of the CCL18-CCR8 axis on total IgG, IgG2, and IgG4 production by peripheral blood mononuclear cells (PBMCs) stimulated with CD40L, IL-4, IL-10, and IL-21 were examined by in vitro assays. Results: CCL18 was specifically upregulated in LSGs of patients with IgG4-RD, compared with only a few cells in pSS patients and none of the controls. The numbers of CCL18-producing macrophages, CD11c+ cells, and plasmacytes in LSGs were significantly higher in IgG4-RD patients than in pSS patients and control (p <.05, each). Many T and B cells and some plasmacytes expressed CCR8 in LSGs of IgG4-RD and pSS patients. CCL18 specifically enhanced IgG4 production by stimulated PBMCs. Conclusion: CCL18-CCR8 axis was upregulated in LSGs of patients with IgG4-RD, suggesting possible roles of this axis in the pathogenesis of IgG4-RD.Key messages The CCL18-CCR8 axis in labial salivary glands (LSGs) and lacrimal glands of IgG4-RD patients was specifically upregulated compared with primary Sjögren’s syndrome and control subjects. This axis might be a potentially novel therapeutic target in IgG4-RD, based on its important etiopathogenic roles, such as chemotaxis of various cells, induction of fibrosis, and enhancement of IgG4 production.

Original languageEnglish
JournalModern Rheumatology
DOIs
Publication statusAccepted/In press - Jan 1 2019

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Up-Regulation
Immunoglobulin G
Ligands
Lip
Salivary Glands
Plasma Cells
Fluorescent Antibody Technique
B-Lymphocytes
Staining and Labeling
Blood Cells
CCR Receptors
Macrophages
CC Chemokines
Lacrimal Apparatus
CD40 Ligand
Proteins
Chemotaxis
Interleukin-4
Interleukin-10
Fibrosis

All Science Journal Classification (ASJC) codes

  • Rheumatology

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Tsuboi, H., Iizuka-Koga, M., Asashima, H., Takahashi, H., Kudo, H., Ono, Y., ... Sumida, T. (Accepted/In press). Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease. Modern Rheumatology. https://doi.org/10.1080/14397595.2019.1632061

Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease. / Tsuboi, Hiroto; Iizuka-Koga, Mana; Asashima, Hiromitsu; Takahashi, Hiroyuki; Kudo, Hanae; Ono, Yuko; Honda, Fumika; Iizuka, Akira; Segawa, Seiji; Abe, Saori; Yagishita, Mizuki; Yokosawa, Masahiro; Kondo, Yuya; Moriyama, Masafumi; Matsumoto, Isao; Nakamura, Seiji; Sumida, Takayuki.

In: Modern Rheumatology, 01.01.2019.

Research output: Contribution to journalArticle

Tsuboi, H, Iizuka-Koga, M, Asashima, H, Takahashi, H, Kudo, H, Ono, Y, Honda, F, Iizuka, A, Segawa, S, Abe, S, Yagishita, M, Yokosawa, M, Kondo, Y, Moriyama, M, Matsumoto, I, Nakamura, S & Sumida, T 2019, 'Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease', Modern Rheumatology. https://doi.org/10.1080/14397595.2019.1632061
Tsuboi, Hiroto ; Iizuka-Koga, Mana ; Asashima, Hiromitsu ; Takahashi, Hiroyuki ; Kudo, Hanae ; Ono, Yuko ; Honda, Fumika ; Iizuka, Akira ; Segawa, Seiji ; Abe, Saori ; Yagishita, Mizuki ; Yokosawa, Masahiro ; Kondo, Yuya ; Moriyama, Masafumi ; Matsumoto, Isao ; Nakamura, Seiji ; Sumida, Takayuki. / Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease. In: Modern Rheumatology. 2019.
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abstract = "Objectives: To determine the protein expression level, expressing cell types, and pathogenic roles of chemokine (C-C motif) ligand 18 (CCL18) and its receptor chemokine (C-C motif) receptor 8 (CCR8) in affected tissues of patients with IgG4-related disease (IgG4-RD). Methods: The protein expression levels of CCL18 in labial salivary glands (LSGs) assessed by immunofluorescence (IF) staining were compared among patients with IgG4-RD (n = 3), primary Sj{\"o}gren’s syndrome (pSS; n = 4), and control subjects (n = 5). CCL18 expression levels in macrophages, CD11c+ cells, B cells, and plasmacytes in LSGs were examined by double IF staining. The protein expression levels of CCR8 and expressing cells (T, B cells, and plasmacytes) in LSGs were also compared among patients with IgG4-RD, pSS, and control subjects by double IF staining. The effects of the CCL18-CCR8 axis on total IgG, IgG2, and IgG4 production by peripheral blood mononuclear cells (PBMCs) stimulated with CD40L, IL-4, IL-10, and IL-21 were examined by in vitro assays. Results: CCL18 was specifically upregulated in LSGs of patients with IgG4-RD, compared with only a few cells in pSS patients and none of the controls. The numbers of CCL18-producing macrophages, CD11c+ cells, and plasmacytes in LSGs were significantly higher in IgG4-RD patients than in pSS patients and control (p <.05, each). Many T and B cells and some plasmacytes expressed CCR8 in LSGs of IgG4-RD and pSS patients. CCL18 specifically enhanced IgG4 production by stimulated PBMCs. Conclusion: CCL18-CCR8 axis was upregulated in LSGs of patients with IgG4-RD, suggesting possible roles of this axis in the pathogenesis of IgG4-RD.Key messages The CCL18-CCR8 axis in labial salivary glands (LSGs) and lacrimal glands of IgG4-RD patients was specifically upregulated compared with primary Sj{\"o}gren’s syndrome and control subjects. This axis might be a potentially novel therapeutic target in IgG4-RD, based on its important etiopathogenic roles, such as chemotaxis of various cells, induction of fibrosis, and enhancement of IgG4 production.",
author = "Hiroto Tsuboi and Mana Iizuka-Koga and Hiromitsu Asashima and Hiroyuki Takahashi and Hanae Kudo and Yuko Ono and Fumika Honda and Akira Iizuka and Seiji Segawa and Saori Abe and Mizuki Yagishita and Masahiro Yokosawa and Yuya Kondo and Masafumi Moriyama and Isao Matsumoto and Seiji Nakamura and Takayuki Sumida",
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T1 - Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease

AU - Tsuboi, Hiroto

AU - Iizuka-Koga, Mana

AU - Asashima, Hiromitsu

AU - Takahashi, Hiroyuki

AU - Kudo, Hanae

AU - Ono, Yuko

AU - Honda, Fumika

AU - Iizuka, Akira

AU - Segawa, Seiji

AU - Abe, Saori

AU - Yagishita, Mizuki

AU - Yokosawa, Masahiro

AU - Kondo, Yuya

AU - Moriyama, Masafumi

AU - Matsumoto, Isao

AU - Nakamura, Seiji

AU - Sumida, Takayuki

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Objectives: To determine the protein expression level, expressing cell types, and pathogenic roles of chemokine (C-C motif) ligand 18 (CCL18) and its receptor chemokine (C-C motif) receptor 8 (CCR8) in affected tissues of patients with IgG4-related disease (IgG4-RD). Methods: The protein expression levels of CCL18 in labial salivary glands (LSGs) assessed by immunofluorescence (IF) staining were compared among patients with IgG4-RD (n = 3), primary Sjögren’s syndrome (pSS; n = 4), and control subjects (n = 5). CCL18 expression levels in macrophages, CD11c+ cells, B cells, and plasmacytes in LSGs were examined by double IF staining. The protein expression levels of CCR8 and expressing cells (T, B cells, and plasmacytes) in LSGs were also compared among patients with IgG4-RD, pSS, and control subjects by double IF staining. The effects of the CCL18-CCR8 axis on total IgG, IgG2, and IgG4 production by peripheral blood mononuclear cells (PBMCs) stimulated with CD40L, IL-4, IL-10, and IL-21 were examined by in vitro assays. Results: CCL18 was specifically upregulated in LSGs of patients with IgG4-RD, compared with only a few cells in pSS patients and none of the controls. The numbers of CCL18-producing macrophages, CD11c+ cells, and plasmacytes in LSGs were significantly higher in IgG4-RD patients than in pSS patients and control (p <.05, each). Many T and B cells and some plasmacytes expressed CCR8 in LSGs of IgG4-RD and pSS patients. CCL18 specifically enhanced IgG4 production by stimulated PBMCs. Conclusion: CCL18-CCR8 axis was upregulated in LSGs of patients with IgG4-RD, suggesting possible roles of this axis in the pathogenesis of IgG4-RD.Key messages The CCL18-CCR8 axis in labial salivary glands (LSGs) and lacrimal glands of IgG4-RD patients was specifically upregulated compared with primary Sjögren’s syndrome and control subjects. This axis might be a potentially novel therapeutic target in IgG4-RD, based on its important etiopathogenic roles, such as chemotaxis of various cells, induction of fibrosis, and enhancement of IgG4 production.

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