Send to

Choose Destination
Mod Rheumatol. 2019 Jun 15:1-25. doi: 10.1080/14397595.2019.1632061. [Epub ahead of print]

Up-regulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease.

Author information

a Department of Internal Medicine, Faculty of Medicine , University of Tsukuba , Ibaraki , Japan.
b Department of Microbiology and Immunology , Keio University School of Medicine , Tokyo , Japan.
c Faculty of Dental Science , Kyushu University , Fukuoka , Japan.


Objective: 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 < 0.05, 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 up-regulated 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 up-regulated 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.


Chemokine (C-C motif) ligand 18; Chemokine (C-C motif) receptor 8; IgG4-related disease; Labial salivary glands; Sjögren’s syndrome

Supplemental Content

Full text links

Icon for Taylor & Francis
Loading ...
Support Center