Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease
Upregulation and pathogenic roles of CCL18-CCR8 axis in IgG4-related disease
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DOI：
10.1080/14397595.2019.1632061
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发表时间：
2019-07-04
影响因子：
2.2
通讯作者：
Sumida, Takayuki
中科院分区：
文献类型：
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作者：
Tsuboi, Hiroto;Iizuka-Koga, Mana;Sumida, Takayuki
目的：探讨趋化因子（C-C motif）配体18（CCL 18）及其受体趋化因子（C-C motif）受体8（CCR 8）在IgG 4相关疾病（IgG 4-RD）患者病变组织中的蛋白表达水平、表达细胞类型及其致病作用。研究方法：通过免疫荧光（IF）染色评估的唇唾液腺（LSG）中CCL 18的蛋白表达水平在IgG 4-RD（n = 3）、原发性干燥综合征（pSS; n = 4）和对照受试者（n = 5）中进行比较。通过双重IF染色检测LSG中巨噬细胞、CD 11 c（+）细胞、B细胞和浆细胞中的CCL 18表达水平。还通过双重IF染色比较了IgG 4-RD、pSS患者和对照受试者中LSG中CCR 8和表达细胞（T、B细胞和浆细胞）的蛋白表达水平。通过体外试验检测了CCL 18-CCR 8轴对用CD 40 L、IL-4、IL-10和IL-21刺激的外周血单核细胞（PBMC）产生的总IgG、IgG 2和IgG 4的影响。结果：与pSS患者中仅有少数细胞和对照组中无细胞相比，CCL 18在IgG 4-RD患者的LSG中特异性上调。IgG 4-RD患者LSG中产生CCL 18的巨噬细胞、CD 11 c（+）细胞和浆细胞的数量显著高于pSS患者和对照组（p <0.05）。在IgG 4-RD和pSS患者的LSG中，许多T和B细胞以及一些浆细胞表达CCR 8。CCL 18特异性地增强刺激的PBMC的IgG 4产生。结论：CCL 18-CCR 8轴在IgG 4-RD患者的LSG中上调，表明该轴在IgG 4-RD的发病机制中的可能作用。关键信息与原发性干燥综合征和对照受试者相比，IgG 4-RD患者的唇唾液腺（LSG）和泪腺中的CCL 18-CCR 8轴特异性上调。该轴可能是一个潜在的新的治疗靶点在IgG 4-RD，基于其重要的致病作用，如各种细胞的趋化性，诱导纤维化，并增强IgG 4的生产。
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 Sjogren'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 Sjogren'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.