Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjogren's Syndrome: Potential New Axis in Lymphoid Neogenesis
Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjogren's Syndrome: Potential New Axis in Lymphoid Neogenesis
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DOI：
10.1002/art.40182
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发表时间：
2017-10-01
影响因子：
13.3
通讯作者：
van Roon, Joel A. G.
中科院分区：
文献类型：
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作者：
Blokland, Sofie L. M.;Hillen, Maarten R.;van Roon, Joel A. G.
Objective.滤泡辅助性T（Tfh）细胞在生发中心形成和B细胞活化中起关键作用，这两者都是原发性干燥综合征（SS）的标志。表达CCR 9的T辅助细胞具有Tfh样特征，并且在几种炎症条件下，它们的数量在粘膜相关部位增加。由于这些细胞的特征是独特的，评价一直是有限的，本研究进行调查的局部和全身的CCL 25/CCR 9轴原发性SS患者。评估了原发性SS患者和未诊断为原发性SS的干燥综合征患者（非SS干燥对照）唇唾液腺（LSG）中CCL 25蛋白和信使RNA（mRNA）以及CCR 9 + T辅助细胞的水平。评估CCL 25水平与炎症参数和临床特征的相关性。根据表型和功能特性比较循环CCR 9+和CXCR 5+辅助性T细胞。结果。与非SS干燥对照组相比，原发性SS患者LSG中CCL 25蛋白和mRNA水平升高。CCL 25水平升高与B细胞过度活跃、自身免疫、白细胞介素-21（IL-21）和可溶性IL-7受体α链（IL-7 α）水平相关。此外，在原发性SS患者中，LSG中CCR 9表达细胞的频率增加，表达程序性死亡1和诱导性T细胞共刺激因子的循环CCR 9 + T辅助细胞的水平升高。与CXCR 5 + T辅助细胞相比，CCR 9 + T辅助细胞显示出更高的IL-7 R表达，并分泌更高水平的干扰素、IL-17、IL-4和IL-21，离体和用抗原或IL-7触发后。CCR 9+和CXCR 5+辅助性T细胞诱导B细胞产生IgG的能力均强于CCR 9-CXCR 5-辅助性T细胞。在原发性SS患者的LSG中CCL 25的增强表达可以促进CCR 9 + T辅助细胞的吸引，并且当用抗原或IL-7触发时，这些细胞分泌高水平的促炎细胞因子。观察到的与B细胞过度活跃、自身免疫和淋巴新生标志物的相关性表明，CCL 25/CCR 9轴在原发性SS的免疫病理学中发挥着重要作用，这表明该轴可能代表该疾病的新治疗靶点。
Objective. Follicular helper T (Tfh) cells play a critical role in germinal center formation and B cell activation, both of which are hallmarks of primary Sjogren's syndrome (SS). CCR9-expressing T helper cells have Tfh-like characteristics and their numbers are increased at mucosa-associated sites in several inflammatory conditions. Because the characteristics of these cells are unique and evaluation has been limited, this study was undertaken to investigate the local and systemic CCL25/CCR9 axis in patients with primary SS.Methods. Levels of CCL25 protein and messenger RNA (mRNA) and CCR9+ T helper cells were evaluated in the labial salivary glands (LSGs) of patients with primary SS and patients with sicca syndrome without a diagnosis of primary SS (non-SS sicca controls). CCL25 levels were assessed for correlation with parameters of inflammation and clinical features. Circulating CCR9+ and CXCR5+ T helper cells were compared on the basis of phenotypic and functional properties.Results. CCL25 protein and mRNA levels were elevated in the LSGs of patients with primary SS as compared to non-SS sicca controls. Increased levels of CCL25 were associated with B cell hyperactivity, autoimmunity, and levels of interleukin-21 (IL-21) and soluble IL-7 receptor alpha-chain (IL-7 alpha). Furthermore, the frequency of CCR9-expressing cells in the LSGs was increased and levels of circulating CCR9+ T helper cells expressing programmed death 1 and inducible T cell costimulator were elevated in patients with primary SS. CCR9+ T helper cells displayed higher expression of IL-7R and secreted higher levels of interferon-, IL-17, IL-4, and IL-21 as compared to CXCR5+ T helper cells, ex vivo and upon triggering with antigen or IL-7. Both CCR9+ and CXCR5+ T helper cells induced IgG production by B cells more potently than that induced in the cultures with CCR9-CXCR5- T helper cells.Conclusion. Enhanced expression of CCL25 in LSGs of patients with primary SS can facilitate attraction of CCR9+ T helper cells, and these cells secrete high levels of proinflammatory cytokines when triggered with antigen or IL-7. The observed associations with B cell hyperactivity, autoimmunity, and markers of lymphoid neogenesis indicate that the CCL25/CCR9 axis plays a significant role in the immunopathology of primary SS, suggesting that this axis could represent a novel therapeutic target for the disease.