The crucial roles of IFN-γ in the development of M3 muscarinic acetylcholine receptor induced Sjögren’s syndrome-like sialadenitis
The crucial roles of IFN-γ in the development of M3 muscarinic acetylcholine receptor induced Sjögren’s syndrome-like sialadenitis
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IFN-γ 在 M3 毒蕈碱乙酰胆碱受体诱导的干燥综合征样唾液腺炎发展中的关键作用
DOI：
10.3109/s10165-012-0785-8
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发表时间：
2013
影响因子：
2.2
通讯作者：
T. Sumida
中科院分区：
文献类型：
--
作者：
M. Iizuka;H. Tsuboi;N. Matsuo;Y. Kondo;H. Asashima;M. Matsui;I. Matsumoto;T. Sumida
干燥综合征（SS）是一种慢性自身免疫性疾病，其特征是淋巴细胞浸润到泪腺和唾液腺中，并且临床上表现为干眼症和口干症。已经分析了浸润SS患者唾液腺的T细胞识别的自身抗原，并且已经鉴定了几种候选自身抗原，例如M3毒蕈碱乙酰胆碱受体（M3 R）。已经检查了SS患者中抗M3 R抗体的存在和特异性[1-3]。我们还报告了40%的SS患者中存在产生IFN-c的M3 R反应性CD 4 T细胞[4]。几项研究还检测到SS患者唾液腺中的高水平IFN-c，然后增强T细胞、B细胞和巨噬细胞的活性，导致组织腺体的破坏和功能障碍[5，6]。相比之下，在SS患者的唾液腺中也发现了产生IL-17的T细胞[7]。我们以前的研究表明，M3 R-反应性T细胞参与了涎腺炎的发病机制，使用M3 R诱导的涎腺炎（MIS）小鼠，这被认为是SS的模型小鼠。在MIS小鼠中，CD 3 T细胞对于涎腺炎的产生是必需的。此外，IFN-c和IL-17均由M3 R反应性T细胞产生，并在唾液腺中检测到，而在血清中未检测到IFNc和IL-17 [8]。然而，我们没有证据表明细胞因子INF-c和/或IL-17在涎腺炎的发展中是重要的。在本研究中，为了解决IFN-c在涎腺炎的发展中是否重要的问题，我们产生了M3 R9 IFN-c小鼠，用M3 R肽免疫，并将它们的脾细胞转移到Rag-1小鼠。组织学结果显示，M3 R9 IFN-c？Rag 1比M3 R？Rag 1小鼠，但比M3 R中的轻微？Rag 1小鼠（图1a）。使用组织学评分的定量分析表明，单核细胞浸润在M3 R9 IFNc？Rag 1小鼠与M3 R？Rag 1组小鼠（P <0.05），但与M3 R组相比，Rag 1组小鼠的P25、P2 Rag 1小鼠（P <0.05）（图1b）。这些观察结果支持IFN-c可能在SS样涎腺炎的产生中起关键作用的观点。在M3 R9 IFN-c的唾液腺中没有IFN-c和存在IL-17产生细胞？通过免疫组织化学染色验证Rag 1小鼠（图1c）。IL-17产生细胞在炎症病变中被确定在两个M3 R9 IFN-c？Rag 1和M3 R？Rag 1小鼠。IFN-c和IL-17在M3 R9 IFN-c？Rag 1小鼠，也不是在M3 R？Rag 1小鼠（数据未显示）。在M3 R？在Rag 1小鼠中，在唾液腺中也观察到IL-17的表达，IFN-c的表达也是如此。由于我们没有直接证据支持IL-17在MIS中的致病作用，因此有必要使用M3 R9 IL-17小鼠进行进一步研究以阐明产生IL-17的M3 R反应性T细胞的功能。M.饭冢湾坪井湾松尾Y近藤湖朝岛岛松本T. Sumida（&）Department of Internal Medicine，Faculty of Medicine，University of Tsukuba，1-1-1 Tenodai，Tsukuba，茨木305-8575，Japan电子邮件：tsumida@md.tsukuba.ac.jp
Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by infiltration of lymphocytes into lacrimal and salivary glands, and clinically by dry eyes and dry mouth. Auto-antigens recognized by T cells infiltrating the salivary glands of patients with SS have been analyzed, and several candidate auto-antigens such as M3 muscarinic acetylcholine receptor (M3R) have been identified. The presence and specificity of anti-M3R antibodies in patients with SS have been examined [1–3]. We also reported the presence of IFN-c-producing M3R-reactive CD4 T cells in 40 % of SS patients with SS [4]. Several studies also detected high levels of IFN-c in the salivary glands of SS patients, and then enhanced activity of T cells, B cells, and macrophages, resulting in the destruction and dysfunction of tissue glands [5, 6]. In contrast, IL-17-producing T cells were also found in salivary glands from patients with SS [7]. Our previous study showed that M3R-reactive T cells were involved in the pathogenesis of sialadenitis using M3R-induced sialadenitis (MIS) mice, which are thought to be model mice for SS. In MIS mice, CD3 T cells were essential for the generation of sialadenitis. Moreover, both IFN-c and IL-17 were produced by M3R-reactive T cells and were detected in salivary glands, whereas neither IFNc nor IL-17 was detected in the sera [8]. However, we have no evidence that the cytokines INF-c and/or IL-17 are important in the development of sialadenitis. In the present study, to address the question of whether IFN-c is important in the development of sialadenitis, we generated M3R9IFN-c mice, immunized with M3R peptides, and transferred their splenic cells to Rag-1 mice. Histological findings showed that sialadenitis was more severe in M3R9IFN-c ? Rag1 than that in M3R ? Rag1 mice, but milder than that in M3R ? Rag1 mice (Fig. 1a). Quantitative analysis using histological scores indicated that mononuclear cell infiltration was significantly increased in M3R9IFNc ? Rag1 mice compared with that in M3R ? Rag1 mice (P \ 0.05), but significantly decreased compared with that in M3R ? Rag1 mice (P \ 0.05) (Fig. 1b). These observations support the notion that IFN-c might play a crucial role in the generation of SS-like sialadenitis. The absence of IFN-cand presence of IL-17-producing cells in the salivary glands of M3R9IFN-c ? Rag1 mice were verified by immunohistochemical staining (Fig. 1c). IL-17-producing cells in inflammatory lesions were identified in both M3R9IFN-c ? Rag1 and M3R ? Rag1 mice. IFN-c and IL-17 were not detected in sera from M3R9IFN-c ? Rag1 mice, nor in M3R ? Rag1 mice (data not shown). In M3R ? Rag1 mice, the expression of IL-17 was also observed in salivary glands, as was IFN-c expression. As we have no direct evidence in support of a pathogenic role of IL-17 in MIS, further studies using M3R9IL-17 mice will be necessary to clarify the function of IL-17-producing M3R-reactive T cells. M. Iizuka H. Tsuboi N. Matsuo Y. Kondo H. Asashima I. Matsumoto T. Sumida (&) Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, 1-1-1 Tenodai, Tsukuba, Ibaraki 305-8575, Japan e-mail: tsumida@md.tsukuba.ac.jp