M3 muscarinic acetylcholine receptor-reactive Th17 cells in primary Sjogren's syndrome
M3 muscarinic acetylcholine receptor-reactive Th17 cells in primary Sjogren's syndrome
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DOI：
10.1172/jci.insight.135982
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发表时间：
2020-08-06
期刊：
影响因子：
8
通讯作者：
Sumida, Takayuki
中科院分区：
文献类型：
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作者：
Abe, Saori;Tsuboi, Hiroto;Sumida, Takayuki
M3毒蕈碱乙酰胆碱受体（M3R）是与干燥综合征（SS）相关的自身抗原之一，定位于疾病特异性炎症发生的外分泌腺。炎症病变的特征是CD4(+) T细胞浸润，包括克隆扩增的Th17细胞。我们进行了这项研究，以鉴定循环m3r特异性Th17细胞，并确定这些细胞的功能特性。采用酶联免疫斑点法（ELISpot）检测原发性SS （pSS）患者外周血中m3r反应性Th17细胞。在10例pSS患者、10例健康受试者（HS）和5例igg4相关疾病（IgG4-RD）患者中，5例pSS患者的m3r反应性IL-17分泌细胞显著升高。通过体外分离的CO4(+)T细胞与抗原提呈细胞和M3R肽共培养分析并证实，最常见的T细胞表位是M3R肽83-95。肽识别部分以hla - dr限制性方式进行，阻断试验证实。m3r反应性Th17细胞阳性与抗m3r抗体滴度越高相关，其全身性疾病活动性评分越高。我们的研究强调了组织特异性自身抗原衍生的循环Th17细胞在pSS中的作用，进一步的研究可能会导致抗原特异性靶向治疗。
M3 muscarinic acetylcholine receptor (M3R) is one of the autoantigens associated with Sjogren's syndrome (SS) and is localized in exocrine glands where disease-specific inflammation occurs. The inflammatory lesion is characterized by infiltration of CD4(+) T cells, including clonally expanded Th17 cells. We undertook this study to identify circulating M3R-specific Th17 cells and to determine functional properties of those cells. Using the enzyme-linked immunospot assay (ELISpot) method, we identified M3R-reactive Th17 cells in the peripheral blood of patients with primary SS (pSS). Among 10 examined pSS patients, 10 healthy subjects (HS), and 5 IgG4-related disease (IgG4-RD) patients, M3R-reactive IL-17 secreting cells were significantly increased in 5 pSS patients specifically. The most common T cell epitope, which was analyzed and confirmed by coculture of isolated CO4(+)T cells with antigen presenting cells plus M3R peptides in vitro, was peptide 83-95 of M3R. Peptide recognition was partly in an HLA-DR-restricted manner, confirmed by blocking assay. M3R-reactive Th17 cells positivity correlated with higher titers of anti-M3R antibodies, whose systemic disease activity score tended to be higher. Our studies highlight the role of tissue-specific autoantigen-derived circulating Th17 cells in pSS, for which further work might lead to antigen-specific targeted therapy.