Autoantibodies against muscarinic type 3 receptor in Sjögren's syndrome inhibit aquaporin 5 trafficking.
Autoantibodies against muscarinic type 3 receptor in Sjögren's syndrome inhibit aquaporin 5 trafficking.
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DOI：
10.1371/journal.pone.0053113
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Cha S
中科院分区：
文献类型：
--
作者：
Lee BH;Gauna AE;Perez G;Park YJ;Pauley KM;Kawai T;Cha S
Sjögren’s综合征（SjS）是一种以唾液腺和泪腺为主要靶点的慢性自身免疫性疾病。SjS患者抗毒菌碱3型受体（α-M3R）自身抗体是否抑制水转运蛋白AQP5在细胞内的转运，导致分泌功能障碍一直存在争议。为了解决这一问题，gfp标记的人AQP5在人唾液腺细胞中过表达（HSG-hAQP5），并监测在甲醇（CCh， M3R激动剂）刺激后AQP5向质膜的运输。AQP5的转运确实是由M3R刺激介导的，表现为M3R拮抗剂4-DAMP部分阻断转运。与健康对照（HC）血浆相比，HSG-hAQP5与SjS血浆预孵育24小时可显著减少AQP5与CCh的转运。单克隆α-M3R抗体和预吸收血浆证实了这种抑制作用。有趣的是，与HC血浆孵育的细胞相比，HSG-hAQP5与SjS血浆孵育的细胞体积在cch刺激后收缩了20%，而HSG-hAQP5与SjS血浆孵育的细胞体积没有变化。我们的研究结果清楚地表明，免疫沉淀证实了抗m3r自身抗体与受体的结合抑制了AQP5向膜的运输，并导致SjS中液体分泌受损。我们目前的研究敦促进一步研究SjS症状（如分泌功能障碍程度、认知障碍和/或膀胱刺激）与SjS个体中抗m3r自身抗体的不同谱（滴度、同型和/或特异性）之间的临床关联。
Sjögren's syndrome (SjS) is a chronic autoimmune disease that mainly targets the salivary and lacrimal glands. It has been controversial whether anti-muscarinic type 3 receptor (α-M3R) autoantibodies in patients with SjS inhibit intracellular trafficking of aquaporin-5 (AQP5), water transport protein, leading to secretory dysfunction. To address this issue, GFP-tagged human AQP5 was overexpressed in human salivary gland cells (HSG-hAQP5) and monitored AQP5 trafficking to the plasma membrane following carbachol (CCh, M3R agonist) stimulation. AQP5 trafficking was indeed mediated by M3R stimulation, shown in partial blockage of trafficking by M3R-antagonist 4-DAMP. HSG-hAQP5 pre-incubated with SjS plasma for 24 hours significantly reduced AQP5 trafficking with CCh, compared with HSG-hAQP5 pre-incubated with healthy control (HC) plasma. This inhibition was confirmed by monoclonal α-M3R antibody and pre-absorbed plasma. Interestingly, HSG-hAQP5 pre-incubated with SjS plasma showed no change in cell volume, compared to the cells incubated with HC plasma showing shrinkage by twenty percent after CCh-stimulation. Our findings clearly indicate that binding of anti-M3R autoantibodies to the receptor, which was verified by immunoprecipitation, suppresses AQP5 trafficking to the membrane and contribute to impaired fluid secretion in SjS. Our current study urges further investigations of clinical associations between SjS symptoms, such as degree of secretory dysfunction, cognitive impairment, and/or bladder irritation, and different profiles (titers, isotypes, and/or specificity) of anti-M3R autoantibodies in individuals with SjS.
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