Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease
Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease
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DOI：
10.1002/art.40059
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发表时间：
2017-06-01
影响因子：
13.3
通讯作者：
Hendriks, Rudi W.
中科院分区：
文献类型：
--
作者：
Corneth, Odilia B. J.;Verstappen, Gwenny M. P.;Hendriks, Rudi W.
Bruton酪氨酸激酶（BTK）从B细胞中的B细胞受体（BCR）传递关键的存活信号。药理学BTK抑制有效地减少了自身免疫小鼠模型中的疾病症状;相反，转基因BTK过表达在小鼠中诱导全身性自身免疫。我们进行了这项研究，以调查BTK的表达和活动在人类B细胞的背景下，自身免疫性diseases.MethodsUsing细胞内流式细胞术，我们定量BTK的表达和磷酸化的外周血B细胞亚群从30例类风湿关节炎（RA），26例原发性干燥综合征（SS），和匹配的健康对照。BTK蛋白表达水平与BTK磷酸化相关。BTK表达在体外BCR刺激后上调，并且在CD 27+记忆B细胞中显著高于CD 27-IgD+幼稚B细胞。重要的是，BTK蛋白和磷酸化BTK在抗瓜氨酸化蛋白抗体（ACPA）阳性RA患者的B细胞中显著增加，但在ACPA阴性RA患者的B细胞中没有增加。BTK在初始B细胞和记忆B细胞中均增加，并且与循环CCR6 + Th17细胞的频率相关。同样，BTK蛋白在原发性SS患者的大部分B细胞中增加，并与血清类风湿因子水平和腮腺T细胞浸润相关。有趣的是，在原发性SS患者中使用CTLA-4 Ig融合蛋白阿巴西普靶向T细胞活化恢复BTK蛋白在B细胞中的表达到正常水平。ConclusionThese数据表明，在人类自身免疫性疾病的特点是增强BTK活性，这不仅与自身抗体的形成，而且与T细胞活性。
ObjectiveBruton's tyrosine kinase (BTK) transmits crucial survival signals from the B cell receptor (BCR) in B cells. Pharmacologic BTK inhibition effectively diminishes disease symptoms in mouse models of autoimmunity; conversely, transgenic BTK overexpression induces systemic autoimmunity in mice. We undertook this study to investigate BTK expression and activity in human B cells in the context of autoimmune disease.MethodsUsing intracellular flow cytometry, we quantified BTK expression and phosphorylation in subsets of peripheral blood B cells from 30 patients with rheumatoid arthritis (RA), 26 patients with primary Sjogren's syndrome (SS), and matched healthy controls.ResultsIn circulating B cells, BTK protein expression levels correlated with BTK phosphorylation. BTK expression was up-regulated upon BCR stimulation in vitro and was significantly higher in CD27+ memory B cells than in CD27-IgD+ naive B cells. Importantly, BTK protein and phospho-BTK were significantly increased in B cells from anti-citrullinated protein antibody (ACPA)-positive RA patients but not in B cells from ACPA-negative RA patients. BTK was increased both in naive B cells and in memory B cells and correlated with frequencies of circulating CCR6+ Th17 cells. Likewise, BTK protein was increased in B cells from a major fraction of patients with primary SS and correlated with serum rheumatoid factor levels and parotid gland T cell infiltration. Interestingly, targeting T cell activation in patients with primary SS using the CTLA-4Ig fusion protein abatacept restored BTK protein expression in B cells to normal levels.ConclusionThese data indicate that autoimmune disease in humans is characterized by enhanced BTK activity, which is linked not only to autoantibody formation but also to T cell activity.