Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases
Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases
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DOI：
10.3389/fimmu.2019.02136
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发表时间：
2019-09-24
影响因子：
7.3
通讯作者：
Doerner, Thomas
中科院分区：
文献类型：
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作者：
Weissenberg, Sarah Y.;Szelinski, Franziska;Doerner, Thomas
自身免疫性疾病（AID），如系统性红斑狼疮（SLE）、原发性干燥综合征（pSS）和类风湿性关节炎（RA）是慢性炎症性疾病，其中B细胞功能异常起核心作用。尽管人们普遍认为自身免疫B细胞在体内是过度活跃的，但对其在AID中的功能状态尚未有充分的了解。在这里，我们详细分析了AID B细胞的功能能力，并剖析了B细胞功能改变的机制。在BCR激活后，AID记忆B细胞中发现脾脏酪氨酸激酶（Syk）和布鲁顿酪氨酸激酶（Btk）磷酸化降低，CD22和蛋白酪氨酸磷酸酶（PTP）非受体6型（SHP-1）的组成共定位，以及对TLR9信号的低反应性，这是一种Syk依赖性反应。在SLE CD27-B细胞中也注意到类似的BCR低反应性，同时在SLE B细胞中PTP活性增加，PTPN2、PTPN11、PTPN22、PTPRC和PTPRO转录物增加。其他研究表明，对正常B细胞的BCR重复刺激可诱导BCR低反应性，并且AID患者的组织驻留记忆B细胞在体外也表现出反应性立即下降，这表明低反应状态可能通过体内反复暴露于自身抗原而获得。克服B细胞低反应性的功能研究表明，CD40共刺激增加BCR信号，诱导增殖，下调PTP表达（PTPN2， PTPN22和受体型PTP）。这些数据支持以下结论：AID，特别是SLE B细胞的低反应性是由CD40-CD154相互作用介导的无T细胞帮助的BCR慢性体内刺激引起的，表现为BCR相关近端信号分子磷酸化降低和ptp增加。AID B细胞的低反应性类似于功能性能量的一种形式。
Autoimmune diseases (AID) such as systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSS), and rheumatoid arthritis (RA) are chronic inflammatory diseases in which abnormalities of B cell function play a central role. Although it is widely accepted that autoimmune B cells are hyperactive in vivo, a full understanding of their functional status in AID has not been delineated. Here, we present a detailed analysis of the functional capabilities of AID B cells and dissect the mechanisms underlying altered B cell function. Upon BCR activation, decreased spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (Btk) phosphorylation was noted in AID memory B cells combined with constitutive co-localization of CD22 and protein tyrosine phosphatase (PTP) non-receptor type 6 (SHP-1) along with hyporesponsiveness to TLR9 signaling, a Syk-dependent response. Similar BCR hyporesponsiveness was also noted specifically in SLE CD27-B cells together with increased PTP activities and increased transcripts for PTPN2, PTPN11, PTPN22, PTPRC, and PTPRO in SLE B cells. Additional studies revealed that repetitive BCR stimulation of normal B cells can induce BCR hyporesponsiveness and that tissue-resident memory B cells from AID patients also exhibited decreased responsiveness immediately ex vivo, suggesting that the hyporesponsive status can be acquired by repeated exposure to autoantigen(s) in vivo. Functional studies to overcome B cell hyporesponsiveness revealed that CD40 co-stimulation increased BCR signaling, induced proliferation, and downregulated PTP expression (PTPN2, PTPN22, and receptor-type PTPs). The data support the conclusion that hyporesponsiveness of AID and especially SLE B cells results from chronic in vivo stimulation through the BCR without T cell help mediated by CD40-CD154 interaction and is manifested by decreased phosphorylation of BCR-related proximal signaling molecules and increased PTPs. The hyporesponsiveness of AID B cells is similar to a form of functional anergy.