Increase of MZB1 in B cells in systemic lupus erythematosus: proteomic analysis of biopsied lymph nodes.
Increase of MZB1 in B cells in systemic lupus erythematosus: proteomic analysis of biopsied lymph nodes.
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DOI：
10.1186/s13075-018-1511-5
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发表时间：
2018-01-30
影响因子：
4.9
通讯作者：
Tsuruyama T
中科院分区：
文献类型：
--
作者：
Miyagawa-Hayashino A;Yoshifuji H;Kitagori K;Ito S;Oku T;Hirayama Y;Salah A;Nakajima T;Kiso K;Yamada N;Haga H;Tsuruyama T
系统性红斑狼疮（SLE）是一种典型的自身免疫性疾病，其中B细胞失调已被确认。在这里，我们使用液相色谱-串联质谱（LC-MS）寻找SLE的潜在生物标志物。采用LC-MS对SLE患者和对照组的淋巴结进行分析。为了验证鉴定的分子，进行免疫印迹和免疫组织化学，并通过定量RT-PCR分析SLE患者的B细胞。表现出类似人类SLE的自身免疫性疾病的NZB/W F1小鼠的b细胞亚群通过流式细胞术进行分析。tunicamycin诱导内质网（ER）应激，ELISA法测定血清抗dsdna抗体浓度。采用TUNEL法和免疫印迹法评价tunicamycin的作用。MZB1包含b细胞特异性ER伴侣复合物的一部分，是抗体分泌的关键角色，是LC-MS鉴定和免疫印迹证实的差异表达蛋白之一。免疫组化结果显示，与对照组相比，SLE患者标本中MZB1+细胞数量较多，主要位于滤泡间区，分散在生发中心。MZB1与CD138+浆细胞和IRTA1+边缘区B细胞共定位。SLE活动性患者（SLE疾病活动性指数2000≥6）B细胞中MZB1 mRNA较对照升高2.1倍。老龄NZB/W F1小鼠脾边缘区B细胞和浆细胞MZB1水平升高。Tunicamycin诱导靶器官MZB1+细胞凋亡，导致血清抗dsdna抗体水平下降。此外，MZB1+细胞在类风湿性关节炎患者的滑膜组织标本中增加。MZB1可能是SLE中过多抗体分泌细胞的潜在治疗靶点。本文的在线版本（10.1186/s13075-018-1511-5）包含补充材料，仅供授权用户使用。
Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease in which dysregulation of B cells has been recognized. Here, we searched for potential biomarkers of SLE using liquid chromatography-tandem mass spectrometry (LC-MS). Lymph nodes from SLE patients and controls were analyzed by LC-MS. To validate the identified molecules, immunoblotting and immunohistochemistry were performed and B cells from SLE patients were analyzed by quantitative RT-PCR. B-cell subsets from NZB/W F1 mice, which exhibit autoimmune disease resembling human SLE, were analyzed by flow cytometry. Endoplasmic reticulum (ER) stress was induced by tunicamycin and the serum concentration of anti-dsDNA antibodies was determined by ELISA. TUNEL methods and immunoblotting were used to assess the effect of tunicamycin. MZB1, which comprises part of a B-cell-specific ER chaperone complex and is a key player in antibody secretion, was one of the differentially expressed proteins identified by LC-MS and confirmed by immunoblotting. Immunohistochemically, larger numbers of MZB1+ cells were located mainly in interfollicular areas and scattered in germinal centers in specimens from SLE patients compared with those from controls. MZB1 colocalized with CD138+ plasma cells and IRTA1+ marginal zone B cells. MZB1 mRNA was increased by 2.1-fold in B cells of SLE patients with active disease (SLE Disease Activity Index 2000 ≥ 6) compared with controls. In aged NZB/W F1 mice, splenic marginal zone B cells and plasma cells showed elevated MZB1 levels. Tunicamycin induced apoptosis of MZB1+ cells in target organs, resulting in decreased serum anti-dsDNA antibody levels. Additionally, MZB1+ cells were increased in synovial tissue specimens from patients with rheumatoid arthritis. MZB1 may be a potential therapeutic target in excessive antibody-secreting cells in SLE. The online version of this article (10.1186/s13075-018-1511-5) contains supplementary material, which is available to authorized users.
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