Nucleosome in patients with systemic sclerosis: possible association with immunological abnormalities via abnormal activation of T and B cells
Nucleosome in patients with systemic sclerosis: possible association with immunological abnormalities via abnormal activation of T and B cells
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DOI：
10.1136/annrheumdis-2015-207405
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发表时间：
2016-10-01
影响因子：
27.4
通讯作者：
Sato, Shinichi
中科院分区：
文献类型：
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作者：
Yoshizaki, Ayumi;Taniguchi, Takashi;Sato, Shinichi
目的检测系统性硬化症(SSC)患者血清中的核小体水平，并将其与SSc的临床特征相关联。用流式细胞仪检测T、B细胞TLR9的表达。并分析了核小体对淋巴细胞的影响。此外，我们还利用野生型和CD19缺陷的博莱霉素处理的人SSc的实验模型，评估了核小体在纤维化中的作用。结果SSC患者血清核小体水平高于健康对照组，并与皮肤和肺纤维化的程度和免疫异常呈正相关。回顾性纵向分析显示，在随访期内，血清核小体水平有所降低。核小体刺激的TLR9在SSC患者受累T、B细胞中表达上调。此外，与健康对照组相比，核小体刺激显著增加SSC T细胞IL-4和IL-17的表达、B细胞免疫球蛋白G的产生和淋巴细胞的增殖。博莱霉素诱导的SSC模型小鼠血清核小体水平较对照组升高。此外，核小体可促进小鼠B细胞产生免疫球蛋白G和促进其增殖。TLR9在野生型和CD19缺陷型脾B细胞中的表达相似，但CD19缺陷降低了这些核小体的作用。结论B细胞和T细胞中的核小体及其信号转导途径可能通过TLR9参与SSC的疾病发展。
Objective To determine the serum levels of nucleosome in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc.Methods Serum nucleosome levels in 91 patients with SSc were examined by ELISA. The expression of Toll-like receptor (TLR) 9 in T and B cells was quantified by flow cytometric intracellular protein analysis. The effects of nucleosomes on lymphocytes were also analysed. Moreover, we assessed the effects of nucleosomes on fibrosis, using wild type and CD19-deficient bleomycin-treated mice, an experimental model for human SSc.Results Serum nucleosome levels were elevated in SSc compared with healthy controls and correlated positively with the extent of skin and pulmonary fibrosis and immunological abnormalities. The retrospective longitudinal analysis showed the serum nucleosome levels to be attenuated during the follow-up period. TLR9, which can be stimulated by nucleosome expression was upregulated in the affected T and B cells of patients with SSc. Moreover, nucleosome stimulation strongly increased interleukin (IL)-4 and IL-17 expression of T cells, B-cell IgG production and proliferation of lymphocytes in SSc compared with those in healthy controls. In bleomycin-induced SSc model mice, serum nucleosome levels were elevated compared with control mice. Furthermore, nucleosomes increased IgG production and proliferation of mouse B cells. Although TLR9 expression was similar between wild type and CD19-deficient splenic B cells, CD19 deficiency reduced these nucleosome effects.Conclusion These results suggest that nucleosomes and its signalling in B and T cells contribute to disease development in SSc via TLR9.