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作 者:Kongyang Ma Wenhan Du Fan Xiao Man Han Enyu Huang Na Peng Yuan Tang Chong Deng Lixiong Liu Yulan Chen Jingjing Li Shiwen Yuan Qin Huang Xiaoping Hong Dajun Hu Xiaoyan Cai Quan Jiang Dongzhou Liu Liwei Lu
机构地区:[1]Department of Pathology and Shenzhen Institute of Research and Innovation,The University of Hong Kong,Chongqing International Institute for Immunology,Hong Kong,China [2]Department of Rheumatology and Immunology,Second Clinical Medical College of Jinan University,Shenzhen People’s Hospital,Shenzhen,China [3]Division of Rheumatology,Guang’anmen Hospital,China Academy of Chinese Medical Sciences,Beijing,China [4]Department of Rheumatology and Nephrology,the Second People’s Hospital,China Three Gorges University,Yichang,China [5]Department of Rheumatology,Guangzhou First People’s Hospital,School of Medicine,South China University of Technology,Guangzhou,China
出 处:《Cellular & Molecular Immunology》2021年第7期1739-1750,共12页中国免疫学杂志(英文版)
基 金:funded by grants from the National Natural Science Foundation of China(Nos.81771761,91842304,and 81901635);Chongqing International Institute for Immunology(2020YJC10);Sanming Project of Medicine in Shenzhen(SZSM201512019)。
摘 要:Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases,such as systemic lupus erythematosus(SLE).Currently,both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear.In this study,we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A(IL-17)stimulation in SLE patients and lupus mice.Using a humanized lupus mouse model,we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs.Moreover,long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU+subsets among IL-17 receptor-expressing plasma cells.Lupus mice deficient in IL-17 or IL-17 receptor C(IL-17RC)exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage,while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice.In reconstituted chimeric mice,IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells.Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediated Bcl-xL transcript stabilization.Together,our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis,which may provide new therapeutic strategies for the treatment of SLE.
关 键 词:Systemic lupus erythematosus(SLE) Plasma cell(PC) AUTOANTIBODY Interleukin-17A(IL-17)
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