B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation

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外文摘要：Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus(SLE).However,both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis(LN)remain largely unclear.Here,we report a pathogenic role of anti-phosphatidylserine(PS)autoantibodies in the development of LN.Elevated serum PS-specific IgG levels were measured in model mice and SLE patients,especially in those with LN.PS-specific IgG accumulation was found in the kidney biopsies of LN patients.Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice.ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients.Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice,whereas depletion of B1a cells attenuated lupus progression.In culture,PS-specific B1a cells were significantly expanded upon treatment with chromatin components,while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells.Thus,our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development.Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.

外文关键词：

B1 cellAnti-phosphatidylserine antibodiesLupus nephritisTLRSyk

作者：

Kongyang Ma、Wenhan Du、Shiyun Wang、Fan Xiao、Jingyi Li、Jie Tian、Yida Xing、Xiaodan Kong、Ke Rui、Rencai Qin、Xiaoxia Zhu、Jing Wang、Cainan Luo、Haijing Wu、Yun Zhang、Chengping Wen、Lan He、Dongzhou Liu、Hejian Zou、Qianjin Lu、Lijun Wu、Liwei Lu

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作者单位：

Centre for Infection and Immunity Studies,School of Medicine,The Sun Yat-sen University,Shenzhen 518107 Guangdong,China

Department of Pathology and Shenzhen Institute of Research and Innovation,The University of Hong Kong,Hong Kong 999077,China

Department of Rheumatology,Shenzhen People's Hospital,The Second Clinical Medical College,Jinan University,Shenzhen,China

Chongqing International Institute for Immunology,Chongqing 400038,China

Department of Rheumatology and Immunology,Southwest Hospital,The First Hospital Affiliated to Army Medical University,Chongqing 400038,China

Department of Laboratory Medicine,Affiliated Hospital and Institute of Medical Immunology,Jiangsu University,Zhenjiang,China

Department of Rheumatology,The Second Affiliated Hospital of Dalian Medical University,Dalian,China

Department of Rheumatology,Huashan Hospital,Fudan University,Shanghai,China

Department of Rheumatology and Immunology,The First Affiliated Hospital of Xi'an Jiaotong University,Xi'an 710061 Shaanxi,China

Department of Rheumatology and Immunology,People's Hospital of Xinjiang Uygur Autonomous Region,Urumqi,China

Department of Dermatology,Hunan Key Laboratory of Medical Epigenomics,Second Xiangya Hospital,Central South University,Changsha,Hunan,China

Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province,Institute of Basic Research in Clinical Medicine,College of Basic Medical Science,Zhejiang Chinese Medical University,Hangzhou 310053,China

Centre for Oncology and Immunology,Hong Kong Science Park,Hong Kong,China

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基金：

funding for Chongqing International Institute for ImmunologyNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaShenzhen Science and Technology ProgramHong Kong Research Grants Council Theme-Based Research SchemeCentre for Oncology and Immunology under the Health@InnoHK Initiative by the Innovation and Technology Commission,Hong Kong,

项目编号：

2020YJC1081901635821717828226032681971464CYJ20210324114602008T12-703/19 R

出版年：

2023

DOI：

10.1038/s41423-023-01049-2

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(8)

参考文献量55