The study reveals for the first time the regulatory function and mechanism of the transcriptional factor ZEB2 on the specialization of the ABC cell lineage, a new subset of lupus-pathogenic B cells, which provides insights into the pathogenesis of autoimmune diseases, and contributes to the development of more effective therapeutic tools and protocols.
Systemic lupus erythematosus (SLE) is a prototype autoimmune disease characterized by overactivation of self-reactive B cells and massive production of autoantibodies, accompanied by systemic immune system disorders and inflammatory damage to target tissues. Current therapies for B cells mainly include monoclonal antibody drugs and inhibitor molecular drugs targeting important B cell pathways, and these therapies tend to attack the overall B cell population, which may lead to two types of problems: firstly, patients are prone to side effects such as infections due to the removal of protective B cells; and secondly, the lack of precise therapeutic range and the decrease in the targeting efficiency of pathogenic B cells do not allow for in-depth removal of B cells, resulting in a poor response to drugs in some patients and a poor long-term prognosis. Therefore, identifying pathogenic B cell subpopulations in SLE and searching for the regulatory mechanisms of their dysfunction have been the focus and hotspot of lupus research. Conducting research in this area is important for developing more precise and effective therapeutic strategies, as well as reducing therapeutic side effects and improving long-term prognosis.
In this study, the unique transcriptome features and differentially expressed transcription factors of ABC cells were comprehensively analyzed by single-cell sequencing of primary lupus patients. Combined with Cas9 gene editing technology and in vitro induced differentiation system, we successfully screened for ZEB2, a key transcription factor that regulates the differentiation of human and mouse ABC cells.In the study, the team performed high-dimensional flow analysis of peripheral blood immune cells from children with the rare disease Mowat-Wilson Syndrome (ZEB2 single-dose insufficiency), and found that the ZEB2 deficiency, caused by genetic mutation, significantly reduced ABC cell differentiation in peripheral blood. of ZEB2 deficiency significantly reduced the proportion of ABC cells in the peripheral blood. In a mouse model of lupus, ZEB2 deficiency in B cells was found to reduce the accumulation of ABC cells and alleviate the autoimmune phenotype.
Meanwhile, this study revealed the regulatory mechanism of ZEB2 in ABC cells in detail, and found that ZEB2 was able to bind to the human-mouse conserved enhancer element in the first intronic region of the Mef2b gene, inhibit the expression of the Mef2b gene and its-mediated germinal center response, and thus promote the follicular extra effector B-cell response of the ABC pathway. In addition, ZEB2 promotes the expression of ABC signature genes and regulates the unique phagocytic function of ABC cells. The comprehensive analysis of phenotypes and mechanisms elucidated that ZEB2 plays a key role in determining the lineage specialization of ABC cells.
The study also found that ZEB2 can regulate ABC cell differentiation and function by affecting JAK-STAT signaling. Tofacitinib and baricitinib are JAK inhibitor drugs that are currently approved for the treatment of wind-like passages. In in vitro experiments, the addition of both drugs effectively reduced ABC cell differentiation. The researchers observed the intervention effect of tofacitinib in lupus mice, effectively reducing the accumulation of ABC cells and autoantibody levels. Through a cohort study of tofacitinib for the treatment of autoimmune diseases, they found that targeting the JAK-STAT pathway was effective in reducing the percentage of peripheral ABCs, thereby alleviating disease activity. These findings suggest that the ZEB2-JAK-STAT regulatory axis plays an important role in the process of ABC-induced differentiation, and that intervention of the JAK-STAT pathway downstream of ZEB2 is expected to alleviate the onset and progression of autoimmune diseases.
The corresponding authors of the research paper are Professor Shen Nan of the Department of Rheumatology, Renji Hospital and Professor Carola Venuesa of the Sino-Australia Joint Research Center for Individualized Immunology, while Dai Dai, assistant researcher of the Department of Rheumatology, and doctoral students of the Department of Rheumatology, Gu Shuangshang, who is currently trained at the Internal Medicine Base of Renji Hospital, and Han Xiaxia, are the co-first authors of the paper. Ding Huihua, Chen Sheng and Guo Qiang, chief physicians of the Department of Rheumatology at Renji Hospital, made significant contributions to the study.
Shen Nan
Shen Nan, Chief Physician of the Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Distinguished Professor of Shanghai Jiao Tong University, Distinguished Honorary Professor of the Australian National University, and Doctoral Supervisor. He is currently the Director of Shanghai Clinical Medical Center for Autoimmune Diseases, Director of Shanghai Institute of Rheumatology, and Co-Executive Director of China-Australia Individualized Immunity Research Center, Chief Scientist of 973, Recipient of Distinguished Youth Fund of the National Natural Fund of China, Young and Middle-aged Expert of the National Health Outstanding Contributions, National "Ten Thousand People Plan" and One Hundred Million Project Leader, and Shanghai Leading Talent. He is also the recipient of the Outstanding Youth Fund of the National Natural Science Foundation of China, a young and middle-aged expert with outstanding contributions to national health care, a leader of the National "Ten Thousand People Program" and a leader of the Shanghai Municipality. He has served as an editorial board member and associate editor of many important international academic journals. He has served as an editorial board member and associate editor of several important international academic journals. By now he has published over 100 papers on key journals globally, includingCell, Nature Genetics, Nature Medicine, Immunity, J Exp Med, Arthritis Rheumatol, J Clin Invest, Nature Communication, Blood, PNAS, PLoS Genetics, etc.
Prof. Shen Nan has long been engaged in research on the pathogenesis, molecular diagnosis and targeted therapy of autoimmune diseases represented by SLE. In recent years, he has made significant progress in the study of key pathogenic pathways in SLE through functional genomics, cellular and molecular immunology, and other strategies: 1) he was the first to discover that abnormal activation of the type I interferon pathway is the main molecular phenotype of lupus patients, and on this basis, he established a new biomarker analysis system for the evaluation of lupus clinical subgroup classification and efficacy evaluation; 2) he systematically elaborated the cellular and molecular mechanisms of the damage to lupus immunopathology caused by over-activation of the type I interferon pathway; 3) he has elaborated the genetic and epigenetic mechanisms of the abnormal activation of the interferon pathway in lupus erythematosus; and 4) he elaborated the important regulatory roles of non-coding RNAs in key pathogenic pathways of lupus.
Prof. Shen Nan believes that the different stages of development are all important milestones for the rheumatology department at Renji Hospital, Shanghai Jiaotong University School of Medicine, and that each stage has accumulated a wealth of experience and achieved important scientific results. These results provide the basis for precise treatment of lupus erythematosus and are expected to be the basis for drug targets and diagnostic kits in the future. Meanwhile, the Department of Rheumatology hopes to translate the results of cutting-edge scientific research into clinical practice and provide patients with more precise and individualized treatment plans, which is the direction and goal of future efforts.
Through the efforts of generations, Renji Hospital has narrowed the gap with the international advanced study on rheumatology and immunity, and has made great progress in basic research, and will continue to make constant efforts to increase research efforts in translational research.
