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A Common Functional Variant at the Enhancer of the Rheumatoid Arthritis Risk Gene ORMDL3 Regulates its Expression Through Allele-Specific JunD Binding

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Phenomics

Phenomics 2023年第5期3卷 485-495页

作者： Wenjing Ye Yiyun Yu Xiaoxia Zhu Weiguo Wan Yun Liu hejian zou Zaihua Zhu Division of Rheumatology and Immunology Huashan HospitalFudan UniversityShanghai 200040China Institute of Rheumatology Immunology and AllergyFudan UniversityShanghai 200040China The Ministry of Education Key Laboratory of Metabolism and Molecular Medicine Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesFudan UniversityShanghai 200032China

Genome-wide association studies(GWASs)have identified over 100 loci associated with rheumatoid arthritis(RA);how-ever,the functionally affected genes and the underlying molecular mechanisms contributing to these associations are often unknown.In this study,we conducted an integrative genomic analysis incorporating multiple“omics”data and identified a functional regulatory DNA variant,rs56199421,and a plausible mechanism by which it regulates the expression of a puta-tive RA risk gene,ORMDL Sphingolipid Biosynthesis Regulator 3(ORMDL3).The T allele of rs56199421,located in the enhancer region of ORMDL3,exhibited stronger direct binding ability than the other C allele of rs56199421 did in vitro with the transcription factor JunD and demonstrated higher transcriptional activity.Moreover,the T allele of rs56199421 is associated with elevated RA risk,and ORMDL3 expression is increased in RA patients.Thus,these findings suggest that the T allele of rs56199421 enhances JunD transcription factor binding,increases enhancer activity,and elevates the expression of the RA risk gene ORMDL3.

关键词： Rheumatoid arthritis Genome-wide association study Enhancer ORMDL Sphingolipid Biosynthesis Regulator 3

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

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Cellular & Molecular Immunology 2022年第11期19卷 1215-1234页

作者： Fan Xiao Ke Rui Xiaofei Shi Haijing Wu Xiaoyan Cai Kathy O.Lui Qianjin Lu Esteban Ballestar Jie Tian hejian zou Liwei Lu Department of Pathology Shenzhen Institute of Research and Innovation and Shenzhen HospitalThe University of Hong KongHong KongChongqing International Institute for ImmunologyChongqingChina Institute of Medical Immunology Affiliated Hospital of Jiangsu UniversityZhenjiangChina Department of Rheumatology and Immunology The First Affiliated Hospital and School of MedicineHenan University of Science and TechnologyLuoyangChina Department of Dermatology Second Xiangya HospitalCentral South UniversityHunan Key Laboratory of Medical EpigenomicsChangshaHunanChina Department of Rheumatology Guangzhou First People’s HospitalSchool of MedicineSouth China University of TechnologyGuangzhouChina Department of Chemical Pathology Faculty of MedicinePrince of Wales HospitalThe Chinese University of Hong KongHong KongChina Epigenetics and Immune Disease Group Josep Carreras Research InstituteBadalona08916 BarcelonaSpain Epigenetics in Inflammatory and Metabolic Diseases Laboratory Health Science CenterEast China Normal UniversityShanghaiChina Department of Rheumatology Huashan HospitalFudan UniversityShanghaiChina Centre for Oncology and Immunology Hong Kong Science ParkHong KongChina

B cells play a pivotal role in the pathogenesis of autoimmune diseases.Although previous studies have shown many genetic polymorphisms associated with B-cell activation in patients with various autoimmune disorders,progress in epigenetic research has revealed new mechanisms leading to B-cell hyperactivation.Epigenetic mechanisms,including those involving histone modifications,DNA methylation,and noncoding RNAs,regulate B-cell responses,and their dysregulation can contribute to the pathogenesis of autoimmune diseases.Patients with autoimmune diseases show epigenetic alterations that lead to the initiation and perpetuation of autoimmune inflammation.Moreover,many clinical and animal model studies have shown the promising potential of epigenetic therapies for patients.In this review,we present an up-to-date overview of epigenetic mechanisms with a focus on their roles in regulating functional B-cell subsets.Furthermore,we discuss epigenetic dysregulation in B cells and highlight its contribution to the development of autoimmune diseases.Based on clinical and preclinical evidence,we discuss novel epigenetic biomarkers and therapies for patients with autoimmune disorders.

关键词： B cells Epigenetic regulation Autoimmune disease Biomarker Therapy

Aryl hydrocarbon receptor activation drives polymorphonuclear myeloid-derived suppressor cell response and efficiently attenuates experimental Sjögren’s syndrome

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Cellular & Molecular Immunology 2022年第12期19卷 1361-1372页

作者： Yanxia Wei Na Peng Chong Deng Futao Zhao Jie Tian Yuan Tang Sulan Yu Yacun Chen Yu Xue Fan Xiao Yingbo Zhou Xiaomei Li hejian zou Ke Rui Xiang Lin Liwei Lu Department of Pathology and Shenzhen Institute of Research and Innovation The University of Hong KongHong KongChina Department of Pathogenic Biology and Immunology Jiangsu Key Laboratory of Immunity and MetabolismXuzhou Medical UniversityXuzhouChina Department of Rheumatology the Second People’s HospitalChina Three Gorges UniversityYichangChina Centre for Oncology and Immunology Hong Kong Science ParkHong KongChina Department of Rheumatology Shanghai Ninth People’s HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Department of Laboratory Medicine Affiliated Hospital and Institute of Medical ImmunologyJiangsu UniversityZhenjiangChina School of Chinese Medicine and Shenzhen Institute of Research and Innovation The University of Hong KongHong KongChina Department of Rheumatology Huashan HospitalFudan UniversityShanghaiChina Department of Rheumatology and Immunology The First Affiliated Hospital of USTCUniversity of Science and Technology of ChinaHefeiAnhuiChina

Myeloid-derived suppressor cells(MDSCs)comprise heterogeneous myeloid cell populations with immunosuppressive capacity that contribute to immune regulation and tolerance induction.We previously reported impaired MDSC function in patients with primary Sjögren’s syndrome(pSS)and mice with experimental SS(ESS).However,the molecular mechanisms underlying MDSC dysfunction remain largely unclear.In this study,we first found that aryl hydrocarbon receptor(AhR)was highly expressed by human and murine polymorphonuclear MDSCs(PMN-MDSCs).Indole-3-propionic acid(IPA),a natural AhR ligand produced from dietary tryptophan,significantly promoted PMN-MDSC differentiation and suppressive function on CD4^(+)T cells.In contrast,feeding a tryptophan-free diet resulted in a decreased PMN-MDSC response,a phenotype that could be reversed by IPA supplementation.The functional importance of PMN-MDSCs was demonstrated in ESS mice by using a cell-depletion approach.Notably,AhR expression was reduced in PMN-MDSCs during ESS development,while AhR antagonism resulted in exacerbated ESS pathology and dysregulated T effector cells,which could be phenocopied by a tryptophan-free diet.Interferon regulatory factor 4(IRF4),a repressive transcription factor,was upregulated in PMN-MDSCs during ESS progression.Chromatin immunoprecipitation analysis revealed that IRF4 could bind to the promoter region of AhR,while IRF4 deficiency markedly enhanced AhR-mediated PMN-MDSC responses.Furthermore,dietary supplementation with IPA markedly ameliorated salivary glandular pathology in ESS mice with restored MDSC immunosuppressive function.Together,our results identify a novel function of AhR in modulating the PMN-MDSC response and demonstrate the therapeutic potential of targeting AhR for the treatment of pSS.

关键词： myeloid-derived suppressor cell Sjogren's syndrome Aryl hydrocarbon receptor

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

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Cellular & Molecular Immunology 2023年第8期20卷 881-894页

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 Centre for Infection and Immunity Studies School of MedicineThe Sun Yat-sen UniversityShenzhen518107GuangdongChina Department of Pathology and Shenzhen Institute of Research and Innovation The University of Hong KongHong Kong999077China Department of Rheumatology Shenzhen People’s HospitalThe Second Clinical Medical CollegeJinan UniversityShenzhenChina Chongqing International Institute for Immunology Chongqing400038China Department of Rheumatology and Immunology Southwest HospitalThe First Hospital Affiliated to Army Medical UniversityChongqing400038China Department of Laboratory Medicine Affiliated Hospital and Institute of Medical ImmunologyJiangsu UniversityZhenjiangChina Department of Rheumatology The Second Affiliated Hospital of Dalian Medical UniversityDalianChina Department of Rheumatology Huashan HospitalFudan UniversityShanghaiChina Department of Rheumatology and Immunology The First Affiliated Hospital of Xi’an Jiaotong UniversityXi’an710061ShaanxiChina Department of Rheumatology and Immunology People’s Hospital of Xinjiang Uygur Autonomous RegionUrumqiChina Department of Dermatology Hunan Key Laboratory of Medical EpigenomicsSecond Xiangya HospitalCentral South UniversityChangshaHunanChina Key Laboratory of Chinese Medicine Rheumatology of Zhejiang Province Institute of Basic Research in Clinical MedicineCollege of Basic Medical ScienceZhejiang Chinese Medical UniversityHangzhou310053China Centre for Oncology and Immunology Hong Kong Science ParkHong KongChina

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.

关键词： B1 cell Anti-phosphatidylserine antibodies Lupus nephritis TLR Syk

The Contribution of LTB4/BLT1 Axis to the Progression of Systemic Sclerosis by Regulating Myofibroblast Formation

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The Contribution of LTB4/BLT1 Axis to the Progression of Sys...

第十一届全国免疫学学术大会

作者： Liang Minrui Jiaoyan lv Zhixing Jiang Yinluo Xiong Rui He hejian zou Division of Rheumatology Huashan Hospital Institute of Rheumatology Immunology and AllergyFudan University Department of Immunology School of Basic Medical SciencesFudan University Biotherapy Research Center Fudan University

Leukotriene B4(LTB4),a lipid mediator of inflammation,plays a key role in the autoimmune and inflammatory diseases via its high affinity receptor BLT1.Myofibroblast is recognized to be critical in the progression of systemic sclerosis(SSc),but the mechanism is still unknown.We aimed to use BLT1-/-mice and BLT1 specific inhibitor to reveal the contribution of LTB4/BLT1 axis to the progression of SSc in a modified SSc-interstitial lung disease(ILD) mouse model by delivering bleomycin(BLM) via an osmotic mini-pump.In the present study,LTB4 was observed to be up-regulated in the plasma of SSc patients.Also,immunohistochemical analysis demonstrated overexpressions of BLT1 and leukotriene A4 hydrolase(LTA4H),the biosynthetic enzyme for LTB4,in both skin and lung tissues of SSc-ILD subjects.In addition,the levels of BLT1 and LTB4 H were also increasedin the skin and lung tissues of SSc-ILD mouse.BLT1-/-mice did not manifest the phenotype of SSc following the BLM treatment in the SSc-ILD mouse model.And the reduction of α-SMA+ myofibroblasts was also found in the skin and lung tissues of BLT1-/-mice following the administration of BLM,compared with those in wide type mice.Furthermore,the addition of LTB4 was observed to promote fibroblast-myofibroblast transition and endothelial-myofibroblast transition in vitro using primary cell culture,which were reversed by BLT1 inhibition.In addition,LTB4 induced phosphorylation of Akt and m TOR in a time dependent manner in fibroblast,also fibroblast-myofibroblast transition induced by LTB4 was blocked by Akt or m TOR inhibitor.However,LTB4 was not shown to stimulate the release of TGF-β1 in fibroblast,and TGF-β receptor antagonist was not shown to inhibit fibroblast-myofibroblast transition.These results uncover a possible role for LTB4/BLT1 driven myofibroblast formation in SSc-ILD pathogenesis and identify a pathway that may be amenable to therapeutic targeting.

关键词： Leukotriene B4（LTB4） BLT1 systemic sclerosis（SSc） interstitial lung disease（ILD）

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痛风规范诊疗亟待解决

中华内科杂志 2020年第6期59卷 412-413页

作者：邹和建复旦大学附属华山医院风湿免疫科上海200040

痛风和高尿酸血症患病率逐年升高,是目前风湿免疫科就诊量最多的常见病之一,但并未得到应有的重视,尤其是临床医生对该病的诊疗尚未形成足够的规范。近期,由中国医师协会风湿免疫科医师分会痛风专业委员会撰写了《痛风诊疗规范》,在痛... 详细信息

痛风和高尿酸血症患病率逐年升高,是目前风湿免疫科就诊量最多的常见病之一,但并未得到应有的重视,尤其是临床医生对该病的诊疗尚未形成足够的规范。近期,由中国医师协会风湿免疫科医师分会痛风专业委员会撰写了《痛风诊疗规范》,在痛风的分类诊断、临床分期、生活方式管理、降尿酸治疗以及抗炎治疗等方面进行了详尽阐述,以规范痛风和高尿酸血症的诊疗水平,改善患者预后,提高患者生活质量。

关键词：痛风高尿酸血症诊疗规范

类风湿关节炎患者利妥昔单抗相关进行性多灶性白质脑病的临床特点分析

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药物不良反应杂志 2022年第10期24卷 534-539页

作者：刘寄语赵力邹和建薛愉复旦大学附属华山医院风湿免疫科复旦大学风湿免疫过敏性疾病研究中心上海200040

目的探讨类风湿关节炎(RA)患者利妥昔单抗相关进行性多灶性白质脑病(PML)的临床特点。方法检索国内外相关数据库(截至2021年11月),收集RA患者接受利妥昔单抗治疗后发生PML的病例报告类文献,提取患者的性别、年龄、基础疾病、利妥昔单抗... 详细信息

目的探讨类风湿关节炎(RA)患者利妥昔单抗相关进行性多灶性白质脑病(PML)的临床特点。方法检索国内外相关数据库(截至2021年11月),收集RA患者接受利妥昔单抗治疗后发生PML的病例报告类文献,提取患者的性别、年龄、基础疾病、利妥昔单抗使用情况、联合用药情况、PML发生时间、临床表现、辅助检查(影像学、脑脊液)结果、干预及转归等临床资料,进行描述性统计分析。结果纳入分析的患者共10例,男性1例,女性9例;年龄51~83岁,平均66岁;均为中至重度RA,病程≥3年者9例,1例无病程记录。10例患者利妥昔单抗用法用量均符合规定,均联合使用抗风湿药或糖皮质激素。9例患者有末次使用利妥昔单抗至发生PML的时间记录,7例为2~8个月,2例分别为16和18个月,中位时间6个月。6例患者有临床症状记录,主要为共济失调、言语障碍、认知功能减退和局灶性感觉障碍等。6例患者行头部MRI检查,均符合PML的影像学改变。4例患者行脑脊液乳头多瘤空泡病毒检测,3例病毒DNA阳性,1例阴性者经脑组织活检诊断为PML。诊断PML后1例未进行干预,3例无干预措施记录,5例单用或联用甲氟喹、米氮平治疗(其中2例联合血浆置换,1例加用糖皮质激素),1例联用米氮平和呋喃妥因治疗。7例因治疗无效死亡,2例存活但有严重神经损伤后遗症,1例未报告最终结局。结论利妥昔单抗相关PML多发生于末次应用该药后2~8个月,临床表现和影像学检查与其他原因所致PML相似,通常呈进行性加重,病死率高,幸存者可能有严重的神经损伤后遗症。

关键词：关节炎,类风湿脑白质病,进行性多灶性利妥昔单抗

Clinical correlations with disease-associated auto-antibodies in a Chinese cohort with systemic sclerosis

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Chinese Medical Journal 2022年第15期135卷 1878-1880页

作者： Sen Yang Minrui Liang Chen Chen Wenjing Ye Xiaoxia Zhu Yu Xue Ning Kong Yiyun Yu Dandan Xuan Shucong Zheng Xue Yang Zaihua Zhu Tianyi Zhao Weiguo Wan Hejan zou Division of Rheumatology Huashan HospitalFudan UniversityShanghai 200040China institute of Rheumatology Immunology and AllergyFudan UniversityShanghai 200040China

To the Editor:Systemic sclerosis(SSc)is an autoimmune disease characterized by,progressive skin and visceral fibrosis,microvasculopathy,and autoimmunity.Circulating auto-antibodies(AAbs)are detectable in 90%to 95%of p... 详细信息

关键词： antibodies sclerosis autoimmune

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系统性硬化病诊疗规范

中华内科杂志 2022年第8期61卷 874-882页

作者：邹和建朱小霞戴生明王晓冰赵东宝赵岩复旦大学附属华山医院风湿免疫科上海200040 上海交通大学附属第六人民医院风湿免疫科上海200233 温州医科大学附属第一医院风湿免疫科温州325000 海军军医大学第一附属医院风湿免疫科上海200433 中国医学科学院北京协和医学院北京协和医院风湿免疫科国家皮肤与免疫疾病临床医学研究中心疑难重症及罕见病国家重点实验室风湿免疫病学教育部重点实验室北京100730

系统性硬化病是一类以皮肤纤维化为主要特征的多脏器受累的自身免疫性结缔组织病。在我国, 系统性硬化病的规范化诊疗依然欠缺。中华医学会风湿病学分会在借鉴国内外诊疗指南的基础上, 制定了本规范, 旨在规范我国系统性硬化病临床管理... 详细信息

系统性硬化病是一类以皮肤纤维化为主要特征的多脏器受累的自身免疫性结缔组织病。在我国, 系统性硬化病的规范化诊疗依然欠缺。中华医学会风湿病学分会在借鉴国内外诊疗指南的基础上, 制定了本规范, 旨在规范我国系统性硬化病临床管理方案, 对评估疾病的关键方法予以解读, 并对疾病的治疗原则、方案给予建议。

关键词：系统性硬化病诊断治疗