Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to organs.The dysregulation of double-negative(DN)T cells is consi...Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to organs.The dysregulation of double-negative(DN)T cells is considered as a crucial commander during SLE.Neddylation,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune response.However,the function of neddylation in SLE is still unknown.Here,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development.Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus mice.Then double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression.Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression.Clinically,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was reduced.Moreover,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels.Meantime,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients.Altogether,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.展开更多
Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure.Mesothelial cell loss is an initiating event for peritoneal fibrosis.We find that the elevated glucose concen...Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure.Mesothelial cell loss is an initiating event for peritoneal fibrosis.We find that the elevated glucose concentrations in peritoneal dialysate drive mesothelial cell pyroptosis in a manner dependent on caspase-3 and Gasdermin E,driving downstream inflammatory responses,including the activation of macrophages.Moreover,pyroptosis is associated with elevated vascular endothelial growth factor A and C,two key factors in vascular angiogenesis and lymphatic vessel formation.GSDME deficiency mice are protected from high glucose induced peritoneal fibrosis and ultrafiltration failure.Application of melatonin abrogates mesothelial cell pyroptosis through a MT1R-mediated action,and successfully reduces peritoneal fibrosis and angiogenesis in an animal model while preserving dialysis efficacy.Mechanistically,melatonin treatment maintains mitochondrial integrity in mesothelial cells,meanwhile activating m TOR signaling through an increase in the glycolysis product dihydroxyacetone phosphate.These effects together with quenching free radicals by melatonin help mesothelial cells maintain a relatively stable internal environment in the face of high-glucose stress.Thus,Melatonin treatment holds some promise in preserving mesothelium integrity and in decreasing angiogenesis to protect peritoneum function in patients undergoing peritoneal dialysis.展开更多
Millions of cells undergo daily cell death,a process essential for maintaining physiological homeostasis and pathogenesis.Various forms of cell death,such as apoptosis,necroptosis,ferroptosis and pyroptosis,have been ...Millions of cells undergo daily cell death,a process essential for maintaining physiological homeostasis and pathogenesis.Various forms of cell death,such as apoptosis,necroptosis,ferroptosis and pyroptosis,have been extensively studied for their distinct biological functions[1,2].Generally,programmed cell death,like apoptosis,is considered physiological and results in little to no inflammatory response.展开更多
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 develop...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.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has had a significant impact on healthcare systems and economies worldwide.The continuous emergence...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has had a significant impact on healthcare systems and economies worldwide.The continuous emergence of new viral strains presents a major challenge in the development of effective antiviral agents.Strategies that possess broad-spectrum antiviral activities are desirable to control SARS-CoV-2 infection.ACE2,an angiotensin-containing enzyme that prevents the overactivation of the renin angiotensin system,is the receptor for SARS-CoV-2.ACE2 interacts with the spike protein and facilitates viral attachment and entry into host cells.Yet,SARS-CoV-2 infection also promotes ACE2 degradation.Whether restoring ACE2 surface expression has an impact on SARS-CoV-2 infection is yet to be determined.Here,we show that the ACE2-spike complex is endocytosed and degraded via autophagy in a manner that depends on clathrin-mediated endocytosis and PAK1-mediated cytoskeleton rearrangement.In contrast,free cellular spike protein is selectively cleaved into S1 and s2 subunits in a lysosomal-dependent manner.Importantly,we show that the pan-PAK inhibitor FRAX-486 restores ACE2 surface expression and suppresses infection by different SARS-CoV-2 strains.FRAX-486-treated Syrian hamsters exhibit significantly decreased lung viral load and alleviated pulmonary inflammation compared with untreated hamsters.In summary,our findings have identified novel pathways regulating viral entry,as well as therapeutic targets and candidate compounds for controlling the emerging strains of SARS-CoV-2 infection.展开更多
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 ...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.展开更多
Follicular helper T (Tfh) cells play a key role in driving B cell activation and differentiation during germinal center reactions in immune responses and autoimmune development, and these cells are characterized by hi...Follicular helper T (Tfh) cells play a key role in driving B cell activation and differentiation during germinal center reactions in immune responses and autoimmune development, and these cells are characterized by high expression of CXCR5, PD1, ICOS, IL-21 and BCL6. Increasing evidence indicates that the functional dysregulation of Tfh cells contributes to the pathogenesis of autoimmune diseases, including primary Sjögren’s syndrome (pSS), which is a common autoimmune disease characterized by lymphocytic infiltration and tissue inflammation in salivary glands (SGs) and lacrimal glands that leads to dry mouth and dry eyes.1 Here, we provide a brief commentary on recent advances in understanding the Tfh cell response with a focus on new insights into Tfh cell regulation and therapeutic implications in autoimmune diseases.展开更多
Dear Editor,Primary Sjogren's syndrome(pSS)is an autoimmune disease characterized by dry eyes and dry mouth caused by glandular inflammation in salivary glands(SG)and lacrimal glands.Currently,pSS patients are suf...Dear Editor,Primary Sjogren's syndrome(pSS)is an autoimmune disease characterized by dry eyes and dry mouth caused by glandular inflammation in salivary glands(SG)and lacrimal glands.Currently,pSS patients are suffering from a lack of effective therapies.Many studies have revealed dysregulated immune responses during pSS development,in which Th17 cells are considered as the key driver in disease initiation and perpetuation.展开更多
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,pr...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.展开更多
基金supported by Regional Innovation and Development Joint Fund of the National Foundation of China(U21A20402)to C.W.National Natural Science Foundation of China(No.82074375)+2 种基金the Research Project of Zhejiang Chinese Medical University(No.2023JKZDZC01)to Y.Z.Chongqing International Institute for Immunology(2020YJC10)to L.L.National Natural Science Foundation of China(No.82074217)to Z.H.
文摘Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to organs.The dysregulation of double-negative(DN)T cells is considered as a crucial commander during SLE.Neddylation,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune response.However,the function of neddylation in SLE is still unknown.Here,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development.Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus mice.Then double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression.Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression.Clinically,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was reduced.Moreover,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels.Meantime,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients.Altogether,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.
基金supported by the National Key Research and Development Program of China(2020YFC2005002)the National Natural Science Foundation of China(81970642,81370460,81700580,81670668,22222409)+1 种基金Key research and development grant from The Department of Science and Technology,Liaoning ProvinceInnovative Leading Researcher grant from the Department of Science and Technology,Dalian,and Key Laboratory of Immune,Genetic and Metabolic Kidney Diseases,Dalian,and Youth Innovation Promotion Association of CAS(2018212)。
文摘Peritoneal fibrosis together with increased capillaries is the primary cause of peritoneal dialysis failure.Mesothelial cell loss is an initiating event for peritoneal fibrosis.We find that the elevated glucose concentrations in peritoneal dialysate drive mesothelial cell pyroptosis in a manner dependent on caspase-3 and Gasdermin E,driving downstream inflammatory responses,including the activation of macrophages.Moreover,pyroptosis is associated with elevated vascular endothelial growth factor A and C,two key factors in vascular angiogenesis and lymphatic vessel formation.GSDME deficiency mice are protected from high glucose induced peritoneal fibrosis and ultrafiltration failure.Application of melatonin abrogates mesothelial cell pyroptosis through a MT1R-mediated action,and successfully reduces peritoneal fibrosis and angiogenesis in an animal model while preserving dialysis efficacy.Mechanistically,melatonin treatment maintains mitochondrial integrity in mesothelial cells,meanwhile activating m TOR signaling through an increase in the glycolysis product dihydroxyacetone phosphate.These effects together with quenching free radicals by melatonin help mesothelial cells maintain a relatively stable internal environment in the face of high-glucose stress.Thus,Melatonin treatment holds some promise in preserving mesothelium integrity and in decreasing angiogenesis to protect peritoneum function in patients undergoing peritoneal dialysis.
基金supported by the National Natural Science Foundation of China(82025002,32230036,82394411 and 82170113)the 1.3.5 Project of Disciplines of Excellence(ZYGD22005)the National Clinical Research Center for Geriatrics from West China Hospital,Sichuan University(No.Z2021JC009).
文摘Millions of cells undergo daily cell death,a process essential for maintaining physiological homeostasis and pathogenesis.Various forms of cell death,such as apoptosis,necroptosis,ferroptosis and pyroptosis,have been extensively studied for their distinct biological functions[1,2].Generally,programmed cell death,like apoptosis,is considered physiological and results in little to no inflammatory response.
基金supported by funding for Chongqing International Institute for Immunology(2020YJC10)National Natural Science Foundation of China(81901635,82171782,82260326,81971464)+2 种基金Shenzhen Science and Technology Program(CYJ20210324114602008)Hong Kong Research Grants Council Theme-Based Research Scheme(T12-703/19 R)the Centre for Oncology and Immunology under the Health@InnoHK Initiative by the Innovation and Technology Commission,Hong Kong,China.
文摘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.
基金the National Natural Science Foundation of China(NSFCNos.#82000007 toM.L.,#82001676 and#91842304 to B.T.L,#82125015 to Y.X.Z.#82272337 to J.F.W.C.)+7 种基金the GWCMC Postdoc Fund(Nos.#5001-3001061 to M.L.,#5001-3001060 to B.T.L.)Chongqing International Institute for Immunology(No.#2021YJC02 to Y.X.Z.)the Guangzhou Basic and Applied Basic Research Fund for Young Ph.D.scientists(No.#202102020194 to M.L.)Zhongnanshan Medical Foundation of Guangdong Province(No.#ZNSA-2020013 to J.C.Z.and Y.X.Z.)the General Research Fund(No.#17122322 to J.F.W.C.)Sanming Project of Medicine in Shenzhen,China(No.#SZSM201911014 to J.F.W.C.)the High Level-Hospital Program,Health Commission of Guangdong Province,China(to J.F.W.C.)and Emergency Collaborative Project(No.#EKPG22-01)of Guangzhou Laboratory(to J.F.W.C.).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent of coronavirus disease 2019(COVID-19),has had a significant impact on healthcare systems and economies worldwide.The continuous emergence of new viral strains presents a major challenge in the development of effective antiviral agents.Strategies that possess broad-spectrum antiviral activities are desirable to control SARS-CoV-2 infection.ACE2,an angiotensin-containing enzyme that prevents the overactivation of the renin angiotensin system,is the receptor for SARS-CoV-2.ACE2 interacts with the spike protein and facilitates viral attachment and entry into host cells.Yet,SARS-CoV-2 infection also promotes ACE2 degradation.Whether restoring ACE2 surface expression has an impact on SARS-CoV-2 infection is yet to be determined.Here,we show that the ACE2-spike complex is endocytosed and degraded via autophagy in a manner that depends on clathrin-mediated endocytosis and PAK1-mediated cytoskeleton rearrangement.In contrast,free cellular spike protein is selectively cleaved into S1 and s2 subunits in a lysosomal-dependent manner.Importantly,we show that the pan-PAK inhibitor FRAX-486 restores ACE2 surface expression and suppresses infection by different SARS-CoV-2 strains.FRAX-486-treated Syrian hamsters exhibit significantly decreased lung viral load and alleviated pulmonary inflammation compared with untreated hamsters.In summary,our findings have identified novel pathways regulating viral entry,as well as therapeutic targets and candidate compounds for controlling the emerging strains of SARS-CoV-2 infection.
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)。
文摘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.
基金supported by grants from the National Natural Science Foundation of China(Nos.82071817 and 82004171)the Chongqing International Institute for Immunology(2020YJC10)+3 种基金the Hong Kong Research Grants Council(17149716)Fundamental Research Funds for Central Public Welfare Research Institutes(ZZ13-YQ-033-C1)the Young Elite Scientist Sponsorship Program of CACM(CACM-2020-QNRC2-05)HKU Seed Funding for Strategic Interdisciplinary Research Scheme.
文摘Follicular helper T (Tfh) cells play a key role in driving B cell activation and differentiation during germinal center reactions in immune responses and autoimmune development, and these cells are characterized by high expression of CXCR5, PD1, ICOS, IL-21 and BCL6. Increasing evidence indicates that the functional dysregulation of Tfh cells contributes to the pathogenesis of autoimmune diseases, including primary Sjögren’s syndrome (pSS), which is a common autoimmune disease characterized by lymphocytic infiltration and tissue inflammation in salivary glands (SGs) and lacrimal glands that leads to dry mouth and dry eyes.1 Here, we provide a brief commentary on recent advances in understanding the Tfh cell response with a focus on new insights into Tfh cell regulation and therapeutic implications in autoimmune diseases.
基金This work was supported by Chongqing International Institute for Immunology(2020YJC10)National Natural Science Foundation of China(82071817,82171771,82004171,81971542)+4 种基金Shenzhen Science and Technology Program(YCYJ20210324114602008)Young Elite Scientist Sponsorship Program by CACM(CACM-2020-QNRC2-05)Hong Kong Research Grants Council(17113319,17103821)RGC Theme-based Research Scheme(TRS)(T12-703/19-R)the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission,The Government of Hong Kong SAR,China.
文摘Dear Editor,Primary Sjogren's syndrome(pSS)is an autoimmune disease characterized by dry eyes and dry mouth caused by glandular inflammation in salivary glands(SG)and lacrimal glands.Currently,pSS patients are suffering from a lack of effective therapies.Many studies have revealed dysregulated immune responses during pSS development,in which Th17 cells are considered as the key driver in disease initiation and perpetuation.
基金This work was supported by Chongqing International Institute for Immunology(2020YJC10)National Natural Science Foundation of China(82071817,91842304,82171771,and 82271854)+2 种基金Shenzhen Science and Technology Program(JCYJ20210324114602008)Hong Kong Research Grants Council(17113319 and 17103821),RGC Theme-based Research Scheme(TRS)(T12-703/19-R)the Centre for Oncology and Immunology under the Health@InnoHK Initiative funded by the Innovation and Technology Commission,Hong Kong,China.The figures were created with BioRender.com.
文摘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.