A rationally designed CD19 monoclonal antibody-triptolide conjugate for the treatment of systemic lupus erythematosus

Tripterygium wilfordii Hook F(TWHF)is a traditional Chinese medicine widely used in the treatment of systemic lupus erythematosus(SLE),with triptolide(TP)as its main active ingredient.However,its side effects also induced by TP,especially hepatotoxicity and reproductive toxicity,largely limit its application in a subset of patients.Monoclonal antibodies(mAbs)developed for the treatment of SLE that deplete B cells by targeting B cell-expressing antigens,such as CD19,have failed in clinical trials,partly due to their poor efficacy in consuming B cells.Here,we report the development of a rationally designed antibody‒drug conjugate(ADC),CD19 mAb-TP conjugate,to alleviate the side effects of TWHF and simultaneously improve the therapeutic efficacy of CD19 mAb.The CD19 mAb-TP conjugate,which was named ADC-TP,selectively depleted B cell subsets both in vitro and in vivo and effectively alleviated disease symptoms in mouse lupus models with enhanced therapeutic efficacy than CD19 mAb and fewer side effects than TP.Our present study proposes a CD19 mAb‒TP conjugate strategy to mitigate the toxicity of TWHF while also enhancing the therapeutical efficacy of CD19 mAbs for the treatment of SLE,providing a feasible method for improving the current agents used for treating SLE.

Author Correction:Genetic and epigenetic influences on the loss of tolerance in autoimmunity

Correction to:Cellular and Molecular Immunology(2018)15:575-85 https://doi.org/10.1038/cmi.2017.137,published online 05 March 2018 In the caption of Fig.1a,the sentence“In the thymus,both high-affinity T and B cells undergo apoptosis.”was corrected as follows:“In the thymus,T cells with high affinity for self-antigens undergo apoptosis,while B cells undergo a similar process in the bone marrow.”The original article has been corrected.

Inhibitive effect of triptolide on invasiveness of human fibrosarcoma cells by downregulating matrix metalloproteinase-9 expression

Objective:To explore the molecular mechanisms of antitumor properties of triptolide,a bioactive component isolated from the Chinese herb Tripterygium wolfordii Hook F.Methods:Human fibrosarcoma HT-1080 cells were treated with different doses of triptolide for 72 h.Then the expression and activity of matrix metalloproteinase(MMP)-2 and -9 were measured and the invasiveness of triptolide-treated HT-1080 cells was compared with that of anti-MMP-9- treated HT-1080 cells.Results:18 nmol/L triptolide inhibited the gene expression and activity of MMP-9,but not those of MMP-2,in HT-1080 cells.In addition,both 18 nmol/L triptolide and 3μg/mL anti-MMP-9 significantly reduced the invasive potential of HT-1080 cells,by about 50%and 35%, respectively,compared with the control.Whereas there was no significant difference between the effect of 18 nmol/L triptolide and that of anti-MMP-9 on invasive potential of HT-1080 cells. Conclusions:These data suggest that triptolide inhibits tumor cell invasion partly by reducing MMP-9 gene expression and activity.

2021皮肤红斑狼疮的诊断、治疗和长期管理指南

皮肤红斑狼疮(CLE)是一种炎症性自身免疫性疾病,其分型较多,包括急性、亚急性、慢性和间歇性CLE。其中,慢性CLE可以进一步分为红斑狼疮(LE)的几个亚型,如盘状LE、疣状LE、深在性LE、冻疮样LE和Blaschko线状LE等。为了给皮肤科医生和风湿科医生提供CLE的诊断、治疗和长期管理的实用指导建议,本证据和共识指南根据卫生保健实践指南的报告条目(国际RIGHT工作组)目录编制,并在国际实践指南注册平台注册。在亚洲皮肤科学会(ADA)、亚洲皮肤病性病学会(AADV)以及中华医学会皮肤性病学分会(CSD)红斑狼疮研究中心的共同努力下,来自亚洲、美洲、欧洲等16个国家或地区的25名皮肤科医生、7名风湿科医生、1名红斑狼疮领域专家和2名方法学家参与了本指南的制定。所有建议均取得了32名医生中至少80%的同意。作为共识,CLE的诊断主要基于临床和组织病理学表现的评估,并且通过对全身多系统损伤的评估,排除系统性红斑狼疮(SLE)。外用糖皮质激素和钙调磷酸酶抑制剂是局部CLE的一线治疗。对于泛发或严重的CLE皮损和/或局部耐药的病例,可以合并全身治疗,包括抗疟药和/或短期全身使用糖皮质激素。值得注意的是,抗疟药是所有类型CLE的一线全身治疗药物,同样可用于妊娠期患者和儿童。二线治疗用药包括沙利度胺、类维生素A类药物、氨苯砜和甲氨蝶呤,而霉酚酸酯是三线治疗用药。最后,脉冲染料激光或手术可作为四线治疗,用于局部以及发生在不可修饰部位的慢性、难治性CLE皮损。贝利尤单抗亦可作为四线治疗用药,用于活动性SLE患者的泛发性CLE皮损或糖皮质激素逐渐减量期间复发的急性CLE。对于疾病的管理,患者教育和长期随访是必要的。建议在每次随访时适当评估疾病活动度、皮肤和其他器官损伤、生活质量、合并症及可能发生的不良事件。

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

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.

Efficacy and safety of CM310 in moderate-to-severe atopic dermatitis:A multicenter,randomized,double-blind,placebo-controlled phase 2b trial

Background:Atopic dermatitis(AD)affects approximately 10%of adults worldwide.CM310 is a humanized monoclonal antibody targeting interleukin-4 receptor alpha that blocks interleukin-4 and interleukin-13 signaling.This trial aimed to evaluate the efficacy and safety of CM310 in Chinese adults with moderate-to-severe AD.Methods:This multicenter,randomized,double-blind,placebo-controlled,phase 2b trial was conducted in 21 medical institutions in China from February to November 2021.Totally 120 eligible patients were enrolled and randomized(1:1:1)to receive subcutaneous injections of 300 mg CM310,150 mg CM310,or placebo every 2 weeks for 16 weeks,followed by an 8-week follow-up period.The primary endpoint was the proportion of patients achieving≥75%improvement in the Eczema Area and Severity Index(EASI-75)score from baseline at week 16.Safety and pharmacodynamics were also studied.Results:At week 16,the proportion of EASI-75 responders from baseline was significantly higher in the CM310 groups(70%[28/40]for high-dose and 65%[26/40]for low-dose)than that in the placebo group(20%[8/40]).The differences in EASI-75 response rate were 50%(high vs.placebo,95%CI 31%-69%)and 45%(low vs.placebo,95%CI 26%-64%),with both P values<0.0001.CM310 at both doses also significantly improved the EASI score,Investigator’s Global Assessment score,daily peak pruritus Numerical Rating Scale,AD-affected body surface area,and Dermatology Life Quality Index compared with placebo.CM310 treatment reduced levels of thymus and activation-regulated chemokine,total immunoglobulin E,lactate dehydrogenase,and blood eosinophils.The incidence of treatment-emergent adverse events(TEAEs)was similar among all three groups,with the most common TEAEs reported being upper respiratory tract infection,atopic dermatitis,hyperlipidemia,and hyperuricemia.No severe adverse events were deemed to be attributed to CM310.Conclusion:CM310 at 150 mg and 300 mg every 2 weeks demonstrated significant efficacy and was well-tolerated in adults with moderate-to-severe AD.Trial Registration:ClinicalTrials.gov,NCT04805411.

Efficacy and safety of abrocitinib in Chinese patients with moderate-to-severe atopic dermatitis:A post hoc analysis of the JADE REGIMEN phase 3 trial

To the Editor:Atopic dermatitis(AD)is a chronic inflammatory skin disorder with a relapsing-remitting disease course that warrants flexible dosing.[1,2]In China,abrocitinib,an oral,once-daily,Janus kinase 1-selective inhibitor,is approved at a 100 mg starting dose for adults with refractory moderate-to-severe AD who did not inadequately respond to other systemic therapies(i.e.,corticosteroids or biologics),or for whom these treatments are not advisable.If the response achieved with abrocitinib 100 mg is inadequate,200 mg dosing can be considered,which could be administered as a short-term treatment(≤12 weeks).[3]The phase 3 JADE REGIMEN trial(Clinicaltrials.gov,NCT03627767)evaluated maintenance of response with continuous-dose abrocitinib(200 mg),reduced-dose abrocitinib(100 mg),or drug withdrawal(placebo)in patients with moderate-to-severe AD who responded to abrocitinib induction therapy.[4]Here,we aimed to characterize the efficacy and safety of abrocitinib in the Chinese mainland subgroup within JADE REGIMEN.

AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1-Bcl-6 axis-mediated B-cell differentiation

Absent in melanoma 2(AIM2)has been reported to be a component of inflammasomes in innate immune cells.Surprisingly,AIM2 is expressed by B cells,and higher AIM2 expression is observed in the B cells from lupus patients.To date,the inflammasome-indepe ndent functi on of AIM2 in B cells remai ns un clear.Here,we report in creased expressi on of AIM2 in human tonsil memory and germinal center(GC)B cells and in memory B cells and plasma cells from the circulation and skin lesions of lupus patients.Conditional knockout of AIM2 in B cells reduces the CD19^(+)B-cell frequency in lymph nodes and spleens,and dampens KLH-induced lgG1-antibody production.In a pristane-induced mouse model of lupus,AIM2 deficiency in B cells attenuates lupus symptoms and reduces the frequency of GC B cells,T follicular helper(Tfh)cells,plasmablast cells,and plasma cells.Furthermore,the loss of AIM2 in human B cells leads to the increased expression of Blimp-1 and reduces the expression of Bcl-6.However,the silendng of Blimp-1 and Bcl-6 has no significant effect on AIM2 expression,indicating that AIM2 might be the upstream regulator for Blimp-1 and Bcl-6.In addition,IL-10 is found to upregulate AIM2 expression via DNA demethylation.Together,our findings reveal that AIM2 is highly expressed in the B cells of lupus patients and promotes B-cell differentiation by modulating the Bcl-6-Blimp-1 axis,providing a novel target for SLE treatment.

Genetic and epigenetic influences on the loss of tolerance in autoimmunity

Immunological tolerance loss is fundamental to the development of autoimmunity;however,the underlying mechanisms remain elusive.Immune tolerance consists of central and peripheral tolerance.Central tolerance,which occurs in the thymus for T cells and bone marrow for B cells,is the primary way that the immune system discriminates self from non-self.Peripheral tolerance,which occurs in tissues and lymph nodes after lymphocyte maturation,controls self-reactive immune cells and prevents over-reactive immune responses to various environment factors.Loss of tolerance results in autoimmune disorders,such as systemic lupus erythematosus(SLE),rheumatoid arthritis(RA),type 1 diabetes(T1D)and primary biliary cirrhosis(PBC).The etiology and pathogenesis of autoimmune diseases are highly complicated.Both genetic predisposition and epigenetic modifications are implicated in the loss of tolerance and autoimmunity.In this review,we will discuss the genetic and epigenetic influences on tolerance breakdown in autoimmunity.Genetic and epigenetic influences on autoimmune diseases,such as SLE,RA,T1D and PBC,will also be briefly discussed.

Are BCL6 and EZH2 novel therapeutic targets for systemic lupus erythematosus?

As a chronic systemic autoimmune disease,systemic lupus erythematosus(SLE)can influence multiple organs and systems.Although the pathological basis and risk factors for SLE have been extensively investigated,the exact pathogenesis of SLE remains to be explored.However,there is increasing evidence that T-cell−Bcell interactions promote the development of SLE,resulting in the generation of high-affinity antibodies[1].Tfh cells,a subgroup of T cells,can promote the formation of germinal centers,the maturation of B cells,and the differentiation of plasma cells[2].It has been found that multiple transcription factors(TFs)can regulate the generation of Tfh cells.For instance,B-cell lymphoma-6(BCL-6),an evolutionarily conserved zinc-finger protein,is an important positive transcription factor responsible for the differentiation and maturation of Tfh cells.In addition to maintaining the phenotype and GC response of Tfh cells,BCL-6 can also regulate the dynamics of T-cell−B-cell interactions and improve the efficiency of delivering help to B cells[3].

Recent advances in systemic lupus erythematosus and microbiota: from bench to bedside

Systemic lupus erythematosus(SLE)is a complicated autoimmune disease affecting multiple systems and organs.It is highly heterogeneous,and it preferentially affects women at childbearing age,causing worldwide social burden.The pathogenesis of SLE mostly involves genetic predisposition,epigenetic dysregulation,overactivation of the immune system,and environment factors.Human microbiome,which is mostly composed of microbiota colonized in the gut,skin,and oral cavity,provides a natural microbiome barrier against environmental risks.The past decade of research has demonstrated a strong association between microbiota and metabolic diseases or gastrointestinal diseases.However,the role of microbiota in autoimmunity remains largely unknown until recently,when the technological and methodological progress facilitates further microbiota research in SLE.In this review,the latest research about the role and mechanisms of microbiota in SLE and the advances in the development of diagnostic and therapeutic strategies based on microbiota for SLE were summarized.

The critical importance of epigenetics in autoimmune-related skin diseases

Autoimmune-related skin diseases are a group of disorders with diverse etiology and pathophysiology involved in autoimmunity.Genetics and environmental factors may contribute to the development of these autoimmune disorders.Although the etiology and pathogenesis of these disorders are poorly understood,environmental variables that induce aberrant epigenetic regulations may provide some insights.Epigenetics is the study of heritable mechanisms that regulate gene expression without changing DNA sequences.The most important epigenetic mechanisms are DNA methylation,histone modification,and noncoding RNAs.In this review,we discuss the most recent findings regarding the function of epigenetic mechanisms in autoimmune-related skin disorders,including systemic lupus erythematosus,bullous skin diseases,psoriasis,and systemic sclerosis.These findings will expand our understanding and highlight the possible clinical applications of precision epigenetics approaches.

The modulation of co-stimulatory molecules by circulating exosomes in primary biliary cirrhosis

Exosomes are nanoparticles of endocytic origin, secreted by a myriad of cell populations that are attracting increased attention by virtue of their ability to modulate cell-to-cell communications. They are also attracting attention in a variety of immunological issues, including autoimmunity and, in particular, their ability to regulate cytokine and chemokine activation. Primary biliary cirrhosis （PBC） is considered a model autoimmune disease, which has a highly focused cytotoxic response against biliary epithelial cells. We have isolated exosomes from plasma from 29 patients with PBC and 30 healthy controls （HCs）, and studied the effect of these exosomes on co-stimulatory molecule expression and cytokine production in mononuclear cell populations using an ex vivo system. We also identified the microRNA （miRNA） populations in PBC compared to HC exosomes. We report herein that although exosomes do not change cytokine production, they do significantly alter co-stimulatory molecule expression on antigen-presenting populations. Further, we demonstrated that CD86 up-regulated expression on CD14＋ monocytes, whereas CD40 up-regulated on CD11c＋ dendritic cells by exosomes from patients with PBC. In addition, there were differences of miRNA expression of circulating exosomes in patients with PBC. These data have significant importance based on observations that co-stimulatory molecules play a differential role in the regulation of T-cell activation. Our observation indicated that aberrant exosomes from PBC selectively induce expression of co-stimulatory molecules in different subset of antigen-presenting cells. These alterations may involve in pathogenesis of autoimmune liver disease.

Epigenetic regulation in B-cell maturation and its dysregulation in autoimmunity

B cells have a critical role in the initiation and acceleration of autoimmune diseases, especially those mediated byautoantibodies. In the peripheral lymphoid system, mature B cells are activated by self or/and foreign antigens andsignals from helper T cells for differentiating into either memory B cells or antibody-producing plasma cells.Accumulating evidence has shown that epigenetic regulations modulate somatic hypermutation and class switchDNA recombination during B-cell activation and differentiation. Any abnormalities in these complex regulatoryprocesses may contribute to aberrant antibody production, resulting in autoimmune pathogenesis such as systemiclupus erythematosus. Newly generated knowledge from advanced modern technologies such as next-generationsequencing, single-cell sequencing and DNA methylation sequencing has enabled us to better understand B-cellbiology and its role in autoimmune development. Thus this review aims to summarize current research progress inepigenetic modifications contributing to B-cell activation and differentiation, especially under autoimmuneconditions such as lupus, rheumatoid arthritis and type 1 diabetes.

Exosomal microRNA in autoimmunity

Exosomes are small extracellular vesicles that contain a potpourri of nucleic acids,including microRNAs(miRNAs).Importantly,exosomes and these miRNAs are actively secreted from multiple cell populations and play a critical role in intercellular communication.The exosomal miRNA profile reflects the cellular pathophysiological status and modulates multiple biological processes.Accumulating evidence indicates that exosomes and miRNAs are biomarkers for disease diagnosis and may have therapeutic targets.Research studies on exosomal miRNAs have brought new insights into understanding autoimmune diseases.This article summarizes the detection methodologies and updates the potential applications of exosomal miRNAs in autoimmune diseases.

The pathogenic role of innate lymphoid cells in autoimmune-related and inflammatory skin diseases

Innate lymphoid cells(ILCs),as an important component of the innate immune system,arise from a common lymphoid progenitor and are located in mucosal barriers and various tissues,including the intestine,skin,lung,and adipose tissue.ILCs are heterogeneous subsets of lymphocytes that have emerging roles in orchestrating immune response and contribute to maintain metabolic homeostasis and regulate tissue inflammation.Currently,more details about the pathways for the development and differentiation of ILCs have largely been elucidated,and cytokine secretion and downstream immune cell responses in disease pathogenesis have been reported.Recent research has identified that several distinct subsets of ILCs at skin barriers are involved in the complex regulatory network in local immunity,potentiating adaptive immunity and the inflammatory response.Of note,additional studies that assess the effects of ILCs are required to better define how ILCs regulate their development and functions and how they interact with other immune cells in autoimmune-related and inflammatory skin disorders.In this review,we will distill recent research progress in ILC biology,abnormal functions and potential pathogenic mechanisms in autoimmune-related skin diseases,including systemic lupus erythematosus(SLE),scleroderma and inflammatory diseases,as well as psoriasis and atopic dermatitis(AD),thereby giving a comprehensive review of the diversity and plasticity of ILCs and their unique functions in disease conditions with the aim to provide new insights into molecular diagnosis and suggest potential value in immunotherapy.

Epigenetic regulation of B cells and its role in autoimmune pathogenesis

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.

BCL-6 suppresses miR-142-3p/5p expression in SLE CD4^(+) T cells by modulating histone methylation and acetylation of the miR-142 promoter

The reduced expression of miR-142-3p/5p in CD4^(+) T cells of SLE patients caused T cell hyperactivity and B cell hyperstimulation.This study aimed to investigate the mechanisms of regulating miR-142-3p/5p expression in SLE CD4^(+) T cells.The BCL-6 expression was significantly increased in SLE CD4^(+) T cells compared with normal controls,and the BCL-6 expression was inversely correlated with miR-142-3p/5p expression.BCL-6 suppresses the expression of miR-142-3p/5p by increasing H3K27me3 level and reducing H3K9/K14ac levels in SLE CD4^(+) T cells.BCL-6 regulates histone modifications in miR-142 promoter by recruiting EZH2 and HDAC5.Furthermore,we observed significantly decreased CD40L,ICOS,and IL-21 expression levels in SLE CD4^(+) T cells with BCL-6 interference,and obviously reduced autoantibody IgG production in autologous B cells co-cultured with BCL-6 inhibited SLE CD4^(+) T cells.Our study found that increased BCL-6 up-regulates H3K27me3 and down-regulates H3K9/14ac at miR-142 promoter in SLE CD4^(+) T cells.These factors induce a declination in miR-142-3p/5p expression,consequently resulting in CD4^(+) T cell hyperactivity.

Weights and Empirical Analysis of RMB Exchange Rate Adjustments with Reference to a Basket of Currencies Following the Exchange Rate System Reform of 2010

This paper constructs an RMB/USD exchange rate index and a basket currency exchange rate index. The correlation maximization of the RMB/USD and the basket currency index may determine the weight and quantity of the basket currency. The currency basket indicates that the weight of the USD is highest, whereas that of the GB Pound is the lowest. Our currency basket has a high linear dependence on that of the central bank. We found that the RMB/USD and currency basket indices have a long-term co-integration relationship according to the optimal currency weights. The results of the error-correcting model manifest as the RMB/USD exchange rate deviates from the long-term equilibrium level, wherein 76.3% will be corrected. This paper checks the prediction capacity, which indicates the good fit of the model. By using the Granger causality test the findings show that the People＇s Bank of China adjusts the RMB/USD exchange rate with reference to the currency basket.