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Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders

SIGNAL TRANSDUCTION AND TARGETED THERAPY 2024年第1期9卷 263页

作者： Song, Yi Li, Jian wu, yuzhang Third Mil Med Univ Army Med Univ Inst Immunol PLA Chongqing Peoples R China Chongqing Int Inst Immunol Chongqing Peoples R China

Autoimmune disorders are characterized by aberrant T cell and B cell reactivity to the body's own components, resulting in tissue destruction and organ dysfunction. Autoimmune diseases affect a wide range of people in many parts of the world and have become one of the major concerns in public health. In recent years, there have been substantial progress in our understanding of the epidemiology, risk factors, pathogenesis and mechanisms of autoimmune diseases. Current approved therapeutic interventions for autoimmune diseases are mainly non-specific immunomodulators and may cause broad immunosuppression that leads to serious adverse effects. To overcome the limitations of immunosuppressive drugs in treating autoimmune diseases, precise and target-specific strategies are urgently needed. To date, significant advances have been made in our understanding of the mechanisms of immune tolerance, offering a new avenue for developing antigen-specific immunotherapies for autoimmune diseases. These antigen-specific approaches have shown great potential in various preclinical animal models and recently been evaluated in clinical trials. This review describes the common epidemiology, clinical manifestation and mechanisms of autoimmune diseases, with a focus on typical autoimmune diseases including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and sj & ouml;gren's syndrome. We discuss the current therapeutics developed in this field, highlight the recent advances in the use of nanomaterials and mRNA vaccine techniques to induce antigen-specific immune tolerance.

关键词： autoimmune epidemiology therapeutic

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Nanoparticle targeting cGAS-STING signaling in disease therapy

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Nano Research 2024年第8期17卷 7315-7336页

作者： Lan Zhou Yu Huang yuzhang wu Shupei Tang Frontier Medical Training Brigade Third Military Medical UniversityHutubi 831200China Department of Gastroenterology Xinqiao HospitalThird Military Medical UniversityChongqing 400037China Institute of Immunology Third Military Medical UniversityChongqing 400038China Shigatse Branch Xinqiao HospitalThird Military Medical UniversityShigatse 857000China

The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon(IFN)genes(cGAS-STING)signaling pathway is crucial for sensing abnormal DNA accumulation in the *** binds to abnormal DNA,cGAS catalyzes the production of second messenger cyclic dinucleotides,followed by the activation of downstream *** activation induces the expression of type I interferon and other inflammatory cytokines,ultimately initiating an immune *** to the involvement of the cGAS-STING pathway in various diseases,including infection,tumor,autoimmune disease and kidney disease,ongoing research is focused on developing drugs and treatment methods to target and regulate this *** the development of nanotechnology,nanomedicines targeting cGAS-STING signaling are of great significance in clinical applications due to their targeted delivery,controlled drug release,improved solubility,multifunctionality,and enhanced *** comprehensive review focuses on the most recent progress of nanoplatforms targeting cGAS-STING in disease therapy,aiming to provide references and guidelines for further design and optimization of nanomedicines.

关键词： nanomedicine cGAS-STING pathway and related disease anti-tumor nanotherapy anti-viral nanotherapy

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Screening of HLA-A2 restricted CTL epitopes using molecular simulation

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Chinese Science Bulletin 2003年第18期48卷 1962-1966页

作者： GENG Miao wu yuzhang LIN Zhihua JIA Zhengcai ZHOU Wei ZOU Liyun Institute of Immunology PLA Third Military Medical UniversityChongqing 400038China College of Bioengineering Chongqing Institute of TechnologyChongqing 400050China

A new technology has been established to screen CTL epitope by using molecular simulation and mo-lecular dynamics. By using this technology, four peptides of MAGE-2 were screened and further identified by peptide binding assay and cytotoxic assay. Results showed that three candidate peptides had higher affinity to HLA-A2 molecule and were able to pulse CTL activities in vitro in human PBMC. The results indicated that identification of CTL epi-topes with computer assistant could overcome the compli-cated experimental steps, particularly the peptide elution step, and could directly observe peptide-MHC-Ⅰ compound binding pattern and could be used to screen CTL epitopes quickly.

关键词： CTL epitope HLA-A2 identification computer assis-tant molecular simulation.

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CD49a^(+)CD49b^(+) NK cells induced by viral infection reflect an activated state of conventional NK cells

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Science China(Life Sciences) 2020年第11期63卷 1725-1733页

作者： Wenhan Li Jing Zhou Xianwei Wang yuzhang wu Lilin Ye Haiming Wei Rui Sun Zhigang Tian Hui Peng Division of Molecular Medicine Hefei National Laboratory for Physical Sciences at Microscalethe CAS Key Laboratory of Innate Immunity and Chronic DiseaseSchool of Life SciencesUniversity of Science and Technology of ChinaHefei 230027China Institue of Immunology University of Science and Technology of ChinaHefei 230027China Institute of Immunology Third Military Medical UniversityChongqing 400038China

Natural killer(NK) cells are important innate effectors that play a pivotal role in the defense against tumors and infections and participate in regulating adaptive immunity. Recent studies have revealed phenotypic and functional heterogeneity of NK ***, using murine models of acute and chronic lymphocytic choriomeningitis virus infection, we observed that a CD49a^(+)CD49b^(+) NK cell subset emerged in the liver and other tissues, and underwent vigorous expansion following viral infection,before progressively decreasing in cell number. These viral infection-induced CD49a^(+)CD49b^(+) NK cells displayed an activated and mature phenotype. Moreover, compared with liver-resident NK cells and conventional NK(cNK) cells, CD49a^(+)CD49b^(+) NK cells showed increased functional competence, as evidenced by higher amounts of IFN-γ production and stronger cytotoxic capabilities during viral infection. Generation of these CD49a^(+)CD49b^(+) NK cells was shown to be independent of the T-bet transcription factor. Adoptive transfer experiments revealed that c NK cells could convert into CD49a^(+)CD49b^(+) NK cells following viral infection. Collectively, these results suggest that viral infection-induced CD49a^(+)CD49b^(+) NK cells represent a transiently activated state of cNK cells.

关键词： NK cells liver viral infection cell activation effector function

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Efficient control of chronic LCMV infection by a CD4 T cell epitope-based heterologous prime-boost vaccination in a murine model

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Cellular & Molecular Immunology 2018年第9期15卷 815-826页

作者： Ran He Xinxin Yang Cheng Liu Xiangyu Chen Lin Wang Minglu Xiao Jianqiang Ye yuzhang wu Lilin Ye Center for Clinical Laboratory Zhujiang HospitalSouthern Medical UniversityGuangzhou 510515China Institute of Immunology Medical SchoolThird Military Medical UniversityChongqing 400038China Ministry of Education Key Laboratory for Avian Preventive Medicine College of Veterinary MedicineYangzhou UniversityYangzhouJiangsu 225009China Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses YangzhouJiangsu 225009China

CD4^(+)T cells are essential for sustaining CD8^(+)T cell responses during a chronic *** adoptive transfer of virus-specific CD4^(+)T cells has been shown to efficiently rescue exhausted CD8^(+)T ***,the question of whether endogenous virus-specific CD4^(+)T cell responses can be enhanced by certain vaccination strategies and subsequently reinvigorate exhausted CD8^(+)T cells remains *** this study,we developed a CD4^(+)T cell epitope-based heterologous prime-boost immunization strategy and examined the efficacy of this strategy using a mouse model of chronic lymphocytic choriomeningitis virus(LCMV)*** primed chronically LCMV-infected mice with a Listeria monocytogenes vector that expressed the LCMV glycoprotein-specific I-Ab-restricted CD4^(+)T cell epitope GP61–80(LM-GP61)and subsequently boosted the primed mice with an influenza virus A(PR8 strain)vector that expressed the same CD4^(+)T cell epitope(IAV-GP61).This heterologous prime-boost vaccination strategy elicited strong anti-viral CD4^(+)T cell responses,which further improved both the quantity and quality of the virusspecific CD8^(+)T cells and led to better control of the viral *** combination of this strategy and the blockade of the programmed cell death-1(PD-1)inhibitory pathway further enhanced the anti-viral CD8^(+)T cell responses and viral ***,a heterologous prime-boost immunization that selectively induces virus-specific CD4^(+)T cell responses in conjunction with blockade of the inhibitory pathway may represent a promising therapeutic approach to treating patients with chronic viral infections.

关键词： CD4^(+)T cell epitope CD8^(+)T cell exhaustion chronic viral infection prime-boost

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An altered CD8^(+) T cell epitope of insulin prevents type 1 diabetes in humanized NOD mice

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Cellular & Molecular Immunology 2019年第6期16卷 590-601页

作者： Mengjun Zhang Shufeng Wang Binbin Guo Gang Meng Chi Shu Wenli Mai Qian Zheng Xiaoling Chen yuzhang wu Li Wang Department of Pharmaceutical Analysis College of PharmacyArmy Medical University(Third Military Medical University)400038 ChongqingChina Institute of Immunology PLA&Department of Immunology Army Medical University(Third Military Medical University)400038 ChongqingChina Department of Pathology Southwest HospitalArmy Medical University(Third Military Medical University)400038 ChongqingChina Function Center North Sichuan Medical College637100 NanchongSichuanChina

Autoreactive CD8^(+)T cells,which play an indispensable role inβcell destruction,represent an emerging target for the prevention of type 1 diabetes(T1D).Altered peptide ligands(APLs)can efficiently induce antigen-specific T cells anergy,apoptosis or shifts in the immune ***,we found that HLA-A*0201-restricted CD8^(+)T cell responses against a primaryβ-cell autoantigen insulin epitope InsB15–14 were present in both NOD.β2m *** NOD mice and T1D *** generated several APL candidates for InsB15–14 by residue substitution at the p6 *** H6F exhibited an inhibitory effect on mInsB1_(5–14)-specific CD8^(+)T cell responses in vitro.H6F treatment significantly reduced the T1D incidence,which was accompanied by diminished autoreactive CD8^(+)T cell responses to mInsB15-14,inhibited infiltration of CD8^(+)and CD4^(+)T cells in the pancreas and reduced pro-inflammatory cytokine production in pancreatic and splenic T cells in NOD.β2m^(null).HHD ***,H6F treatment significantly augmented a tiny portion of CD8^(+)CD25^(+)Foxp3^(+)T cells in the spleen and especially in the *** subset exhibited typical Treg phenotypes and required peptide-specific restimulation to exert immunosuppressive ***,this APL H6F may be a promising candidate with potential clinical application value for antigen-specific prevention of T1D.

关键词： Type 1 diabetes Altered peptide ligand CD8^(+)CD25^(+)Foxp3^(+)regulatory T cells InsB1_(5–14) NOD.β2m^(null).HHD mice

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Liver X receptorβis required for the survival of single-positive thymocytes by regulating IL-7Rαexpression

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Cellular & Molecular Immunology 2021年第8期18卷 1969-1980页

作者： Huang Huang Xiaoping wu Dongwei Meng Yizhou Feng Lan Zhou Zhenyu Liu Shupei Tang Xueqin Li Yi Cao Haiyang He Zhunyi Xie Jingbo Zhang Yongwen Chen Tingting Zhao yuzhang wu Xinyuan Zhou Institute of Immunology College of Basic Medical SciencesThird Military Medical UniversityChongqing400038China Institute for Cancer Medicine and School of Basic Medical Sciences Southwest Medical UniversityLuzhouSichuan646000China Chengdu No.7 Wanda High School ChengduSichuan610036China Department of Nephrology Xinqiao HospitalThird Military Medical UniversityChongqing400038China Department of Urology Xinqiao HospitalThird Military Medical UniversityChongqing400038China

Liver X receptors(LXRs)are known as key transcription factors in lipid metabolism and have been reported to play an important role in T-cell ***,whether LXRs play a role in thymocyte development remains largely ***,we demonstrated that LXRβdeficiency caused a reduction in single-positive(SP)thymocytes,whereas the transitions from the double-negative to SP stage were ***,LXRβ-null SP thymocytes exhibited increased apoptosis and impairment of the IL-7Rα-Bcl2 *** addition,the LXR agonist T0901317 promoted the survival of SP thymocytes with enhanced IL-7Rαexpression in wild-type mice but not in LXRβ-deficient ***,LXRβpositively regulated the expression of IL-7Rαvia direct binding to the Il7r allele in SP thymocytes,and forced expression of IL-7Rαor Bcl2 restored the survival of LXRβ-defective SP ***,our results indicate that LXRβfunctions as an important transcription factor upstream of IL-7Rαto promote the survival of SP thymocytes.

关键词： LXRβ IL-7Rα Single-positive thymocytes Cell survival Transcriptional regulation

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Insight into Erythropoietin Signaling and Autoimmunity

Insight into Erythropoietin Signaling and Autoimmunity

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第十三届全国免疫学学术大会

作者： yuzhang wu Institute of Immunology PLAArmy Medical University

Apoptosis occurs throughout life in many tissues and the failure to properly clear apoptotic cells by phagocytes has been linked to autoimmune diseases,nonresolvinginflammation and developmental abnormalities. Dying cells release ‘find-me’signals to recruit phagocytes to initiate their clearance. However, one intriguing hypothesis suggests the primary role of‘find me’ signalsfor priming rather than recruitment of phagocytes, yet underlying mechanisms remain poorly *** we demonstrate that the ‘find me’ signalsphingosine 1-phosphate (S1P) activated macrophage erythropoietin (EPO)

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The role of microRNAs in B-cell development and function

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Cellular & Molecular Immunology 2013年第2期10卷 107-112页

作者： Jingyi Li Ying Wan Qing Ji Yongfei Fang yuzhang wu Department of Rheumatology Southwest Hospital Third Military Medical University Chongqing 400038 China lnstitute of Immunology PLA Third Military Medical University Chongqing 400038 China RNA Biology Lab Biomedical Analysis Center Third Military Medical University Chongqing 400038 China Department of Digestive Diseases Southwest Hospital Third Military Medical University Chongqing 400038 China

MicroRNA （miRNA）-mediated gene silencing at the translational level has led to novel discoveries for numerous biological processes. Recently, there has been increasing evidence to indicate that miRNAs are involved in normal immune functions and inflammation. In this review, we focus on recent advances that have elucidated the role of miRNAs in B-cell development, differentiation, apoptosis and function. While the regulatory mechanisms of miRNAs in controlling and maintaining B-cell fate remain largely uncharacterized, further studies on miRNAs and their targets will increase our understanding of B-cell development and function. Such studies may be able to provide new therapeutic strategies for treating autoimmune diseases.

关键词： microRNA B cell development function

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Artesunate suppresses Th17 response via inhibiting IRF4-mediated glycolysis and ameliorates Sjogren's syndrome

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Signal Transduction and Targeted Therapy 2022年第9期7卷 3210-3212页

作者： Fan Xiao Ke Rui Man Han Liyun Zou Enyu Huang Jie Tian Lijun Zhang Quan Jiang yuzhang wu Liwei Lu Department of Pathology and Shenzhen Institute of Research and Innovation Shenzhen HospitalThe University of Hong Kong Chongqing International Institute for Immunology Hong KongChina Department of Laboratory Medicine Affliated Hospital andInstitute of Medical ImmunologyJiangsu UniversityZhenjiangChina Division of Rheumatology Guang'anmen HospitalChina Academy of Chinese Medical SciencesBejjingChina Institute of ImmunologyArmy Medical UniversityChongqingChina

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 ***,pSS patients are suffering from a lack of effective *** studies have revealed dysregulated immune responses during pSS development,in which Th17 cells are considered as the key driver in disease initiation and perpetuation.

关键词： Th17 Sjogren inhibiting

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