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ACPAs promote IL-1β production in rheumatoid arthritis by activating the NLRP3 inflammasome

Cellular & Molecular Immunology 2020年第3期17卷 261-271页

作者： Xiwen Dong Zhaohui Zheng Peng Lin Xianghui Fu Fanni Li Jianli Jiang Ping Zhu Department of Clinical Immunology Branch of Immune Cell BiologyState Key Discipline of Cell BiologyPLA Specialized Research Institute of Rheumatology&ImmunologyXijing HospitalFourth Military Medical UniversityNo.127 West Changle Road710032 Xi’anShaanxi ProvinceChina National Translational Science Center for Molecular Medicine 710032 Xi’anChina Department of Cell Biology State Key Discipline of Cell BiologyFourth Military Medical University710032 Xi’anChina

OBJECTIVES:Anti-citrullinated protein antibodies(ACPAs)are a group of autoantibodies targeted against citrullinated proteins/peptides and are informative rheumatoid arthritis(RA)*** also play a crucial role in RA pathogenesis,and their underlying mechanism merits ***:Immunohistochemical(IHC)assays were carried out to determine IL-1βlevels in ACPA+and ACPA−RA *** monocytes were differentiated into macrophages before stimulation with ACPAs purified from RA *** localization and interaction of molecules were analyzed by confocal microscopy,co-IP,and surface plasmon ***:In our study,we found that IL-1βlevels were elevated in ACPA+RA patients and that ACPAs promoted IL-1βproduction by PBMC-derived *** interacted with CD147 to enhance the interaction between CD147 and integrinβ1 and,in turn,activate the Akt/NF-κB signaling *** nuclear localization of p65 promoted the expression of NLRP3 and pro-IL-1β,resulting in ***,ACPA stimulation activated pannexin channels,leading to ATP *** accumulated ATP bound to the P2X7 receptor,leading to NLRP3 inflammasome ***:Our study suggests a new hypothesis regarding IL-1βproduction in RA involving ACPAs,which may be a potential therapeutic target in RA treatment.

关键词： Anti-citrullinated protein antibodies NLRP3 inflammasome IL-1β CD147 rheumatoid arthritis

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Screening disease-associated proteins from sera of patients with rheumatoid arthritis： a comparative proteomic study

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Chinese Medical Journal 2010年第5期123卷 537-543页

作者： LI Tian-wang ZHENG Ben-rong HUANG Zhi-xiang LIN Qu ZHAO Li-ke LIAO Ze-tao ZHAO Ji-jun LIN Zhi-ming GU Jie-ruo Department of Rheumatology Third Affiliated Hospital of Sun Yat-sen University Guangzhou Guangdong 510630 China Department of Rheumatology Beijing Hospital Beijing 100730 China

Background rheumatoid arthritis （RA） is an autoimmune disease characterized by chronic inflammation at the synovial membrane. Although great progress has been made recently in exploring the etiology and pathogenesis of RA, its molecular pathological mechanism remains to be further defined and it is still a great challenge in determining the diagnosis and in choosing the appropriate therapy in early patients. This study was performed to screen candidate RA-associated serum proteins by comparative proteomics to provide research clues to early diagnosis and treatment of RA. Methods Sera isolated from 6 RA patients and 6 healthy volunteers were pooled respectively and high-abundance proteins were depleted by Plasma 7 Multiple Affinity Removal System. The protein expression profiles between the two groups were then compared by two-dimensional gel electrophoresis （2-DE） and the proteins over/under-expressed by more than 3-fold were identified by mass spectrometry analysis. To validate the differential expression levels of the identified proteins between the two groups, ELISA was performed in two of the identified proteins in individual sera from 32 RA patients and 32 volunteers. Results Eight proteins which over/under-expressed in sera of RA patients were identified. Among them, chain A of transthyretin （TTR） was under-expressed, while serum amyloid A protein, apolipoprotein A （ApoA）-IV, ApoA-IV precursor, haptoglobin 2, ceruloplasmin （Cp）, immunoglobulin superfamily 22 and HT016 were over-expressed. ELISA test confirmed that Cp expressed remarkably higher while TTR obviously lower in RA group compared with volunteer group. Conclusion There were 8 identified proteins differentially expressed between RA group and volunteer group, which might be candidate RA-associated proteins and might be promising diagnostic indicators or therapeutic targets for RA.

关键词： rheumatoid arthritis serum proteomics gel electrophoresis, two-dimensional

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Antigen-presenting effects of effector memory Vγ9Vδ2 T cells in rheumatoid arthritis

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Cellular & Molecular Immunology 2012年第3期9卷 245-254页

作者： Chaoying Hu Liu Qian Yi Miao Qiuyu Huang Ping Miao Ping Wang Qiwen Yu Hong Nie Jiying Zhang Dongyi He Rong Xu Xuehua Chen Bingya Liu Dongqing Zhang Shanghai Institute of Immunology Shanghai Jiao Tong University School of MedicineShanghaiChina Central laboratory Shanghai Xuhui Central HospitalShanghaiChina Guanghua rheumatoid arthritis Specialized Hospital ShanghaiChina Shanghai Jiao Tong University School of Medicine Ruijin HospitalShanghaiChina

rheumatoid arthritis is an autoimmune disease that primarily affects the limbs, but the pathogenic mechanism remains unclear. 78 T cells, a T-cell subpopulation, are characterized by multiple biological functions and associated with a variety of diseases. This study investigated the antigen-presenting effects of γδ2 cells and their relationship with rheumatoid arthritis development. We found that Vγ9Vδ2 T cells （the predominant subtype of γδ T cells in peripheral blood） were activated by isopentenyl pyrophosphate to continuously proliferate and differentiate into effector memory cells. The effector memory Vγ9Vδ2 T cells exhibited phenotypic characteristics of specific antigen-presenting cells, including high HLA-DR and CD80/86 expression. These Vγ9Vδ2 T cells could present soluble antigens and synthetic peptides to CD4＋ T cells. Vγ9Vδ2 T cells with different phenotypes showed different cytokine secretion patterns. Effector memoryVγ9Vδ2 T cells simultaneously secreted not only interferon （IFN）-γbut also IL-17. The peripheral blood and joint synovial fluid from RA patients contained numerous heterogeneous γδ T cells that were predominantly effector memory Vγ9Vδ2 T cells with the ability to secrete inflammatory factors. We also found that γδ T cells had a similar antigen-presenting capability to B cells. These results suggest that during the development of rheumatoid arthritis, 78 T cells can aggravate immune dysfunction and produce abnormal immune damage by secreting cytokines and inducing inflammatory cells to participate in synergistic inflammatory responses. Furthermore, γδ T cells can behave similarly to B cells to present viral peptides and autoantigen peptides to CD4＋ T cells, thus sustaining CD4＋ T-cell activation.

关键词： antigen-presenting function rheumatoid arthritis γδT cell TEM Vγ9Vδ2 T cell

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Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis

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Cellular & Molecular Immunology 2019年第8期16卷 694-705页

作者： Weijun Wu Ming Qin Wanwan Jia Zheng Huang Zhongzheng Li Di Yang Mengwei Huang Chenxi Xiao Fen Long Jianchun Mao Philip K.Moore Xinhua Liu Yi Zhun Zhu Department of Pharmacology Shanghai Key Laboratory of Bioactive Small MoleculesSchool of PharmacyFudan UniversityShanghai 201203China State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy Macao University of Science and TechnologyMacaoChina Institute of arthritis Research Shanghai Academy of Chinese Medical SciencesGuanghua Integrative Medicine Hospital/Shanghai University of T.C.MShanghaiChina Ningbo The 9th Hospital Ningbo 315000China Department of Rheumatology Shanghai Longhua HospitalShanghaiChina Department of Pharmacology National University of SingaporeSingaporeSingapore

Cystathionine-γ-lyase(CSE),an enzyme associated with hydrogen sulfide(H2S)production,is an important endogenous regulator of *** domain-containing protein 3(JMJD3)is implicated in the immune response and ***,we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis(RA).Upregulated CSE and JMJD3 were identified in synovial fibroblasts(SFs)from RA patients as well as in the joints of arthritic *** down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 *** addition,CSE−/−mice with collagen-induced arthritis(CIA)developed severe joint inflammation and bone ***,overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated ***,JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs,mainly by controlling the methylation status of H3K27me3 at the promoter of its target ***-J4 markedly attenuated the severity of arthritis in CIA *** conclusion,suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.

关键词： cystathionine-γ-lyase rheumatoid arthritis Jumonji domain-containing protein 3 Sp-1 Toll like receptor 2

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Asymptomatic Cardiac Manifestations in rheumatoid arthritis in Conakry (Guinea)

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Open Journal of Rheumatology and Autoimmune Diseases 2022年第2期12卷 57-64页

作者： Aly Badra Kamissoko Ibrahima Sory Barry Marina Sanda Cletus Dieuval Houngbegnon Mamadou Lamine Diallo Abdoulaye Barry Mamadou Dadhi Baldé Owonayo Oniankitan Department of Rheumatology Ignace Deen National Hospital Conakry Guinea Department of Cardiology Ignace Deen National Hospital Conakry Guinea Department of Rheumatology Sylvanus Olympio University Hospital Lome Togo

Introduction: rheumatoid arthritis (RA) is the most common chronic inflammatory rheumatic disease. It is a systemic disease with extra-articular manifestations that can be life-threatening. In sub-Saharan Africa, there is little published information on cardiovascular manifestations in RA. Objective: The objective is to determine the asymptomatic cardiac manifestations during rheumatoid arthritis in Conakry. Patients and Methods: This was a cross-sectional study lasting 6 months from January 1, 2020 to June 30, 2020 in the rheumatology and cardiology departments of the Ignace Deen National Hospital. Patients with RA diagnosed according to the 2010 ACR/EULAR criteria, asymptomatic at the cardiovascular level, which had an ECG and echocardiography, were included in the study. Left ventricular diastolic dysfunction was considered in any patient with an E/A ratio 1, an E/E’ ratio > 10, and an LVEF = 50%, assessed by the Simpson biplane method and classified according to Redfield. Epidemiological, clinical and paraclinical data were analyzed using SPSS statistics 21.0 software. Results: Seventeen cases of rheumatoid arthritis (5.9%) were collected. There was a predominance of women with 14 cases (82.4%). The mean age of patients was 48.2 ± 11.9 years. The average duration of RA was 7.2 ± 4.2 years. Cardiovascular risk factors were dominated by overweight and obesity (58.8%) and sedentary lifestyle (35.3%). RA was predominantly high activity (DAS 28 ≥ 5.1) in 82.4% of patients. Anti-CCP antibodies were positive in 76.9% of cases. Fourteen patients (82.4%) had abnormal cardiac results. The electrocardiogram showed left atrial hypertrophy in 29.4% of cases, left ventricular hypertrophy (11.8%) and ventricular extrasystole (11.8%). The cardiac Doppler scan showed diastolic dysfunction of the left ventricle (47.1%) and moderate pericardial effusion in 11.8% of cases. Conclusion: The study found asymptomatic cardiac manifestations of rheumatoid arthritis. They were dominated b

关键词： rheumatoid arthritis Asymptomatic Manifestations Electrocardiography Sub-Saharan Africa Guinea

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Programmed cell death 5 correlates with disease activity and interleukin-17 in serum and synovial fluid of rheumatoid arthritis patients

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Chinese Medical Journal 2013年第2期126卷 296-299页

作者： WANG Jun-feng GUAN Zhen-peng ZHANG Shao-long PEI Zheng CHEN Ying-yu PAN Huan arthritis Clinic and Research Center Peking University People'sHospital Beijing 100044 China Peking University Center for Human Disease Genomics Beljing100191 China

Background Programmed cell death 5 （PDCD5） is a novel apoptotic regulatory gene that promotes apoptosis in various tumor cells. Studies have shown that PDCD5 accelerates the apoptosis of synoviocytes in vitro, implying a potential role in rheumatoid arthritis （RA） pathogenesis. This study examined the expression of PDCD5 in serum and synovial fluid of RA patients, its effect on the expression of inflammatory cytokine, interleukin-17 （IL-17）, and the assessment of disease activity in RA. Methods PDCD5 and IL-17 levels in serum and synovial fluid from 18 patients with RA and 22 patients with osteoarthritis （OA） were detected using enzyme-linked immunosorbent assay （ELISA）. Concentrations of serum PDCD5 in 40 healthy people were also detected as controls. As disease activity indices, C-reactive protein （CRP）, erythrocyte sedimentation rate （ESR）, rheumatoid factor （RF）, and X-ray grading scale were also evaluated. Results Serum and synovial fluid PDCD5 levels in RA patients were significantly higher than those in OA and healthy controls. Serum PDCD5 level was inversely correlated to CRP and ESR, and was significantly higher in the RF negative group than in the positive group. PDCD5 level was also negatively correlated with IL-17 levels both in serum and synovial fluid of RA patients. However, differences in synovial fluid PDCD5 level from RA patients at different Larsen stages were not detectable. Conclusions PDCD5 affects RA pathogenesis. Insufficient apoptosis of fibroblast-like synoviocytes and inflammatory cells in RA could increase the expression of PDCD5 protein. As PDCD5 levels correlated negatively with disease activity indices and IL-17 level, PDCD5 could become a target in the diagnosis and treatment of RA.

关键词： rheumatoid arthritis programmed cell death 5 interleukin-17 pathogenesis

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Effect of tumor necrosis factor inhibitors on rheumatoid arthritis-induced peripheral neuropathy A cohort study

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Neural Regeneration Research 2012年第11期7卷 862-866页

作者： Naizhi Wang Yingying Guo Lili Yang Wenyi Fu Yanbing Xu Linxin Hou Shuai Zhao Ning Zhang Department of Rheumatism Shengjing Hospital China Medical University Shenyang 110004 Liaoning Province China

In this historical cohort study, 236 patients with primary rheumatoid arthritis were treated with the tumor necrosis factor inhibitors, etanercept or infliximab （n = 80）, or by conventional methods （n = 156）. Results revealed that 11 patients developed varying types of peripheral neuropathy at 1-2 years post-treatment （mean 16 months）. The incidence of peripheral neuropathy in the tumor necrosis factor inhibitors treatment group was 8.8% （7/80）, which was significantly higher than the conventional treatment group （2.6%; 4/156）. The relative risk of developing peripheral neuropathy in the tumor necrosis factor inhibitors treatment group was 3.41 （95% confidence interval： 1.03 11.31）. Comparison of the tumor necrosis factor inhibitors revealed that etanercept and infliximab had no significant difference in terms of inducing peripheral neuropathy. Experimental findings indicate that tumor necrosis factor inhibitors may increase the risk of peripheral neuropathy.

关键词： tumor necrosis factor inhibitors adverse reactions peripheral neuropathy rheumatoid arthritis cohort study risk factors

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Status of Renal and Liver Function in rheumatoid arthritis (RA) Patients of Chattogram, Bangladesh Treated with Methotrexate (MTX)

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Journal of Biosciences and Medicines 2023年第9期11卷 114-126页

作者： Mohammad Razuanul Hoque Md. Abdur Razzaque Abrar Nafis Mohammad Shahriar Zawad Sharaf Wasima Rahman Department of Biochemistry and Molecular Biology University of Chittagong Chattogram Bangladesh Department of Rheumatology Chittagong Medical College Hospital Chattogram Bangladesh

rheumatoid arthritis (RA) is a chronic autoimmune disorder that is usually manifested as inflammation in multiple joints and several extra-articular symptoms, involving the liver, kidney, eye, skin, blood, blood vessels, heart, lungs, nervous system, and other organs. Methotrexate (MTX) is the anchor drug that treats RA. As renal and liver abnormalities are more common during disease conditions as well as during the treatment period, we tried to find out if there is any impact of MTX in these organs during the treatment of RA patients. Once the disease complications are developed, it is quite difficult to reverse the disease, and treatment in this situation is not very effective. Consequently, patients suffer a lot. So, early evaluation of renal and liver function is essential for the treatment of RA patients and it might also help prevent different complications which are usually very frequently observed. This was a cross-sectional study. A total of 150 RA patients treated with MTX were evaluated for the study where female and male respondents were 115 and 35 respectively. In this study, we found that 82% of RA patients had creatinine levels ≤ 1.1 mg/dL although the normal range of serum creatinine is below 1.4 mg/dL. Usually, a 15% increase in Serum creatinine level from the baseline is considered renal impairment. We found 4% of such cases. Moreover, 2% of RA patients had creatinine levels above the normal range of 1.4 mg/dL and those patients were hypertensive as well. So, a total (4 + 2 = 6)% had renal impairments. Among them, 5% had diabetes mellitus. On the other hand, the ultrasonogram (USG) of RA patients with kidney disease showed signs of renal parenchymal disease and 3% of RA patients having renal problems whose serum creatinine level was within the normal range showed signs of chronic kidney disease (CKD). On the other hand, 2% of RA patients showed signs of hepatic parenchymal disease. In this study, 69% of RA patients had ALT levels ≤ 50 mg/dL, 23% ha

关键词： rheumatoid arthritis Renal Function Liver Function C-Reactive Protein Methotrexate

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Increased interleukin-23 is associated with increased disease activity in patients with rheumatoid arthritis

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Chinese Medical Journal 2013年第5期126卷 850-854页

作者： GUO Ying-ying WANG Nai-zhi ZHAO Shuai HOU Lin-xin XU Yan-bing ZHANG Ning Department of Rheumatism Shengjing Hospital China MedicalUniversity Shenyang Liaoning 110004 China

Background Interleukin-23 （IL-23） is a pro-inflammatory cytokine that is thought to be central to the development of autoimmune diseases. This study was conducted to determine whether or not the serum concentration of IL-23 is elevated in patients with rheumatoid arthritis （RA）, and to determine the relationship between the IL-23 level and disease activity in RA patients. Methods Serum samples were obtained from 59 patients with RA and 30 healthy controls. The clinical parameters of disease activity were determined, including the 28-joint disease activity score （DAS28）, C-reactive protein （CRP）, rheumatoid factor （RF） levels, and the degree of bony erosions based on X-rays. The levels of IL-23 and IL-17 were determined by enzyme-linked immunosorbent assay （ELISA）. The correlations between the serum levels of IL-23 and disease activity parameters of patients with RA were determined. Results The serum IL-23 level was significantly elevated in patients with RA compared to healthy controls. The serum IL-23 levels in the RA patients correlated with IL-17 and CRP levels, and the DAS28. The levels of IL-23 based on X-ray classification phase I, II, III, and IV were gradually elevated in RA patients. Conclusions The levels of serum IL-23 in RA patients were higher than in healthy controls. Thus, elevated serum IL-23 levels may be useful markers to detect active RA. In addition, IL-23 is involved in disease progression and bony erosions in patients with RA.

关键词： rheumatoid arthritis interleukin-23 interleukin-17 C-reactive protein

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Analysis of Accumulating Clonotypes of T Cell in Joints of a Spontaneous Murine Model of rheumatoid arthritis

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Cellular & Molecular Immunology 2004年第4期1卷 300-303页

作者： WenmingZhao LipingZhang YukageKobari YoshikataMisaki KazuhikoYamamoto DepartmentofImmunology CapitalUniversityofMedicalSciencesBeijingChina. DepartmentofAllergyandRheumatology GraduateSchoolofMedicineUniversityofTokyoJapan.

SKG mouse,as a model of spontaneous rheumatoid arthritis (RA) bred recent years,is similar to the patients with *** analyzed the clonotypes of T cell infiltrating into joints of SKG mice in initial stage and late stage of RA by using reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent single-strand conformation polymorphism (SSCP).The results indicated that the percentages of clonotypes TCR Vβ2 and Vβ8.2 of T cell clonotypes increased obviously to 72.3% and 60.2%,*** number with identical TCR Vβ2 and Vβ8.2 clonotypes also clearly increased in late stage of disease to 100% and 75%,respectively. These results mean that T cells with TCR Vβ2 and Vβ8.2 clonotypes probably play an important role in RA progression of SKG *** of the extracted DNA verified that common bands on SSCP gel were derived from the same T cell clones among samples from different *** results we obtained implied that RT-PCR/SSCP method was a sensitive and credible method for analyzing T cell *** the T cells of SKG mouse were adoptively transferred to a nude mouse,it was verified that the T cells infiltrating into joints were related to morbid formation of *** & Molecular Immunology.2004;1(4):300-303.

关键词： TCR T cell clonotype rheumatoid arthritis RT-PCR SSCP

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