Publications by authors named "Huihua Ding"

24 Publications

  • Page 1 of 1

Efficacy and safety of a selective URAT1 inhibitor SHR4640 in Chinese subjects with hyperuricemia: a randomized controlled phase II study.

Rheumatology (Oxford) 2021 Mar 8. Epub 2021 Mar 8.

Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.

Objectives: To evaluate the efficacy and safety of SHR4640, a highly selective urate transporter 1 inhibitor in Chinese subjects with hyperuricemia.

Methods: This was a randomized double-blind dose-ranging phase II study. Subjects whose serum uric acid levels ≥480 µmol/l with gout, or sUA levels ≥480 µmol/l without gout but with comorbidities, or sUA levels ≥540 µmol/l were enrolled. Subjects were randomly assigned (1:1:1:1:1) to receive once daily 2.5 mg/5 mg/10 mg of SHR4640, 50 mg of benzbromarone, and placebo, respectively. The primary end point was the proportion of subjects achieved target sUA level of ≤ 360 µmol/l at week 5.

Results: About 99.5% of subjects (n = 197) were male and 95.9% of subjects had gout history. The proportions of subjects achieved target sUA at week 5 were 32.5%, 72.5% and 61.5% in 5 mg, 10 mg of SHR4640 and benzbromarone groups, respectively, significantly higher than placebo group (0%; p< 0.05 for 5 mg and 10 mg of SHR4640 group). The sUA was reduced by 32.7%, 46.8% and 41.8% at week 5 with 5 mg, 10 mg of SHR4640 and benzbromarone, respectively, vs placebo (5.9%; p< 0.001 for each comparison). The incidences of gout flares requiring intervention were similar among all groups. Occurrences of treatment-emergent adverse events (TEAEs) were comparable across all groups, and serious TEAEs were not reported.

Conclusions: The present study indicated a superior sUA-lowering effect, and well tolerated safety profile after 5-week treatment with once-daily 5 mg/10 mg of SHR4640 as comparing with placebo in Chinese subjects with hyperuricemia.

Trial Registration: ClinicalTrials.gov number, NCT03185793.
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http://dx.doi.org/10.1093/rheumatology/keab198DOI Listing
March 2021

SLE non-coding genetic risk variant determines the epigenetic dysfunction of an immune cell specific enhancer that controls disease-critical microRNA expression.

Nat Commun 2021 01 8;12(1):135. Epub 2021 Jan 8.

Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, 200001, China.

Since most variants that impact polygenic disease phenotypes localize to non-coding genomic regions, understanding the consequences of regulatory element variants will advance understanding of human disease mechanisms. Here, we report that the systemic lupus erythematosus (SLE) risk variant rs2431697 as likely causal for SLE through disruption of a regulatory element, modulating miR-146a expression. Using epigenomic analysis, genome-editing and 3D chromatin structure analysis, we show that rs2431697 tags a cell-type dependent distal enhancer specific for miR-146a that physically interacts with the miR-146a promoter. NF-kB binds the disease protective allele in a sequence-specific manner, increasing expression of this immunoregulatory microRNA. Finally, CRISPR activation-based modulation of this enhancer in the PBMCs of SLE patients attenuates type I interferon pathway activation by increasing miR-146a expression. Our work provides a strategy to define non-coding RNA functional regulatory elements using disease-associated variants and provides mechanistic links between autoimmune disease risk genetic variation and disease etiology.
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http://dx.doi.org/10.1038/s41467-020-20460-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794586PMC
January 2021

Meta-analysis of 208370 East Asians identifies 113 susceptibility loci for systemic lupus erythematosus.

Ann Rheum Dis 2020 Dec 3. Epub 2020 Dec 3.

Department of Dermatology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.

Objective: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations.

Methods: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations.

Results: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (r=-0.242) and non-albumin protein (r=0.238).

Conclusion: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.
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http://dx.doi.org/10.1136/annrheumdis-2020-219209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053352PMC
December 2020

The utility of urinary biomarker panel in predicting renal pathology and treatment response in Chinese lupus nephritis patients.

PLoS One 2020 27;15(10):e0240942. Epub 2020 Oct 27.

Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Given the urgent need for non-invasive biomarkers of LN, we aim to identify novel urinary biomarkers that facilitate diagnosis, assessment of disease activity and prediction of treatment response in a retrospective SLE cohort. A total of 154 SLE patients and 55 healthy controls were enrolled, among whom 73 were active LN patients. We measured renal activity by renal SLEDAI. The treatment response of the active LN patients who finished 6-month induction therapy was assessed based on the American College of Rheumatology response criteria. The expression levels of 10 urinary biomarkers (UBMs): β2-MG, calbindin D, cystatin C, IL-18, KIM-1, MCP-1, nephrin, NGAL, VCAM-1, and VDBP were tested using Luminex high-throughput proteomics technology. All but urinary nephrin levels were significantly increased in active LN compared to healthy controls. uCystatinC, uMCP-1, uKIM-1 levels were significantly higher in active LN group compared to inactive LN group. Correlation analysis revealed positive correlation between uCystatinC, uKIM-1, uMCP-1, uNGAL, uVDBP and RSLEDAI score. In renal pathology, uCystatinC, uKIM-1, uVCAM-1, and uVDBP positively correlated with activity index (AI) while uVCAM-1 positively correlated with chronicity index (CI). Moreover, the combination of uVCAM-1, uCystatinC, uKIM-1 discriminated proliferative LN from membranous LN with an AUC of 0.80 (95%CI: 0.69-0.90). Most importantly, baseline uNGAL demonstrated good prediction ability to discriminate responders from non-responders in active LN patients after 6-month induction therapy. Using a multiplex bead technique, we have identified the combination of uVCAM-1, uCystatinC, uKIM-1 as a biomarker panel to reflect renal pathology and NGAL as a promising urinary biomarker to both reflect disease activity and predict treatment response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240942PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591050PMC
December 2020

Zirconia Hybrid Nanoshells for Nutrient and Toxin Detection.

Small 2020 11 26;16(46):e2003902. Epub 2020 Oct 26.

State Key Laboratory for Oncogenes and Related Genes, School of Biomedical Engineering, and Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, 200030, P.R. China.

Monitoring milk quality is of fundamental importance in food industry, because of the nutritional value and resulting position of milk in daily diet. The detection of small nutrients and toxins in milk is challenging, considering high sample complexity and low analyte abundance. In addition, the slow analysis and tedious sample preparation hinder the large-scale application of conventional detection techniques. Herein, zirconia hybrid nanoshells are constructed to enhance the performance of laser desorption/ionization mass spectrometry (LDI MS). Zirconia nanoshells with the optimized structures and compositions are used as matrices in LDI MS and achieve direct analysis of small molecules from 5 nL of native milk in ≈1 min, without any purification or separation. Accurate quantitation of small nutrient is achieved by introducing isotope into the zirconia nanoshell-assisted LDI MS as the internal standard, offering good consistency to biochemical analysis (BCA) with R  = 0.94. Further, trace toxin is enriched and identified with limit-of-detection (LOD) down to 4 pm, outperforming the current analytical methods. This work sheds light on the personalized design of material-based tool for real-case bioanalysis and opens up new opportunities for the simple, fast, and cost-effective detection of various small molecules in a broad field.
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http://dx.doi.org/10.1002/smll.202003902DOI Listing
November 2020

Long non-coding RNA expression profiles in neutrophils revealed potential biomarker for prediction of renal involvement in SLE patients.

Rheumatology (Oxford) 2021 Apr;60(4):1734-1746

Department of Rheumatology, Renji Hospital, Shanghai Institute of Rheumatology, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Objective: The long non-coding RNA plays an important role in inflammation and autoimmune diseases. The aim of this study is to screen and identify abnormally expressed lncRNAs in peripheral blood neutrophils of SLE patients as novel biomarkers and to explore the relationship between lncRNAs levels and clinical features, disease activity and organ damage.

Methods: RNA-seq technology was used to screen differentially expressed lncRNAs in neutrophils from SLE patients and healthy donors. Based on the results of screening, candidate lncRNA levels in neutrophils of 88 SLE patients, 35 other connective disease controls, and 78 healthy controls were qualified by real-time quantitative polymerase chain reaction.

Results: LncRNA expression profiling revealed 360 up-regulated lncRNAs and 224 down-regulated lncRNAs in neutrophils of SLE patients when compared with healthy controls. qPCR assay validated that the expression of Lnc-FOSB-1:1 was significantly decreased in neutrophils of SLE patients when compared with other CTD patients or healthy controls. It correlated negatively with SLE Disease Activity Index 2000 (SLEDAI-2K) score (r = -0.541, P < 0.001) and IFN scores (r = -0.337, P = 0.001). More importantly, decreased Lnc-FOSB-1:1 expression was associated with lupus nephritis. Lower baseline Lnc-FOSB-1:1 level was associated with higher risk of future renal involvement (within an average of 2.6 years) in patients without renal disease at baseline (P = 0.019).

Conclusion: LncRNA expression profile in neutrophils of SLE patients revealed differentially expressed lncRNAs. Validation study on Lnc-FOSB-1:1 suggest that it is a potential biomarker for prediction of near future renal involvement.
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http://dx.doi.org/10.1093/rheumatology/keaa575DOI Listing
April 2021

Taurine Metabolism Aggravates the Progression of Lupus by Promoting the Function of Plasmacytoid Dendritic Cells.

Arthritis Rheumatol 2020 12 25;72(12):2106-2117. Epub 2020 Oct 25.

Shanghai Institute of Rheumatology, State Key Laboratory of Oncogenes and Related Genes, and Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China, and Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China, and Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, and University of Cincinnati College of Medicine, Cincinnati, Ohio, United States.

Objective: Type I interferons (IFNs) are critical in the development of systemic lupus erythematosus (SLE). Metabolic abnormalities cause dysregulation of multiple immune cells, but the metabolic regulation of type I IFN production is not well clarified in SLE. We undertook this study to define amino acid metabolism features in SLE and to explore the function of disease-relevant metabolites in the control of plasmacytoid dendritic cell (pDC)-mediated type I IFN production and the progression of SLE.

Methods: Metabolomic profiling of the serum from SLE patients and healthy controls was performed by mass spectrometry. The effects of SLE-related metabolites on type I IFN production were explored in human and mouse pDCs. The reactive oxygen species (ROS) levels of pDCs from wild-type and Ncf1 mice were measured by flow cytometry. Mechanisms were investigated by RNA sequencing and immunoblotting. In vivo effects of SLE-relevant metabolites were systemically analyzed in B6.Cg-Sle1 Yaa/DcrJ mice.

Results: Taurine was higher in the serum from SLE patients compared to healthy controls (P < 0.001) and rheumatoid arthritis patients (P < 0.001). Taurine content was positively correlated with disease activity and the expression of IFN signature genes. The addition of taurine facilitated IFN regulatory factor 7 phosphorylation and enhanced type I IFN production by reducing the ROS levels in pDCs in a neutrophil cytosolic factor 1-dependent manner. Taurine supplementation promoted expression of type I IFN-induced genes, activated lymphocytes, and increased autoantibodies and proteinuria, leading to more serious nephritis.

Conclusion: Taurine metabolism is involved in the development of SLE by enhancing pDC-mediated type I IFN production. Targeted inhibition of taurine or implementation of a taurine-restricted diet has therapeutic potential in SLE.
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http://dx.doi.org/10.1002/art.41419DOI Listing
December 2020

Urinary activated leukocyte cell adhesion molecule as a novel biomarker of lupus nephritis histology.

Arthritis Res Ther 2020 05 27;22(1):122. Epub 2020 May 27.

Department of Rheumatology, Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 145 Shandong (M) Rd, Shanghai, 200001, China.

Background: Lupus nephritis (LN) is one of the most severe complications of SLE patients. We aim to validate urinary ALCAM as a biomarker in predicting renal disease histpathology in a Chinese lupus cohort.

Methods: In this cross-sectional study, a total of 256 patients and controls were recruited. Urinary levels of ALCAM were determined by ELISA. Renal histopathology was reviewed by an experienced renal pathologist.

Results: Urinary ALCAM levels were significantly increased in active LN patients when compared to active SLE patients without renal involvement (p < 0.001), inactive LN patients (p = 0.023), inactive SLE patients without renal involvement (p < 0.001), and healthy controls (p < 0.001). Correlation analysis revealed a positive correlation between urinary ALCAM and general disease activity-SLEDAI score (r = 0.487, p < 0.001), as well as renal disease activity-rSLEDAI (r = 0.552, p < 0.001) and SLICC RAS (r = 0.584, p < 0.001). Urinary ALCAM also correlated with lab parameters including 24-h urine protein, hemoglobin, and complement 3. Moreover, urinary ALCAM levels were significantly increased in class III and IV (proliferative) LN as compared to those in class V (membranous) LN. It outperformed conventional biomarkers (anti-dsDNA antibody, C3, C4, proteinuria) in discriminating the two groups of LN. On renal histopathology, urinary ALCAM levels correlated positively with activity index (r = 0.405, p < 0.001) but not chronicity index (r = 0.079, p = 0.448).

Conclusion: Urinary ALCAM is a potential biomarker for predicting renal pathology activity in LN and may serve as a valuable surrogate marker of renal histopathology.
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http://dx.doi.org/10.1186/s13075-020-02209-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251704PMC
May 2020

Spermidine Suppresses Inflammatory DC Function by Activating the FOXO3 Pathway and Counteracts Autoimmunity.

iScience 2020 Jan 27;23(1):100807. Epub 2019 Dec 27.

Shanghai Institute of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), 145 Shan Dong Middle Road, Shanghai 200001, China; Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen 518040, China; Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai 200032, China. Electronic address:

Dendritic cells (DCs) function is intimately linked to microenvironment and metabolism. Type I interferons (IFNs) condition dendritic cells to respond to weak self-signals, leading to autoimmunity. However, the metabolic adaption in the process is unclear. Here, we identified spermidine as a critical metabolite impacting the metabolic fitness of DC. First, dynamic metabolome screening indicated that spermidine decreased during IFN priming and following TLR7 ligand stimulation, accompanied by metabolic change from oxidative phosphorylation to glycolysis. Second, spermidine supplement restrained the glycolysis and prevented the overactivation of IFN-α primed DC both in vivo and in vitro. Third, mechanism study uncovered that the activity of FOXO3 adapted to the metabolic change, mediating the anti-inflammatory effect of spermidine. More importantly, addition of spermidine in vivo greatly alleviated the development of psoriasis-like symptom in mice. Thus, our studies revealed metabolic changes boosting DC responses and identified spermidine as a potential therapeutic agent for autoimmune diseases.
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http://dx.doi.org/10.1016/j.isci.2019.100807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971394PMC
January 2020

Correction to: Urinary pro-thrombotic, anti-thrombotic, and fibrinolytic molecules as biomarkers of lupus nephritis.

Arthritis Res Ther 2019 Aug 7;21(1):185. Epub 2019 Aug 7.

Department of Biomedical Engineering, University of Houston, 3605 Cullen Boulevard, Houston, TX, 77204, USA.

Following publication of the original article [1], it was brought to our attention that the fifth author's name was incorrectly published. The original article [1] is corrected.
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http://dx.doi.org/10.1186/s13075-019-1966-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685224PMC
August 2019

Low dose Epigallocatechin Gallate Alleviates Experimental Colitis by Subduing Inflammatory Cells and Cytokines, and Improving Intestinal Permeability.

Nutrients 2019 Jul 29;11(8). Epub 2019 Jul 29.

Department of Biomedical Engineering, University of Houston, Houston 77204, TX, USA.

Background: In this study, we investigate the impact of epigallocatechin gallate (EGCG), the most abundant and potent catechin in green tea, on a mouse model of inflammatory bowel disease (IBD) and the underlying mechanisms of action.

Methods: C57BL/6J mice were subjected to dextran sulfate sodium (DSS)-induced IBD-like disease and then randomly divided into three groups: Model group (MD), low-dose EGCG group (LE, 20 mg/kg/d), and high-dose EGCG group (HE, 50 mg/kg/d). DSS-induced clinical and macroscopic changes were monitored daily. Intestinal permeability was assessed by FITC-Dextran assay.

Results: Both high- and low-dose EGCG treatment alleviated clinical manifestations including body weight loss and disease activity index (DAI) of DSS-induced colitis. The DAI score was significantly improved after two days of EGCG treatment. At the end of the study, the macroscopic severity score (MSS) of HE and LE treatment groups were 2.4 ± 1.2, and 2.2 ± 1.0, respectively, significantly lower than that of the controls (5.0 ± 2.1). EGCG treatment also prevented colon shortening, and improved intestinal permeability and histopathological changes. In addition, EGCG treatment attenuated colon inflammation by suppressing colonic levels of pro-inflammatory cytokines IL-6, MCP-1, and TNF-alpha, and inhibited CD3+ T cell and CD68+ macrophage infiltration.

Conclusion: EGCG is effective in inflammatory colitis because it reduces cellular and molecular inflammation, and reduces intestinal permeability.
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http://dx.doi.org/10.3390/nu11081743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724056PMC
July 2019

Urinary pro-thrombotic, anti-thrombotic, and fibrinolytic molecules as biomarkers of lupus nephritis.

Arthritis Res Ther 2019 07 18;21(1):176. Epub 2019 Jul 18.

Department of Biomedical Engineering, University of Houston, 3605 Cullen Boulevard, Houston, TX, 77204, USA.

Objective: This study evaluates the utility of urinary pro-thrombotic molecules such as tissue factor (TF), anti-thrombotic molecules such as tissue factor pathway inhibitor (TFPI), and fibrinolytic molecules such as plasmin and d-dimer as biomarkers of lupus nephritis (LN).

Methods: Urine samples from 113 biopsy-proven LN patients (89 active LN and 24 inactive LN), 45 chronic kidney disease patients, and 41 healthy controls were examined for d-dimer, plasmin, TF, and TFPI levels by ELISA. The area under the receiver operating characteristic curve (AUC) analysis, multivariate regression analysis, and Bayesian network analysis were performed to assess the diagnostic value of the assayed molecules in LN.

Results: Although urinary d-dimer, plasmin, TF, and TFPI were all elevated in active LN compared to all control groups, and correlated with rSLEDAI and SLICC RAS disease activity indices, urine plasmin emerged as the strongest independent predictor of eGFR and renal disease status, by multivariate regression analysis and Bayesian network analysis. Whereas urine plasmin discriminated active LN from inactive disease with an AUC of 0.84, the combination of urine plasmin and TFPI discriminated ALN from ILN with an AUC of 0.86, with both surpassing the specificity and positive predictive value of traditional markers such as anti-dsDNA and complement C3.

Conclusion: Both thrombogenic and thrombolytic cascades appear to be upregulated in lupus nephritis, with proteins from both cascades appearing in the urine. Of the coagulation cascade proteins surveyed, urine plasmin emerges as the strongest predictor of eGFR and clinical renal disease in patients with LN.
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http://dx.doi.org/10.1186/s13075-019-1959-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637532PMC
July 2019

Identification of Renal Long Non-coding RNA RP11-2B6.2 as a Positive Regulator of Type I Interferon Signaling Pathway in Lupus Nephritis.

Front Immunol 2019 3;10:975. Epub 2019 May 3.

Shanghai Institute of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Lupus nephritis (LN) is one of the most serious complications of systemic lupus erythematosus (SLE). Type I interferon (IFN-I) is associated with the pathogenesis of LN. Long non-coding RNAs (lncRNAs) have been implicated in the pathogenesis of SLE, however, the roles of lncRNAs in LN are still poorly understood. Here, we identified and investigated the function of LN-associated lncRNA RP11-2B6.2 in regulating IFN-I signaling pathway. RNA sequencing was used to analyze the expression of lncRNAs in kidney biopsies from LN patients and controls. Antisense oligonucleotides and CRISPRi system or overexpression plasmids and CRISPRa system were used to perform loss or gain of function experiments. hybridization, imaging flow cytometry, dual-luciferase reporter assay, and ATAC sequencing were used to study the functions of lncRNA RP11-2B6.2. RT-qPCR, ELISA, and western blotting were done to detect RNA and protein levels of specific genes. Elevated lncRNA RP11-2B6.2 was observed in kidney biopsies from LN patients and positively correlated with disease activity and IFN scores. Knockdown of lncRNA RP11-2B6.2 in renal cells inhibited the expression of IFN stimulated genes (ISGs), while overexpression of lncRNA RP11-2B6.2 enhanced ISG expression. Knockdown of LncRNA RP11-2B6.2 inhibited the phosphorylation of JAK1, TYK2, and STAT1 in IFN-I pathway, while promoted the chromatin accessibility and the transcription of SOCS1. The expression of lncRNAs is abnormal in the kidney of LN. LncRNA RP11-2B6.2 is a novel positive regulator of IFN-I pathway through epigenetic inhibition of SOCS1, which provides a new therapeutic target to alleviate over-activated IFN-I signaling in LN.
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http://dx.doi.org/10.3389/fimmu.2019.00975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509587PMC
October 2020

Structure and Degradation of Circular RNAs Regulate PKR Activation in Innate Immunity.

Cell 2019 05 25;177(4):865-880.e21. Epub 2019 Apr 25.

State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China. Electronic address:

Circular RNAs (circRNAs) produced from back-splicing of exons of pre-mRNAs are widely expressed, but current understanding of their functions is limited. These RNAs are stable in general and are thought to have unique structural conformations distinct from their linear RNA cognates. Here, we show that endogenous circRNAs tend to form 16-26 bp imperfect RNA duplexes and act as inhibitors of double-stranded RNA (dsRNA)-activated protein kinase (PKR) related to innate immunity. Upon poly(I:C) stimulation or viral infection, circRNAs are globally degraded by RNase L, a process required for PKR activation in early cellular innate immune responses. Augmented PKR phosphorylation and circRNA reduction are found in peripheral blood mononuclear cells (PBMCs) derived from patients with autoimmune disease systemic lupus erythematosus (SLE). Importantly, overexpression of the dsRNA-containing circRNA in PBMCs or T cells derived from SLE can alleviate the aberrant PKR activation cascade, thus providing a connection between circRNAs and SLE.
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http://dx.doi.org/10.1016/j.cell.2019.03.046DOI Listing
May 2019

Serum Axl predicts histology-based response to induction therapy and long-term renal outcome in lupus nephritis.

PLoS One 2019 11;14(2):e0212068. Epub 2019 Feb 11.

Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

Axl is a receptor tyrosine kinase with important functions in immune regulation. We investigated serum levels of soluble (s)Axl in lupus nephritis (LN) in association with renal disease activity, tissue damage and treatment response. We surveyed 52 patients with International Society of Nephrology/Renal Pathology Society (ISN/RPS) class III/IV LN and 20 healthy controls. Renal biopsies were performed at the time of active LN and post-treatment. Patients were classified as clinical responders (CRs) or clinical non-responders based on the American College of Rheumatology (ACR) criteria. Improvement by ≥50% in renal activity index scores defined histological responders (HRs). sAxl levels were elevated in patients compared to controls (median: 18.9 ng/mL), both at baseline (median: 45.7; P<0.001) and post-treatment (median: 41.2 ng/mL; P<0.001). Baseline sAxl levels were higher in patients with class IV (median: 47.7 ng/mL) versus class III (median: 37.5 ng/mL) nephritis (P = 0.008), and showed moderate correlations with albuminuria (r = 0.30, P = 0.030) and creatinine (r = 0.35, P = 0.010). Baseline sAxl levels decreased in CRs (P = 0.002) and HRs (P<0.001), but not in non-responders; levels ≥36.6 ng/mL yielded a >5 times higher probability of histology-based response (odds ratio, OR: 5.5; 95% confidence interval, CI: 1.2-25.1). High post-treatment sAxl levels were associated with worsening in chronicity index scores (P = 0.025); low levels predicted favourable renal outcome (creatinine ≤88.4 μmol/L) 10 years after the baseline renal biopsy (area under the curve: 0.71; 95% CI: 0.54-0.89). In conclusion, sAxl may prove useful as a marker of renal activity, histological response to immunosuppression, and renal damage progression in LN. Persistently high sAxl levels after completion of treatment may be indicative of a need for treatment intensification.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0212068PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370217PMC
November 2019

Bradykinin 1 receptor blockade subdues systemic autoimmunity, renal inflammation, and blood pressure in murine lupus nephritis.

Arthritis Res Ther 2019 01 8;21(1):12. Epub 2019 Jan 8.

Department of Nephrology & Rheumatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.

Objective: The goal of this study was to explore the role of bradykinins and bradykinin 1 receptor (B1R) in murine lupus nephritis.

Methods: C57BL/6 and MRL/lpr mice were compared for renal expression of B1R and B2R by western blot and immunohistochemistry. MRL/lpr lupus-prone mice were administered the B1R antagonist, SSR240612 for 12 weeks, and monitored for blood pressure, proteinuria, renal function, and serum autoantibodies.

Results: Renal B1R:B2R ratios were significantly upregulated in MRL/lpr mice compared with B6 controls. B1R blockade ameliorated renal pathology lesions, proteinuria, and blood pressure, accompanied by lower serum IgG and anti-dsDNA autoantibody levels, reduced splenic marginal zone B cells and CD4 T cells, and renal infiltrating CD4 T cells, macrophages, and neutrophils. Both urine and renal CCL2 and CCL5 chemokines were also decreased in the B1R blocked MRL/lpr mice.

Conclusion: Bradykinin receptor B1R blockade ameliorates both systemic immunity and renal inflammation possibly by inhibiting multiple chemokines and renal immune cell infiltration. B1R blockade may be particularly attractive in subjects with concomitant lupus nephritis and hypertension.
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http://dx.doi.org/10.1186/s13075-018-1774-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325757PMC
January 2019

Insulin-Like Growth Factor Binding Proteins in Autoimmune Diseases.

Front Endocrinol (Lausanne) 2018 30;9:499. Epub 2018 Aug 30.

Department of Biomedical Engineering, University of Houston, Houston, TX, United States.

Insulin-like growth factor binding proteins (IGFBPs) are a family of proteins binding to Insulin-like growth factors (IGFs), generally including IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP5, and IGFBP6. The biological functions of IGFBPs can be classified as IGFs-dependent actions and IGFs-independent effects. In this review, we will discuss the structure and function of various IGFBPs, particularly IGFBPs as potential emerging biomarkers and therapeutic targets in various autoimmune diseases, and the possible mechanisms by which IGFBPs act on the pathogenesis of autoimmune diseases.
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http://dx.doi.org/10.3389/fendo.2018.00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125368PMC
August 2018

Association of Abnormal Elevations in IFIT3 With Overactive Cyclic GMP-AMP Synthase/Stimulator of Interferon Genes Signaling in Human Systemic Lupus Erythematosus Monocytes.

Arthritis Rheumatol 2018 12 14;70(12):2036-2045. Epub 2018 Oct 14.

Shanghai Institute of Rheumatology, and China-Australia Centre for Personalised Immunology, Renji Hospital, School of Medicine, and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Objective: Increasing evidence indicates that the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway has a critical pathogenic role in systemic lupus erythematosus (SLE). Expression levels of the interferon (IFN)-inducible gene IFIT3 are elevated in SLE patients. However, it is still not clear how IFIT3 contributes to the pathogenesis of SLE. This study was undertaken to investigate the activation of the cGAS/STING signaling pathway in human SLE monocytes, and to determine how elevated expression of IFIT3 could contribute to overactive cGAS/STING signaling in patients with SLE.

Methods: Monocytes from SLE patients or healthy controls were examined for activity of the cGAS/STING signaling pathway and expression levels of IFIT3. Correlations between cGAS/STING signaling activity and SLE clinical features were analyzed. Gain- or loss-of-function experiments were used to determine the role of IFIT3 in cGAS/STING signaling. Coimmunoprecipitation assays were used to identify the interaction between IFIT3 and other proteins.

Results: The cGAS/STING signaling pathway was found to have enhanced activity in monocytes from SLE patients compared to healthy controls, as indicated by the higher expression of IFNβ downstream. Levels of IFIT3 were significantly elevated in human SLE monocytes, and this was positively correlated with the activity of the cGAS/STING signaling pathway. In vitro, the expression of VACV70-induced IFNβ was reduced by knockdown of IFIT3, whereas overexpression of IFIT3 produced an opposite effect. Finally, IFIT3 was found to interact with both STING and TANK-binding kinase 1.

Conclusion: These findings suggest that IFIT3 is one of the genes that contributes to the overactive cGAS/STING signaling pathway in human SLE monocytes. IFIT3 may therefore serve as a novel therapeutic target for blocking the production of type I IFN and other proinflammatory cytokines by the cGAS/STING signaling pathway in patients with SLE.
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http://dx.doi.org/10.1002/art.40576DOI Listing
December 2018

Connective tissue diseases: Promises and challenges of metabolomics in SLE.

Nat Rev Rheumatol 2016 11 6;12(11):627-628. Epub 2016 Oct 6.

Department of Biomedical Engineering, University of Houston, 3605 Cullen Boulevard, Houston, Texas 77204, USA.

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http://dx.doi.org/10.1038/nrrheum.2016.163DOI Listing
November 2016

The association between reduced folate carrier-1 gene 80G/A polymorphism and methotrexate efficacy or methotrexate related-toxicity in rheumatoid arthritis: A meta-analysis.

Int Immunopharmacol 2016 Sep 24;38:8-15. Epub 2016 May 24.

Department of Biomedical Engineering, University of Houston, Houston, TX, USA. Electronic address:

Methotrexate (MTX), the most commonly used anti-rheumatic drug against RA, enters the cell via the action of the reduced folate carrier 1(RFC1). A major polymorphism of the RFC1 gene, 80G/A, has been reported to influence the activity of RFC1, resulting in variable intracellular MTX-polyglutamate (MTX-PG) levels. However, the association studies addressing the RFC1 80G/A polymorphism and MTX efficacy or toxicity in Rheumatoid arthritis (RA) has yielded conflicting results. In the present meta-analysis, we aimed to evaluate the association between the RFC1 80G/A polymorphism and MTX efficacy or toxicity in RA patients. A total 17 studies met our inclusion criteria. Among them, 12 studies with 2049 subjects reported the association between the RFC1 80G/A and MTX response, and 12 studies involving 2627 subjects were on MTX-related toxicity. Meta-analysis revealed significant association between RFC1 80G/A polymorphism and MTX efficacy (odds ratio (OR) for the A allele=1.29, 95% confidence interval (CI) 1.05-1.67, P=0.02; for AA genotype: OR=1.49, 95%CI 1.17-1.907, P=0.001). However, no association could be detected in the analysis of MTX-related toxicity. Stratification by ethnic population also indicated an association between this polymorphism and MTX efficacy in Asian group (P=0.002 for A allele; P=0.003 for AA genotype), but not in the Caucasian group (P=0.15 for A allele; P=0.05 for AA genotype). In both Asian and Caucasian sub-groups, no influence of the RFC1 80G/A polymorphism on MTX toxicity can be detected. In conclusion, the RFC1 G80A polymorphism is associated with responsiveness to MTX therapy, but may not be associated with MTX toxicity in RA patients.
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http://dx.doi.org/10.1016/j.intimp.2016.05.012DOI Listing
September 2016

Antibody-Array-Based Proteomic Screening of Serum Markers in Systemic Lupus Erythematosus: A Discovery Study.

J Proteome Res 2016 07 7;15(7):2102-14. Epub 2016 Jun 7.

Department Biomedical Engineering, University of Houston , Houston, Texas 77204, United States.

A discovery study was carried out where serum samples from 22 systemic lupus erythematosus (SLE) patients and matched healthy controls were hybridized to antibody-coated glass slide arrays that interrogated the level of 274 human proteins. On the basis of these screens, 48 proteins were selected for ELISA-based validation in an independent cohort of 28 SLE patients. Whereas AXL, ferritin, and sTNFRII were significantly elevated in patients with active lupus nephritis (LN) relative to SLE patients who were quiescent, other molecules such as OPN, sTNFRI, sTNFRII, IGFBP2, SIGLEC5, FAS, and MMP10 exhibited the capacity to distinguish SLE from healthy controls with ROC AUC exceeding 90%, all with p < 0.001 significance. These serum markers were next tested in a cohort of 45 LN patients, where serum was obtained at the time of renal biopsy. In these patients, sTNFRII exhibited the strongest correlation with eGFR (r = -0.50, p = 0.0014) and serum creatinine (r = 0.57, p = 0.0001), although AXL, FAS, and IGFBP2 also correlated with these clinical measures of renal function. When concurrent renal biopsies from these patients were examined, serum FAS, IGFBP2, and TNFRII showed significant positive correlations with renal pathology activity index, while sTNFRII displayed the highest correlation with concurrently scored renal pathology chronicity index (r = 0.57, p = 0.001). Finally, in a longitudinal cohort of seven SLE patients examined at ∼3 month intervals, AXL, ICAM-1, IGFBP2, SIGLEC5, sTNFRII, and VCAM-1 demonstrated the ability to track with concurrent disease flare, with significant subject to subject variation. In summary, serum proteins have the capacity to identify patients with active nephritis, flares, and renal pathology activity or chronicity changes, although larger longitudinal cohort studies are warranted.
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http://dx.doi.org/10.1021/acs.jproteome.5b00905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193538PMC
July 2016

Insulin-Like Growth Factor Binding Protein-4 as a Marker of Chronic Lupus Nephritis.

PLoS One 2016 28;11(3):e0151491. Epub 2016 Mar 28.

Department of Biomedical Engineering, University of Houston, Houston, Texas, United States of America.

Kidney biopsy remains the mainstay of Lupus Nephritis (LN) diagnosis and prognostication. The objective of this study is to identify non-invasive biomarkers that closely parallel renal pathology in LN. Previous reports have demonstrated that serum Insulin-like growth factor binding protein 4 (IGFBP-4) was increased in diabetic nephropathy in both animal models and patients. We proceeded to assess if IGFBP4 could be associated with LN. We performed ELISA using the serum of 86 patients with LN. Normal healthy adults (N = 23) and patients with other glomerular diseases (N = 20) served as controls. Compared to the healthy controls or other glomerular disease controls, serum IGFBP-4 levels were significantly higher in the patients with LN. Serum IGFBP-4 did not correlate well with systemic lupus erythematosus disease activity index (SLEDAI), renal SLEDAI or proteinuria, but it did correlate with estimated glomerular filtration rate (R = 0.609, P < 0.0001). Interestingly, in 18 patients with proliferative LN whose blood samples were obtained at the time of renal biopsy, serum IGFBP-4 levels correlated strongly with the chronicity index of renal pathology (R = 0.713, P < 0.001). IGFBP-4 emerges a potential marker of lupus nephritis, reflective of renal pathology chronicity changes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151491PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809566PMC
August 2016

Evaluation of interferon-gamma release assay (T-SPOT.TB(™) ) for diagnosis of tuberculosis infection in rheumatic disease patients.

Int J Rheum Dis 2016 Jan 13;19(1):38-42. Epub 2015 Oct 13.

Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Aim: Patients with rheumatic diseases are at higher risk of developing tuberculosis (TB). The objective of this prospective study was to evaluate the T-SPOT.TB assay (T cell enzyme-linked immuno-spot assay), for the diagnosis of tuberculosis infection in rheumatic disease patients in China.

Methods: Prospectively enrolled patients came from the Department of Rheumatology, Renji Hospital, Shanghai Jiao Tong University School of Medicine between July 2008 and Aug 2012 for TB screening. Subjects' histories of TB infection, previous TB contact or bacille Calmette-Guérin vaccination and concurrent immunosuppressive therapy, were reviewed carefully and recorded in detail. TST (tuberculin skin test) and TSPOT.TB assay were performed on the subjects. A prospective evaluation by Chi-square test was used for sensitivity and specificity of both TST and T-SPOT assay.

Results: A total of 311 subjects included 114 (36.66%) male and 197 (63.34%) female subjects, with a median age of 37.7 ± 12.6 years (range 17-72). Thirty-two patients (10.29%) had a history of TB infection or previous TB contact; 256 patients (82.32%) were using glucocorticoids or immunosuppressants; 28 patients (9.0%) were clinically diagnosed as having TB infection. The sensitivity and specificity of TST for TB screening in rheumatic disease patients was 81.82% (9/11) and 67% (67/100), respectively. However, the sensitivity and specificity of T-SPOT assay was statistically higher at 92.86% (26/28) and 93.64% (265/283), respectively (P < 0.05).

Conclusion: As a new immunoassay for TB diagnosis, the sensitivity and specificity of T-SPOT is higher than TST. It is of great importance in the diagnosis of active or latent TB infection in rheumatic disease patients.
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http://dx.doi.org/10.1111/1756-185X.12772DOI Listing
January 2016

Fatty Acid Amide Hydrolase Regulates Peripheral B Cell Receptor Revision, Polyreactivity, and B1 Cells in Lupus.

J Immunol 2016 Feb 15;196(4):1507-16. Epub 2016 Jan 15.

Division of Rheumatic Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Biomedical Engineering, University of Houston, Houston, TX 77204; Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; and

C57BL/6 mice bearing the Sle2(z) lupus-susceptibility congenic interval on chromosome 4 display high titers of polyclonal autoantibodies with generalized B cell hyperactivity, hallmarks of systemic lupus erythematosus. In B6.Sle2(z)HEL(Ig).sHEL BCR-transgenic mice, Sle2(z) did not breach central tolerance, but it led to heightened expression of endogenous Ig H and L chains in splenic B cells, upregulation of RAG, and serological polyreactivity, suggestive of excessive receptor revision. Fatty acid amide hydrolase (FAAH), a gene in the minimal subcongenic interval generated through recombinant mapping, was found to be upregulated in Sle2(z) B cells by microarray analysis, Western blot, and functional assays. Pharmacological inhibition of FAAH reversed the increase in receptor revision, RAG expression, and polyreactive autoantibodies in lupus-prone mice. These studies indicate that increased peripheral BCR revision, or selective peripheral expansion of BCR-revised B cells, may lead to systemic autoimmunity and that FAAH is a lupus-susceptibility gene that might regulate this process.
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http://dx.doi.org/10.4049/jimmunol.1500291DOI Listing
February 2016