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1.
Int J Mol Sci ; 22(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206009

RESUMO

Toll-like receptor (TLR) signaling plays a critical role in the induction and progression of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematous, experimental autoimmune encephalitis, type 1 diabetes mellitus and neurodegenerative diseases. Deciphering antigen recognition by antibodies provides insights and defines the mechanism of action into the progression of immune responses. Multiple strategies, including phage display and hybridoma technologies, have been used to enhance the affinity of antibodies for their respective epitopes. Here, we investigate the TLR4 antibody-binding epitope by computational-driven approach. We demonstrate that three important residues, i.e., Y328, N329, and K349 of TLR4 antibody binding epitope identified upon in silico mutagenesis, affect not only the interaction and binding affinity of antibody but also influence the structural integrity of TLR4. Furthermore, we predict a novel epitope at the TLR4-MD2 interface which can be targeted and explored for therapeutic antibodies and small molecules. This technique provides an in-depth insight into antibody-antigen interactions at the resolution and will be beneficial for the development of new monoclonal antibodies. Computational techniques, if coupled with experimental methods, will shorten the duration of rational design and development of antibody therapeutics.


Assuntos
Anticorpos Monoclonais/imunologia , Artrite Reumatoide/imunologia , Encefalite/imunologia , Epitopos/genética , Doença de Hashimoto/imunologia , Doenças Neurodegenerativas/imunologia , Receptor 4 Toll-Like/genética , Sequência de Aminoácidos/genética , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Técnicas de Visualização da Superfície Celular , Encefalite/genética , Encefalite/patologia , Mapeamento de Epitopos/métodos , Epitopos/imunologia , Doença de Hashimoto/genética , Doença de Hashimoto/patologia , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Ligação Proteica/genética , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/imunologia
2.
J Biol Regul Homeost Agents ; 35(3): 921-931, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34212684

RESUMO

Abnormal osteoclast formation plays a significant part in rheumatoid arthritis (RA). As potent therapeutic biomarkers, microRNAs (miRNAs) have obtained increasing attention. Recently, treatment regimens regarding miRNAs have been implicated in skeletal diseases. The aim of this study is to assess the expression and function of miR-20a during osteoclast proliferation and differentiation and its correlation with bone erosion in RA mice. The expression of miR-20a was observed to be diminished in the ankle tissues of RA mice relative to that in normal controls evaluated by RT-qPCR. Hematoxylin and eosin staining, Safranin O-fast green staining, and tartrateresistant acid phosphatase staining were used to evaluate the effects of miR-20a on RA symptoms. The proliferation and differentiation of osteoclasts, and bone erosion were repressed by agomiR-20a injection. 3'UTR luciferase reporter assays were conducted to validate the putative binding between miR-20a and receptor activation of nuclear factor-κB ligand (RANKL). The protein expression and phosphorylation level of toll-like receptor4 (TLR4)/p38 pathway-related factors were detected by Western blot. miR-20a inhibited proliferation and differentiation potentials to osteoclasts partly through the TLR4/p38 pathway. The current work provides evidence that miR-20a hinders proliferation and differentiation of osteoclasts by targeting RANKL through the TLR4/p38 pathway.


Assuntos
Artrite Reumatoide , MicroRNAs , Animais , Artrite Reumatoide/genética , Diferenciação Celular , Ligantes , Camundongos , MicroRNAs/genética , NF-kappa B , Osteoclastos , Osteogênese , Ligante RANK/genética , Receptor 4 Toll-Like/genética
3.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073629

RESUMO

Rheumatoid arthritis (RA) is a typical autoimmune-mediated rheumatic disease presenting as a chronic synovitis in the joint. The chronic synovial inflammation is characterized by hyper-vascularity and extravasation of various immune-related cells to form lymphoid aggregates where an intimate cross-talk among innate and adaptive immune cells takes place. These interactions facilitate production of abundant proinflammatory cytokines, chemokines and growth factors for the proliferation/maturation/differentiation of B lymphocytes to become plasma cells. Finally, the autoantibodies against denatured immunoglobulin G (rheumatoid factors), EB virus nuclear antigens (EBNAs) and citrullinated protein (ACPAs) are produced to trigger the development of RA. Furthermore, it is documented that gene mutations, abnormal epigenetic regulation of peptidylarginine deiminase genes 2 and 4 (PADI2 and PADI4), and thereby the induced autoantibodies against PAD2 and PAD4 are implicated in ACPA production in RA patients. The aberrant expressions of non-coding RNAs (ncRNAs) including microRNAs (miRs) and long non-coding RNAs (lncRNAs) in the immune system undoubtedly derange the mRNA expressions of cytokines/chemokines/growth factors. In the present review, we will discuss in detail the expression of these ncRNAs and their target molecules participating in developing RA, and the potential biomarkers for the disease, its diagnosis, cardiovascular complications and therapeutic response. Finally, we propose some prospective investigations for unraveling the conundrums of rheumatoid pathogenesis.


Assuntos
Artrite Reumatoide/metabolismo , Epigênese Genética , Regulação Enzimológica da Expressão Gênica , Proteína-Arginina Desiminase do Tipo 2/biossíntese , Proteína-Arginina Desiminase do Tipo 4/biossíntese , RNA Longo não Codificante/biossíntese , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Artrite Reumatoide/terapia , Humanos , Proteína-Arginina Desiminase do Tipo 2/genética , Proteína-Arginina Desiminase do Tipo 4/genética , RNA Longo não Codificante/genética
4.
Autoimmun Rev ; 20(8): 102866, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34118460

RESUMO

Circadian rhythm is a natural, endogenous process whose physiological functions are controlled by a set of clock genes. Disturbance of the clock genes have detrimental effects on both innate and adaptive immunity, which significantly enhance pro-inflammatory responses and susceptibility to autoimmune diseases via strictly controlling the individual cellular components of the immune system that initiate and perpetuate the inflammation pathways. Autoimmune diseases, especially rheumatoid arthritis (RA), often exhibit substantial circadian oscillations, and circadian rhythm is involved in the onset and progression of autoimmune diseases. Mounting evidence indicate that the synthetic ligands of circadian clock genes have the property of reducing the susceptibility and clinical severity of subjects. This review supplies an overview of the roles of circadian clock genes in the pathology of autoimmune diseases, including BMAL1, CLOCK, PER, CRY, REV-ERBα, and ROR. Furthermore, summarized some circadian clock genes as candidate genes for autoimmune diseases and current advancement on therapy of autoimmune diseases with synthetic ligands of circadian clock genes. The existing body of knowledge demonstrates that circadian clock genes are inextricably linked to autoimmune diseases. Future research should pay attention to improve the quality of life of patients with autoimmune diseases and reduce the effects of drug preparation on the normal circadian rhythms.


Assuntos
Artrite Reumatoide , Relógios Circadianos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Relógios Circadianos/genética , Ritmo Circadiano/genética , Humanos , Qualidade de Vida
5.
Gen Physiol Biophys ; 40(3): 207-219, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34100377

RESUMO

Circular RNAs (circRNAs) are related to rheumatoid arthritis (RA) development. However, the function and mechanism of circRNA pituitary tumor-transforming 1 interacting protein (circ- PTTG1IP) in RA are unknown. The expression of circ-PTTG1IP in synovial tissues of RA patients and fibroblast-like synoviocytes from RA patients (RA-FLSs) were detected by RT-qPCR. The results uncovered that circ-PTTG1IP was overexpressed in RA patients and RA-FLSs, and circ-PTTG1IP knockdown suppressed cell proliferation, migration, invasion and inflammatory response in RA-FLSs. Besides, we found that circ-PTTG1IP could directly bind to miR-671-5p, and toll-like receptor 4 (TLR4) was a target of miR-671-5p, which was confirmed by dual-luciferase reporter assay. miR-671-5p inhibitor attenuated the effects of circ-PTTG1IP knockdown on RA-FLSs, while the effects of miR-671-5p mimic on RA-FLSs were partly reversed by TLR4 overexpression. Furthermore, circ-PTTG1IP could upregulate TLR4 expression by miR-671-5p. Thus, circ-PTTG1IP knockdown repressed cell proliferation, migration, invasion and inflammatory response in RA-FLSs by regulating the miR-671-5p/TLR4 axis.


Assuntos
Artrite Reumatoide , MicroRNAs , Sinoviócitos , Apoptose , Artrite Reumatoide/genética , Proliferação de Células , Células Cultivadas , Fibroblastos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , MicroRNAs/genética , Receptor 4 Toll-Like/genética
6.
Gene ; 793: 145747, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34077778

RESUMO

BACKGROUND: In addition to being a tumour suppressor, TP53 is a suppressor of inflammation, and dysfunction of this gene has been related to autoimmune diseases. Patients with autoimmunity, such as rheumatoid arthritis (RA) have an increased risk of certain cancers, like lymphomas, indicating that some underlying mechanisms may modulate risk of both cancers and autoimmunity. METHODS: We genotyped 5 common genetic variants in TP53 and its main regulators MDM2 and MDM4 in a sample of 942 RA patients and 3,747 healthy controls, and mined previously published GWAS-data, to assess the potential impact of these variants on risk of RA. RESULTS: For the TP53 Arg72Pro polymorphism (rs1042522), MDM4 SNP34091 (rs4245739) and MDM2 SNP285C (rs117039649), we found no association to risk of RA. For MDM2 SNP309 (rs2279744), the minor G-allele was associated with a reduced risk of RA (OR: 0.87; CI: 0.79-0.97). This association was also seen in genotype models (OR: 0.86; CI: 0.74-0.99 and OR: 0.79; CI 0.63-0.99; dominant and recessive model, respectively), but was not validated in a large GWAS data set. For MDM2 del1518 (rs3730485), the minor del-allele was associated with an increased risk of RA in the dominant model (OR: 1.18; CI: 1.02-1.38). Stratifying RA cases and controls into phylogenetic subgroups according to the combined genotypes of all three MDM2 polymorphism, we found individuals with the del158-285-309 genotype del/ins-G/G-T/T to have an increased risk of RA as compared to those with the ins/ins-G/G-G/G genotype (OR: 1.56; CI: 1.18-2.06) indicating opposite effects of the del1518 del-allele and the SNP309 G-allele. CONCLUSION: We find a potential association between the MDM2 del1518 variant and RA, and indications that combinatorial genotypes and haplotypes in the MDM2 locus may be related to RA.


Assuntos
Artrite Reumatoide/genética , Proteínas de Ciclo Celular/genética , Predisposição Genética para Doença , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas/genética , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Estudos de Casos e Controles , Proteínas de Ciclo Celular/metabolismo , Mineração de Dados , Feminino , Regulação da Expressão Gênica , Frequência do Gene , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Risco , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
7.
Int J Mol Sci ; 22(9)2021 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066338

RESUMO

In rheumatoid arthritis (RA), extracellular vesicles (EVs) are associated with both the propagation and attenuation of joint inflammation and destruction. However, the specific EV content responsible for these processes is largely unknown. Investigations into identifying EV content are confounded by the challenges in obtaining high-quality EV preparations from synovial fluid. Implementing a size exclusion chromatography-based method of EV isolation, coupled with small RNA sequencing, we accurately characterised EV miRNAs in synovial fluid obtained from RA patients and investigated the differences between joints with high- and low-grade inflammation. Synovial fluid was obtained from the joints of 12 RA patients and, based on leukocyte counts, classified as either high (n = 7)- or low (n = 5)-grade inflammation. Using size exclusion chromatography, EVs were purified and small RNA was extracted and sequenced on a NextSeq 500. Sequencing reads were aligned to miRBase v21, and differences in miRNA profiles between RA patients with high- and low-grade joint inflammation were analysed. In total, 1972 distinct miRNAs were identified from RA synovial fluid EVs. miRNAs with less than five reads in fewer than five patients were filtered out, leaving 318 miRNAs for analysis. Analysis of the most abundant miRNAs suggested that they negatively regulate multiple genes relevant to inflammation, including signal transducer and activator of transcription 3 (STAT3), which lies downstream of IL-6 and has a pro-inflammatory role in RA. Synovial fluid from joints with high-grade inflammation contained 3.5-fold more EV miRNA per mL of synovial fluid (p = 0.0017). Seventy-eight EV miRNAs were differentially expressed between RA joints with high- and low-grade inflammation, and pathway analysis revealed that their target genes were commonly involved a variety of processes, including cellular apoptosis, proliferation and migration. Of the 49 miRNAs that were elevated in joints with high-grade inflammation, pathway analysis revealed that genes involved in cytokine-mediated signalling pathways were significantly enriched targets. In contrast, genes associated with reactive oxygen species signalling were significantly enriched as targets of the 29 miRNAs elevated in joints with low-grade inflammation. Our study identified an abundance of EV miRNAs from the synovial fluid of RA patients with the potential to modulate inflammation. In doing so, we defined potential mechanisms by which synovial fluid EVs may contribute to RA pathophysiology.


Assuntos
Artrite Reumatoide/genética , Vesículas Extracelulares/genética , Inflamação/genética , MicroRNAs/genética , Líquido Sinovial/metabolismo , Idoso , Artrite Reumatoide/complicações , Estudos de Coortes , Vesículas Extracelulares/ultraestrutura , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Fatores Imunológicos/metabolismo , Inflamação/complicações , Inflamação/patologia , Masculino , MicroRNAs/metabolismo , Pessoa de Meia-Idade
8.
Egypt J Immunol ; 28(2): 53-64, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34185454

RESUMO

Regulatory T (Treg) cells are the chief player in induction of autotolerance and the transcription factor, Forkhead Box P3 (Foxp3), is the master regulator of their development and function. Polymorphisms in Foxp3 locus affect Foxp3 expression and can influence Treg cell function. This study aimed to determine the frequency of -3279C/A and -924A/G polymorphisms in the promoter region of the Foxp3 gene in Egyptian rheumatoid arthritis (RA) patients in comparison to apparently healthy controls, to test their association with Foxp3 serum levels as well as with patients' clinical and laboratory features. Also, to evaluate Foxp3 serum level as a putative measure of Foxp3+ Treg cells-mediated immune regulation and disease activity. A total of 136 subjects (68 RA patients and 68 controls) were studied for determining the frequency of both -3279 C/A and -924 A/G polymorphisms in the Foxp3 promoter region by PCR-RFLP and measuring their Foxp3 protein serum levels by ELISA. Our results indicated that; -3279 Foxp3 CA and AA genotypes were significantly higher in patients than controls (OR (95% CI) = 2.86 (1.31-6.26) and 2.79 (1.11-7.07), P= 0.008 and p = 0.03, respectively). Similarly, -924 AG genotype was significantly higher in patients than controls (OR (95% CI) = 2.92 (1.35-6.34); P=0.006). A significantly higher risk of RA was associated with the Foxp3 polymorphic variants -3279 A and -924 G. There was a statistically significant elevation in Foxp3 serum levels among patients, which was positively correlated to disease activity score and disease grade. In conclusion, Foxp3 polymorphisms influenced the risk of developing RA, but did not influence disease severity or activity. Serum level of Foxp3 is not a reliable indicator of Treg-mediated immune regulation in RA patients.


Assuntos
Artrite Reumatoide , Polimorfismo de Nucleotídeo Único , Artrite Reumatoide/genética , Estudos de Casos e Controles , Egito , Fatores de Transcrição Forkhead/genética , Humanos , Regiões Promotoras Genéticas , Linfócitos T Reguladores
9.
Aging (Albany NY) ; 13(10): 14109-14130, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-34015765

RESUMO

Many observation studies have demonstrated a close relationship between rheumatoid arthritis (RA) and osteoporosis (OP). However, the causal genetic correlation between RA and OP remains unclear. In this study, we performed bi-directional Mendelian randomization (MR) analyses to explore causal inference between these two traits. The instrumental variables for RA were selected from a large-scale genome-wide association study (GWAS) (1,523 cases and 461,487 controls). Bone mineral density (BMD) at five different sites (heel (n=265,627), forearm (FA) (n=8,143), femoral neck (FN) (n=32,735), lumbar spine (LS) (n=28,498), and total body (n=28,498)) were used as phenotypes for OP. The inverse variance weighted (IVW) method did not detect any causal effect of BMDs on RA except heel BMD (beta = -7.57 × 10-4, p = 0.02). However, other methods (MR-Egger, weighted median, weighted mode, MR-PRESSO, and MR-RAPS) showed no causal association between heel BMD and RA. Likewise, we did not find a causal effect of RA on BMD at any sites. In conclusion, we found no evidence that RA is causally associated with OP/BMD, or vice versa. We suggested that the associations found in previous observational studies between RA and OP/BMD are possibly related to secondary effects such as antirheumatic treatment and reduced physical activity.


Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/genética , Análise da Randomização Mendeliana , Osteoporose/complicações , Osteoporose/genética , Densidade Óssea/genética , Humanos
10.
Mol Biol Rep ; 48(4): 3561-3565, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33939072

RESUMO

Toll-like receptor (TLR)-mediated signaling pathways induce a proinflammatory microenvironment to eradicate pathogens. However, in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), TLRs can promote chronic inflammation. It has been shown that some TLR4 and TLR9 single nucleotide polymorphisms (SNPs) are risk factors for RA and SLE, but these findings have not been replicated in all populations; thus, results are inconclusive. We evaluated the TLR4 Asp299Gly, Thr399Ile, - 1892G/A SNPs, and the TLR9 Pro545Pro SNP to assess potential associations with RA and SLE in Mexican patients. This study included 474 patients with RA, 283 patients with SLE, and 424 healthy controls. We used a 5' nuclease allelic discrimination assay to genotype individuals for the four TLR4 and TLR9 polymorphisms. We found that the genotype or allelic frequencies of the TLR4 Asp299Gly, Thr399Ile, - 1892G/A, and TLR9 Pro545Pro polymorphisms were similar between patients and controls. We found no association under different genetic models. A haplotype analysis of TLR4 showed no association with either RA or SLE. We found no significant differences in the allelic or genotypic frequencies of TLR4 Asp299Gly, Thr399IIe, - 1892G/A, or TLR9 Pro545Pro between patients and controls. These findings suggested that these variants are not risk factors for RA or SLE in Mexican patients.


Assuntos
Artrite Reumatoide/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Receptor 4 Toll-Like/genética , Receptor Toll-Like 9/genética , Adulto , Idoso , Feminino , Haplótipos , Humanos , Masculino , México , Pessoa de Meia-Idade
11.
Zhongguo Zhong Yao Za Zhi ; 46(10): 2371-2379, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34047081

RESUMO

In this paper, network pharmacology method and molecular docking technique were used to investigate the target genes of Olibanum and Myrrha compatibility and the possible mechanism of action in the treatment of rheumatoid arthritis(RA). Our team obtained the main active components of Olibanum-Myrrha based on literatures study, relevant traditional Chinese medicine systematic pharmacological databases and literature retrieval, and made target prediction of the active components through SwissTargetPrediction database. At the same time, RA-related targets were collected through DrugBank, GeneCards and Therapeutic Target Database(TDD) databases; and VENNY 2.1 was use to collect intersection targets to map common targets of drug and disease of Venn diagram online. The team used STRING database to construct PPI protein interaction network diagram, and screen out core targets according to the size of the interaction, and Cytoscape 3.6.0 software was used to construct network models of "traditional Chinese medicine-component-target" "traditional Chinese medicine-component-target-disease" and core target interaction network model. The intersection target was analyzed by using DAVID 6.8 online database for GO function analysis and KEGG pathway enrichment analysis, and Pathon was used to visualization. AutoDock Vina and Pymol were used to connect the core active components with the core targets. Sixteen active components of Olibanum-Myrrha pairs were found and collected in the laboratory, and 320 relevant potential targets, 468 RA-related targets and 62 intersection targets were obtained through the Venn diagram. It mainly acted on multiple targets, such as IL6, TNF, IL1 B and MAPK1, involving TNF signaling pathway and Toll-like receptor signaling pathway in RA treatment. Finally, in this study, possible targets and signaling pathways of Olibanum-Myrrha compatibility therapy for RA were discussed, and molecular docking between core targets and core active components was conducted, which could provide scientific basis for the study on the mechanism of Olibanum-Myrrha compatibility.


Assuntos
Artrite Reumatoide , Medicamentos de Ervas Chinesas , Franquincenso , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Humanos , Medicina Tradicional Chinesa , Simulação de Acoplamento Molecular
12.
Ann Palliat Med ; 10(5): 5218-5230, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33977746

RESUMO

BACKGROUND: Rheumatoid arthritis is a long-term systemic disease that primarily affects multiple synovial joints throughout the body. Some patients with severe joint effusion even require repeated arthrocentesis or arthroscopic debridement to relieve symptoms, which causes them much suffering mentally and physically. This text-mining study was designed to find potential drugs that target key genes in this disease. METHODS: Firstly, we performed text mining by two keywords ("rheumatoid synovitis" and "joint effusion") to get a common set of genes. Secondly, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis performed on these genes, and protein-protein interaction (PPI) network was constructed. Subsequently, the significant genes clustered in the PPI network were chose to execute gene-drug interaction analysis for potential drug discovery. RESULTS: Through text mining, 68 overlapping genes were identified as an initial set of key genes. Construction of the initial gene set's PPI network showed that 25 genes clustered in a significant gene module. Ultimately, 8 out of 25 genes could be targetable by a total of 19 drugs. CONCLUSIONS: The final 8 genes (PTGS2, TNF, VEGFA, IL1B, CCL2, VWF, IL6, and ESR1) and 19 drugs may provide significant therapeutic value for rheumatoid arthritis patients with joint effusion.


Assuntos
Artrite Reumatoide , Descoberta de Drogas , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Biologia Computacional , Mineração de Dados , Perfilação da Expressão Gênica , Humanos
13.
Genome Med ; 13(1): 64, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: covidwho-1195928

RESUMO

BACKGROUND: Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. METHODS: To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-ß) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. RESULTS: We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. CONCLUSIONS: Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Macrófagos/imunologia , SARS-CoV-2 , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/genética , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colo/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Fenótipo , RNA-Seq
14.
Medicina (Kaunas) ; 57(4)2021 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-33916688

RESUMO

Background and Objectives: Rheumatoid arthritis (RA) is a chronic, inflammatory, autoimmune, multi-factorial disease, in which environmental and genetic factors play a major role. RA is possibly linked to vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms, and research demonstrates that FokI variant susceptibility is associated with increased disease risk among Caucasians. The aim of this study was to evaluate vitamin D deficiency prevalence and its correlation to RA clinical parameters, and to determine the possible association of VDR gene polymorphisms and RA susceptibility in the Lithuanian population. Materials and Methods: Overall, 206 RA patients and 180 age- and sex-matched healthy controls were enrolled at Vilnius University Hospital Santaros Klinikos after informed consent was obtained. The disease activity score 28 C-reactive protein (DAS28 CRP), rheumatoid arthritis impact of disease (RAID) score, and health assessment questionnaire (HAQ) were recorded in RA patients, and 25(OH)D serum levels were evaluated by chemiluminescent microparticle immunoassay for all subjects. Four VDR gene polymorphisms, BsmI, FokI, ApaI, and TaqI, were assessed using real-time PCR instruments and genotyping assays in both groups. Results: The study registered a high prevalence of 25(OH)D deficiency (<50 nmol/L) in RA patients (61.55% (n = 127)). The mean serum concentration in RA patients (44.96 ± 21.92 (nmol/L)) was significantly lower than in the healthy controls (54.90 ± 22.82 (nmol/L)), p < 0.0001. A significant inverse correlation between vitamin D level, DAS28 CRP, and HAQ scores was confirmed in RA patients, with p < 0.05. Still, there was no significant association between the overall risk of RA disease for any allele or genotype of the four VDR loci tested. Conclusions: The study confirmed that vitamin D deficiency is prevalent among RA patients and the 25(OH)D level is significantly lower compared with healthy controls. Lower vitamin D concentration was related with increased disease activity and disability scores. However, genetic analysis of four VDR polymorphisms did not confer the susceptibility to RA in Lithuanian population.


Assuntos
Artrite Reumatoide , Receptores de Calcitriol , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo Genético , Receptores de Calcitriol/genética , Vitamina D
15.
Medicine (Baltimore) ; 100(17): e25689, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907143

RESUMO

BACKGROUND: An increasing body of studies has investigated that genetic polymorphisms in microRNA (miRNA) may be related to susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, some results remain controversial. Thus, a meta-analysis was embarked on assessing whether some miRNA polymorphisms are associated with the risk of RA and SLE. METHODS: Relevant studies were acquired on PubMed, Web of Science, Cochrane Library, CNKI, and Embase electronic databases from inception to December 2019. The strength of the association of miRNA polymorphisms with the risk of RA and SLE was assessed by odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Eligible 20 articles (36 studies) involving 5 miRNAs were enrolled in the meta-analysis. For RA, the polled result showed that there was no significant relationship between miR-146a rs2910164 and RA, but subgroup analysis based on ethnicity demonstrated that CC genotype may be a genetic protect factor for RA in Caucasians (CC vs CG+GG, OR = 0.825, 95% CI: 0.684-0.996, Pz = .045, Ph = .166). Besides, statistical significance of miR-499 rs3746444 (T/C) with susceptibility to RA was observed as well in the overall population, and the association was only significant in Caucasians but not Asians. For SLE, the associations of miR-146a rs2431697 T allele/T-carrier with increased risk of SLE were observed. CONCLUSIONS: Our results highlight that miR-499 rs3746444 may contribute to RA susceptibility, particularly in Caucasians. In addition, CC genotype in miR-146a rs2910164 may act as a protector of RA in Caucasians. For SLE, miR-146a rs2431697 (C/T) is most likely to the increased the risk of SLE. These findings do not support the genetic association between miR-196a2 rs11614913 and RA/SLE susceptibility, as well as the association of miR-146a rs2910164, miR-146a rs57095329, miR-499 rs3746444 with SLE.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Lúpus Eritematoso Sistêmico/genética , MicroRNAs/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Genótipo , Humanos , Razão de Chances
16.
J Biol Regul Homeost Agents ; 35(2): 629-640, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33887899

RESUMO

Rheumatoid arthritis (RA) is characterized by inflammation of the synovial membrane, accompanied by hyperplasia and neo-angiogenesis, which promote local inflammation. Macrophage-derived exosomes have been reported to enhance inflammation and the immune response. In the present study, we identified a novel exosomal microRNA (miR)-103a, which aids in the regulation of inflammation and angiogenesis in mice with RA, and attempted to identify the underlying mechanism. Initially, a mouse model of RA was established. Thereafter, exosomes were isolated from macrophage RAW264.7 cells and evaluated through transmission electron microscopy and nanoparticle tracking analysis. After prediction and verification of the target genes of miR-103a, RT-qPCR was used to assess miR-103a and HNF4A expression in mice with RA. High expression of miR-103a and low expression of HNF4A were observed in mice with RA, thus, miR-103a was found to target and downregulate HNF4A. Exosomal miR-103a promoted inflammation and angiogenesis in mice with RA which was accompanied by an increase in the levels of factors associated with inflammation and angiogenesis. However, an opposite trend was observed upon HNF4A elevation. Exosomal miR-103a was also found to activate the JAK/STAT3 signaling pathway. In conclusion, exosomal miR-103a inhibited the expression of HNF4A to activate the JAK/STAT3 signaling pathway, thereby exacerbating RA in mice.


Assuntos
Artrite Reumatoide , MicroRNAs , Animais , Artrite Reumatoide/genética , Regulação para Baixo , Fator 4 Nuclear de Hepatócito , Camundongos , MicroRNAs/genética , Transdução de Sinais
17.
Arthritis Res Ther ; 23(1): 108, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33836822

RESUMO

BACKGROUND: Hormonal reproductive factors have been suggested to play an important role in the etiology of rheumatoid arthritis (RA), an autoimmune inflammatory disorder affecting primarily women. We conducted a two-sample Mendelian randomization (MR) study examining three relevant exposures, age at menarche (AAM), age at natural menopause (ANM), and age at first birth (AFB) with the risk of RA. METHODS: We collected summary statistics from the hitherto largest GWAS conducted in AAM (N = 329,345), ANM (N = 69,360), AFB (N = 251,151), and RA (Ncase = 14,361, Ncontrol = 43,923), all of European ancestry. We constructed strong instruments using hundreds of exposure-associated genetic variants and estimated causal relationship through different MR approaches including an inverse-variance weighted method, an MR-Egger regression and a weighted median method. We conducted a multivariable MR to control for pleiotropic effect acting in particular through obesity and socioeconomic status. We also performed important sensitivity analyses to verify model assumptions. RESULTS: We did not find any evidence in support for a causal association between genetically predicted reproductive factors and risk of RA (ORper-SD increment in AAM = 1.06 [0.98-1.15]; ORper-SD increment in ANM = 1.05 [0.98-1.11], OR per-SD increment in AFB = 0.85 [0.65-1.10]). Results remained consistent after removing palindromic SNPs (ORper-SD increment in AAM = 1.06 [0.97-1.15], ORper-SD increment in ANM = 1.05 [0.98-1.13], ORper-SD increment in AFB = 0.81 [0.61-1.07]) or excluding SNPs associated with potential confounding traits (ORper-SD increment in AAM = 1.03 [0.94-1.12], ORper-SD increment in ANM = 1.04 [0.95-1.14]). No outlying instrument was identified through the leave-one-out analysis. CONCLUSIONS: Our MR study does not convincingly support a casual effect of reproductive factors, as reflected by age at menarche, age at menopause, and age at first birth, on the development of RA. Despite the largely augmented set of instruments we used, these instruments only explained a modest proportion of phenotypic variance of exposures. Our knowledge regarding this topic is still insufficient and future studies with larger sample size should be designed to replicate or dispute our findings.


Assuntos
Artrite Reumatoide , Menarca , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Menarca/genética , Análise da Randomização Mendeliana , Menopausa/genética , Polimorfismo de Nucleotídeo Único/genética
18.
Genome Med ; 13(1): 64, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33879239

RESUMO

BACKGROUND: Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies. METHODS: To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-ß) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF. RESULTS: We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α. CONCLUSIONS: Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.


Assuntos
COVID-19/imunologia , Citocinas/imunologia , Macrófagos/imunologia , SARS-CoV-2 , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , COVID-19/genética , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Colo/imunologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Pulmão/imunologia , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Fenótipo , RNA-Seq
19.
Zhen Ci Yan Jiu ; 46(3): 194-200, 2021 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-33798291

RESUMO

OBJECTIVE: To explore the effect of moxibustion at "Zusanli"(ST36) and "Shenshu"(BL23) on synovitis, and expressions of miR-155, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), interlukine(IL-1) receptor-associated kinase (IRAK1), tumor necrosis factor receptor-associated factor 6 (TRAF6), nuclear factor κB (NF-κB), IL-1ß, tumor necrosis factor receptor (TNF)-α and IL-6 mRNA and protein of synovial membrane in rheumatoid arthritis (RA) rats, so as to explore its mechanism underlying improvement of RA. METHODS: A total of 48 male Wistar rats were randomly divided into normal control, model, moxibustion and antagonist groups (n=12 rats in each group). The RA model was replicated by placing the rats in a wind, cold and wet environment and injection of Freund's complete adjuvant (CFA, 0.5 mL) into the right hindlimb foot plantar. Moxibustion was applied to bilateral ST36 and BL23 for 30 min, once daily for 21 consecutive days. Rats of the antagonist group was treated by injection of TLR4 antagonist (TAK-242, 1 mg/mL, 0.1 mg/kg) via tail vein, once per day for consecutive 21 d. The joint swelling degree (JSD) and arthritis index (AI, red swelling scale) were determined, and the expression levels of various indicators of miR-155, and TLR4, myeloid MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein were assayed by quantitative real time-PCR and Western blot, separately. RESULTS: Compared with the normal control group, the JSD and AI, and the expression levels of synovial miR-155, TLR4, MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein were significantly increased in the model group (P<0.01). Compared with the model group, the increased levels of JSD and AI, and the expression levels of synovial miR-155, TLR4, MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein were notably down-regulated in both moxibustion and antagonist groups (P<0.01). The effects of moxibustion were evidently superior to the antagonist in down-regulating the abovementioned indexes (P<0.01), except TLR4 mRNA and protein. CONCLUSION: Moxibustion at ST36 and BL23 can reduce the synovitis of RA rats, which is related to its effects in suppressing the expressions of miR-155, TLR4, MyD88, IRAK1, TRAF6, NF-κB, IL-1ß, TNF-α and IL-6 mRNA and protein (i.e., inhibition of miR-155/TLR4/NF-κB signaling).


Assuntos
Artrite Reumatoide , MicroRNAs , Moxibustão , Sinovite , Animais , Artrite Reumatoide/genética , Artrite Reumatoide/terapia , Masculino , MicroRNAs/genética , NF-kappa B/genética , Ratos , Ratos Wistar , Receptor 4 Toll-Like/genética
20.
BMC Musculoskelet Disord ; 22(1): 246, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33673829

RESUMO

BACKGROUND: Rheumatoid Arthritis (RA) is a chronic inflammatory condition characterized by autoantibodies development and an elevated spectrum of pro-inflammatory cytokines. Previous reports highlighted a relationship between IL-21and the pathogenesis of RA. Although elevated IL-21 levels have been reported in RA patients, the association of common IL-21 genetic variants with a predisposition to RA development in the Chinese population lacks. MATERIALS AND METHODS: Five hundred and fourteen Chinese subjects (healthy controls: 303 and rheumatoid arthritis patients: 211) were enrolled in the study. Clinical data of patients were collected from medical records, and patients were treated as per the guidelines. Common single nucleotide polymorphisms in the IL-21 gene (rs907715, rs2221903, rs2055979 and rs6822844) were genotyped by TaqMan SNPs genotyping method. IL-21 level in plasma of RA patients and healthy subjects was measured by ELISA. RESULTS: The plasma level of IL-21 was significantly higher in subjects with rheumatoid arthritis relative to healthy controls (p < 0.0001). A positive correlation was observed between IL-21 level and DAS28 score, indicating the association of the cytokine with the worsening of the disease (Spearman r = 0.61, p < 0.0001). The prevalence of AA genotype (rs2055979) was significantly higher in RA subjects than in the controls (p < 0.0001, χ2 = 34.73, OR = 4.34, 95% CI = 2.623 to 7.219). Furthermore, elevated plasma IL-21 was observed in the rs2055979-AA genotype compared to CC type (p < 0.0001). CONCLUSION: IL-21 plays a crucial function in rheumatoid arthritis pathogenesis. IL-21 rs2055979 polymorphism is associated with IL-21 plasma levels and is predisposed to RA development in the Chinese population.


Assuntos
Artrite Reumatoide , Predisposição Genética para Doença , Interleucinas , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Estudos de Casos e Controles , Genótipo , Humanos , Interleucinas/sangue , Interleucinas/genética , Polimorfismo de Nucleotídeo Único
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