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1.
Int J Mol Sci ; 21(24)2020 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-33317138

RESUMO

OBJECTIVE: Coagulation and fibrinolysis are interrelated with the expression of vascular endothelial growth factor (VEGF), which frequently is increased in axial spondyloarthritis (axSpA). We tested whether (i) α2-antiplasmin (A2AP) Arg6Trp, (ii) fibrinogen, factor XIII A-subunit or B-subunit genotypes are associated with VEGF levels and assessed whether the known association between elevated VEGF and radiographic spinal progression in axSpA depends on genetic background. METHODS: One hundred and eighty-six axSpA patients from the German Spondyloarthritis Inception Cohort were genotyped, characterized for VEGF levels, and statistically analyzed. The association between VEGF and radiographic spinal progression was assessed in dependence on genetic background in stratified analyses. RESULTS: A2AP 6Trp carriage was associated with VEGF elevation (OR: 2.37, 95% CI: 1.06-5.29) and VEGF levels (6Trp, 455 ± 334 pg/mL; 6Arg/Arg, 373 ± 293 pg/mL; p < 0.008). Association between elevated VEGF and radiographic spinal progression in axSpA (OR: 3.11, 95% CI: 1.02-8.82) depended remarkably on the fibrinogen (FGA) genotype. When considering axSpA patients with elevated VEGF, in FGA rs6050A>G wild types, 42.1% of patients (8 of 19) progressed, while in G-allele carriers, no radiographic progression happened (0 of 13) (p < 0.04). CONCLUSIONS: The A2AP Arg6Trp genotype seems to influence VEGF levels in axSpA. The predictive value of VEGF elevations in respect of radiographic spinal progression in axSpA depends on FGA genotypes.


Assuntos
Fibrinogênio/genética , Genótipo , Espondilite Anquilosante/genética , Fator A de Crescimento do Endotélio Vascular/genética , alfa 2-Antiplasmina/genética , Adulto , Fator VIII/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
PLoS Genet ; 16(8): e1008906, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804949

RESUMO

The killer immunoglobulin-like receptors (KIRs), found predominantly on the surface of natural killer (NK) cells and some T-cells, are a collection of highly polymorphic activating and inhibitory receptors with variable specificity for class I human leukocyte antigen (HLA) ligands. Fifteen KIR genes are inherited in haplotypes of diverse gene content across the human population, and the repertoire of independently inherited KIR and HLA alleles is known to alter risk for immune-mediated and infectious disease by shifting the threshold of lymphocyte activation. We have conducted the largest disease-association study of KIR-HLA epistasis to date, enabled by the imputation of KIR gene and HLA allele dosages from genotype data for 12,214 healthy controls and 8,107 individuals with the HLA-B*27-associated immune-mediated arthritis, ankylosing spondylitis (AS). We identified epistatic interactions between KIR genes and their ligands (at both HLA subtype and allele resolution) that increase risk of disease, replicating analyses in a semi-independent cohort of 3,497 cases and 14,844 controls. We further confirmed that the strong AS-association with a pathogenic variant in the endoplasmic reticulum aminopeptidase gene ERAP1, known to alter the HLA-B*27 presented peptidome, is not modified by carriage of the canonical HLA-B receptor KIR3DL1/S1. Overall, our data suggests that AS risk is modified by the complement of KIRs and HLA ligands inherited, beyond the influence of HLA-B*27 alone, which collectively alter the proinflammatory capacity of KIR-expressing lymphocytes to contribute to disease immunopathogenesis.


Assuntos
Epistasia Genética , Antígenos HLA/genética , Receptores KIR/genética , Espondilite Anquilosante/genética , Alelos , Aminopeptidases/genética , Humanos , Antígenos de Histocompatibilidade Menor/genética , Polimorfismo de Nucleotídeo Único
3.
PLoS One ; 15(8): e0237219, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764781

RESUMO

Many susceptibility genes of inflammatory bowel disease (IBD) are associated with ankylosing spondylitis (AS). Fucosyltransferase 2 (FUT2) and FUT3 genes are related to IBD. This study aimed to investigate whether these genes correlated with the susceptibility to AS. Questionnaires of 673 patients with AS, and peripheral blood specimens of the patients and 687 healthy controls were collected. FUT2 and FUT3 genes were genotyped using the SNPscan method. Frequency differences of the genes at different levels, haplotypes, and interactions were analyzed. No frequency differences were found between the cases and the controls in all the genotypes and the alleles of rs1047781, rs1800028, rs1800030, and rs812936. For rs28362459, a significant difference in allele frequencies was observed in the total participants between the groups [χ2 = 7.515, Pcorrected = 0.030; adjusted odds ratio (ORadjusted)G/T = 0.782; 95% confidence interval (CI), 0.650-0.941]. The frequencies of haplotypes TT (rs812936-rs28362459) (χ2 = 5.663, Ppermutation = 0.039) and TG (rs812936-rs28362459) (χ2 = 7.456, Ppermutation = 0.013) in the total participants, and TG (rs812936-rs28362459) in the female subgroup (χ2 = 5.624, Ppermutation = 0.047) showed significant differences between the cases and the controls. No frequency differences at the phenotypic level were found. Two-factor interactions were observed between rs28362459-TG and age, rs28362459-TG and sex, rs28362459 and rs1047781, and the Lewis and secretor status. Rs28362459-G was related to some aggravated symptoms of AS (all Pcorrected < 0.05). These findings indicated that FUT3 polymorphisms were associated with human predisposition to AS at the allele and haplotype level. Rs28362459-G might decrease the susceptibility to AS, but aggravate relevant symptoms.


Assuntos
Fucosiltransferases/genética , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Espondilite Anquilosante/epidemiologia , Adulto Jovem
4.
Medicine (Baltimore) ; 99(34): e21629, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846771

RESUMO

RATIONALE: Ankylosing spondylitis (AS) and Kimura's disease (KD) which is quite rare are both chronic inflammatory diseases. Recently we encountered a patient who suffered from KD and AS, and some of his family members also suffer from AS. We, therefore, investigated this unique case and conducted the family-based whole exome sequencing to explore the possible genetic alterations. PATIENT CONCERNS: Here, we reported a case of a 44-year-old Chinese man with multiple painless masses all over his body and a back pain for 32 years. His uncle and sister were diagnosed with AS. DIAGNOSIS: The diagnosis of KD was based on the patient's clinical features and the biopsy of the neck masses. The diagnosis of AS was based on the patient's clinical features, HLA-B27(+) and the radiologic changes of sacroiliac joints. The genetic test showed that ARPC1B gene which was associated with recurrent infections, auto-inflammatory changes and elevated IgE levels was mutated in this patient. INTERVENTIONS: Neck masses were removed by surgery. Systemic glucocorticoid, nonsteroidal anti-inflammatory agents, combined with cyclosporine were orally administered, and Etanercept was injected subcutaneously. OUTCOMES: The masses disappeared rapidly after surgery combined with systemic glucocorticoid, but relapsed shortly after the therapy was discontinued. Low dose glucocorticoid, cyclosporine and Etanercept could keep both KD and AS remained long-term remission. LESSONS: Our experience suggests that low dose glucocorticoid, cyclosporine and Etanercept could be beneficial for the patient with KD and AS. The mutation of ARPC1B gene in this case, which is associated with immunologic disturbance, may increase the susceptibility of KD.


Assuntos
Hiperplasia Angiolinfoide com Eosinofilia/complicações , Espondilite Anquilosante/complicações , Adulto , Hiperplasia Angiolinfoide com Eosinofilia/genética , Humanos , Masculino , Espondilite Anquilosante/genética
5.
Medicine (Baltimore) ; 99(28): e19942, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664053

RESUMO

BACKGROUND: The present study was performed to statistically explore the effect of anthrax toxin receptor 2 (ANTXR2) polymorphism rs4333130 on individual susceptibility to ankylosing spondylitis (AS) using the method of meta-analysis. METHODS: All of the eligible reports were retrieved from well-known electronic databases. The strength of the association between ANTXR2 polymorphism rs4333130 and the susceptibility to AS was evaluated using pooled odds ratios (ORs) with 95% confidence intervals (95% CIs). In addition, subgroup analysis was also performed on the basis of ethnicity to further explore specific correlation between our studied polymorphism and the disease risk. Inter-study heterogeneity was detected with Q test, and P < .05 was considered statistically significant. Sensitivity analysis was implemented through removing each of eligible studies and then recalculating overall effects to test the reliability of final estimates. Publication bias among included studies was inspected with both Begg funnel plot and Egger regression test. RESULTS: A total of 6 eligible papers were finally incorporated into the present meta-analysis. In total analysis, ANTXR2 polymorphism rs4333130 was significantly related to decreased risk of AS under CC versus TT, CC + TC versus TT, CC versus TT + TC, C versus T and TC versus TT contrasts (OR = 0.35, 95% CI = 0.20-0.64; OR = 0.81, 95% CI = 0.69-0.95; OR = 0.38, 95% CI = 0.21-0.68; OR = 0.89, 95% CI = 0.84-0.95; OR = 0.84, 95% CI = 0.72-0.99). Moreover, a similar effect was also observed in Asian and Caucasian subgroups under corresponding genetic models after stratification analysis based on ethnicity. CONCLUSION: ANTXR2 polymorphism rs4333130 may function as a protective factor against AS incidence.


Assuntos
Receptores de Peptídeos/genética , Espondilite Anquilosante/genética , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Proteção
6.
BMC Med Genet ; 21(1): 147, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32650733

RESUMO

BACKGROUND: Ankylosing spondylitis (AS) is considered as a subtype of spondyloarthritis (SpA) that mainly leads to fatigue, stiffness, spinal ankylosis, and impaired physical functions with reduced quality of life. Interleukin (IL)-17A provokes additional inflammatory mediators and recruits immune cells to the inflamed site. IL17 expression increased in various inflammatory disorders including psoriasis, rheumatoid arthritis, multiple sclerosis, crohn's disease, and ankylosing spondylitis. The current study aimed to evaluate the association of IL17RA copy number changes with the susceptibility to AS and their correlation to IL17RA expression in Iranian population. METHODS: IL17RA copy number genotyping assessments were carried out in 455 AS patients and 450 healthy controls, using custom TaqMan CNV assays. TaqMan primers and probe were located in Chr.22:17109553 based on pre-designed IL17RA Copy Number Assay ID, Hs02339506_cn. mRNA expression of IL17RA was also measured by SYBR Green real-time polymerase chain reaction (PCR). RESULTS: A IL17RA copy number loss (< 2) was associated with AS compared to 2 copies as reference (OR:2.18, 95% CI: (1.38-3.44), P-value < 0.001) and increased the risk of AS. IL17RA mRNA expression showed a significant increase in peripheral blood mononuclear cells (PBMCs) of all AS individuals than controls. The mRNA expression level of 2 copies was significantly higher in AS patients. CONCLUSIONS: Our findings revealed that a low copy number of IL17RA might confer a susceptibility risk to AS. However, it is probably not directly involved in the regulation of IL17RA mRNA expression. Epigenetic mechanisms like DNA methylation, post-transcriptional, and -translational modifications that regulate the expression of the genes may contribute in upregulation of IL17RA mRNA expression in the loss of gene copy number condition.


Assuntos
Variações do Número de Cópias de DNA/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Interleucina-17/genética , Espondilite Anquilosante/genética , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-17/metabolismo , Irã (Geográfico) , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Risco
7.
Clin Immunol ; 213: 108374, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32146336

RESUMO

OBJECTIVES: The association between Interleukin (IL)-17A and IL-17F gene polymorphism with inflammatory arthritis were inconsistent among previous studies. This meta-analysis aimed to determine the association between IL-17A and IL-17F gene polymorphism with ankylosing spondylitis (AS), osteoarthritis (OA) and rheumatoid arthritis (RA). METHODS: We searched Medline up to August 2019. The summary Odds Ratio (OR) with corresponding 95% confidence intervals (CIs) was calculated to evaluate the relationship between IL-17A and IL-17F gene polymorphism with genetic susceptibility of AS, OA and RA. RESULTS: A total of 19 studies with 5298 cases and 5675 healthy controls were included. There were significant associations between rs2275913 G allele with OA, RA susceptibility (P < .05) but not AS. Subgroup analysis by ethnicity indicated that rs763780 C allele was closely related to AS and OA in Caucasian populations (P < .001) but not Mongolians. A significant association between rs763780 and RA susceptibility was detected in Caucasian populations (P < .05). CONCLUSION: IL-17F gene rs763780 C allele confers increased risk of inflammatory arthritis in Caucasians; IL-17A gene rs2275913 G allele are protective for OA susceptibility in Mongolians. More well-designed studies with larger sample size are needed to elucidate the role of IL-17A gene rs2275913 G allele in inflammatory arthritis, especially AS.


Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Interleucina-17/genética , Osteoartrite/genética , Espondilite Anquilosante/genética , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética
8.
Clin Exp Rheumatol ; 38(5): 993-1000, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31994481

RESUMO

OBJECTIVES: 2p15 polymorphisms have been reported to increase ankylosing spondylitis (AS) susceptibility in several studies; however, when it comes to whether and how much of this risk exists, the results are inconclusive. The aim of this study is to investigate the correlation between rs10865331 in 2p15 and the risk of AS. METHODS: We conducted a HuGE review and meta-analysis of studies published through September 2019. Studies were identified in PubMed, Scopus, HuGE Navigator, Embase, and Web of Science databases. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk estimations were calculated. Sensitivity analysis, subgroup analysis and analysis for potential publication bias were also estimated. RESULTS: Eleven studies with 18555 AS patients and 43777 unrelated healthy individuals, each with a score greater than 6 on the Newcastle-Ottawa Scale (NOS), that investigated the association between rs10865331 in 2p15 and AS were included in our meta-analysis. Data were classified into the genotype analysis cohort, the OR-value cohort, and the pooled analysis cohort, and then a meta-analysis was performed. The OR value of the recessive model in the genotype analysis cohort was 1.376 (95% CI=1.204-1.572, p<0.001, I²=56.30%), and the OR value of the pooled analysis cohort was 1.295 (95% CI=1.228-1.365, p<0.001, I²=73.70%). These findings suggest that individual who carries this single nucleotide polymorphism (SNP) are about 30% more susceptible to developing AS. CONCLUSIONS: Our results suggest that rs10865331 is associated with a significantly higher risk of AS in all race and country subgroups that we have evaluated. Therefore, rs10865331 may be a useful genetic marker for predicting AS susceptibility. However, further studies are needed to confirm our findings.


Assuntos
Espondilite Anquilosante , Alelos , DNA Intergênico/genética , Predisposição Genética para Doença , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/genética
9.
Sci Rep ; 10(1): 1412, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996699

RESUMO

Lymphotoxin-a (LTA) may be associated with the pathogenesis of inflammatory diseases. To assess the association of the LTA rs909253 A/G polymorphism with plasma level and risk of ankylosing spondylitis (AS) in a Chinese Han population. Genotyping and LTA plasma were tested by mass spectroscopy and enzyme-linked immunosorbent assay (ELISA), respectively. The results showed that the average plasma level of LTA in AS was significantly lower than in the controls (P = 0.000). Our results also indicated that LTA rs909253 A/G was associated with a decreased risk of AS (G vs. A: P = 0.014). Significant differences were also found between the rs909253 A/G genotype and down-regulated plasma level in AS patients, compared with controls. After stratification analysis, a decreased risk of AS was associated with the LTA rs909253 G allele (G vs. A) among female patients, younger patients (Yr. < 30), HLA-B27-positive patients. In addition, In conclusion, LTA rs909253 A/G genotype has a significant relationship with decreased susceptibility to AS.


Assuntos
Linfotoxina-alfa/genética , Espondilite Anquilosante/genética , Adulto , Fatores Etários , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Técnicas de Genotipagem , Antígeno HLA-B27/sangue , Antígeno HLA-B27/imunologia , Humanos , Linfotoxina-alfa/sangue , Masculino , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Espondilite Anquilosante/sangue , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/imunologia , Adulto Jovem
10.
Mol Cell Biochem ; 466(1-2): 17-24, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31894531

RESUMO

Ankylosing spondylitis (AS) is a progressive systemic disease characterized by chronic inflammation response of the sacroiliac joint and spine. Long non-coding RNAs (lncRNAs) are widely involved in the regulation of various diseases. However, the role of lncRNA maternally expressed gene 3 (MEG3) in the inflammatory response of AS has not been studied. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of inflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in tissues and cells. The expression levels of MEG3, microRNA-146a (miR-146a), and inflammatory cytokines were measured by quantitative real-time PCR (qRT-PCR). Correlation between MEG3 or miR-146a and inflammatory cytokines was analyzed by Pearson analysis. Dual-luciferase reporter and RNA immunoprecipitation (RIP) assays were used to clarify the interaction between MEG3 and miR-146a. MEG3 was downregulated in AS patients, negatively correlated with the levels of IL-1ß, IL-6, and TNF-α, and blocked the inflammatory response of AS. MiR-146a was upregulated in AS patients and could interact with MEG3. The expression of miR-146a was positively correlated with IL-1ß, IL-6, and TNF-α levels. Overexpression of miR-146a reversed the inhibitory effect of abnormal MEG3 expression on inflammatory cytokines. LncRNA MEG3 plays an anti-inflammatory role in AS partially through targeting miR-146a, which provides a potential new means for the treatment of AS patients.


Assuntos
MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Espondilite Anquilosante/metabolismo , Citocinas/biossíntese , Citocinas/genética , Regulação da Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Inflamação/terapia , MicroRNAs/genética , RNA Longo não Codificante/genética , Espondilite Anquilosante/genética , Espondilite Anquilosante/patologia , Espondilite Anquilosante/terapia
11.
Immunol Lett ; 217: 31-38, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31711818

RESUMO

BACKGROUND: Ankylosing spondylitis (AS) is a prototype of chronic inflammatory arthritis termed seronegative spondyloarthropathies that typically affects the joints. Among the non-Human leukocyte antigen (HLA) loci, the strongest association has been observed with Endoplasmic reticulum aminopeptidase 1 (ERAP1) gene single nucleotide polymorphisms (SNPs). Moreover, the effect of ERAP1 gene SNPs on the pro-inflammatory and anti-inflammatory cytokines in AS disease has still been poorly elucidated. In this study, we aimed to determine the association of ERAP1 gene SNPs (rs30187 and rs2287987) with AS risk as well as their effect on the mRNA expression of pro-inflammatory and anti-inflammatory cytokines, with emphasis on the immunoregulation of the IL-17/IL-23 pathway, in an Iranian population. METHODS: We performed Single specific primer (SSP)-PCR for genotyping of 160 AS patients and 160 healthy controls. After isolation of peripheral blood mononuclear cells (PBMCs), total RNA of PBMCs was isolated, complementary DNA (cDNA) was synthesized, and quantitative analyses of mRNA expression of cytokines were performed by Real-time PCR for 40 HLA-B27 positive AS patients and 40 healthy individuals as controls. RESULTS: It was seen that T allele of rs30187 (OR = 1.54, 95% CI = 1.07-2.22, P =  0.017) and C allele of rs2287987 (OR 1.50, 95% CI 1.05-2.14, P = 0.024) were associated with the risk of AS. Both of these alleles were associated more strongly in the HLA-B27 positive AS patients. There was a significant overexpression of mRNAs of pro-inflammatory (IL-17A, IL-17F, IL-23, TNF-α and IFN-γ), while downregulation of anti-inflammatory cytokines (IL-10 and TGF-ß) in PBMCs from 40 HLA-B27 positive AS patients in comparison to controls. AS patients with rs30187 SNP TT genotype expressed mRNA of IL-17A, IL-17F, and IL-23 significantly higher than patents with CT and CC genotypes for this SNP. CONCLUSIONS: This study represented the association of ERAP1 gene rs30187 and rs2287987 polymorphism with the risk of AS. Additionally, it appears that rs30187 polymorphism may be involved in the immunomodulation of the IL-17/IL-23 pathway in the AS disease.


Assuntos
Aminopeptidases/genética , Citocinas/sangue , Antígeno HLA-B27/sangue , Leucócitos Mononucleares/metabolismo , Antígenos de Histocompatibilidade Menor/genética , Espondilite Anquilosante/genética , Adulto , Alelos , Aminopeptidases/imunologia , Estudos de Casos e Controles , Citocinas/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Interferon gama/sangue , Interferon gama/genética , Interleucina-10/sangue , Interleucina-10/genética , Interleucina-17/sangue , Interleucina-17/genética , Interleucina-23/sangue , Interleucina-23/genética , Irã (Geográfico) , Masculino , Pessoa de Meia-Idade , Antígenos de Histocompatibilidade Menor/imunologia , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/sangue , Espondilite Anquilosante/enzimologia , Espondilite Anquilosante/imunologia , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/genética , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/genética , Adulto Jovem
12.
Arthritis Rheumatol ; 72(3): 428-434, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31599089

RESUMO

OBJECTIVE: Ankylosing spondylitis (AS) is an inflammatory arthritis in which men have a higher risk of developing progressive axial disease than women. Transcriptomic studies have shown reduced expression of cytotoxic cell genes in the blood of AS patients. HLA-B27 contributes the greatest risk for AS, suggesting a role for CD8+ T cells. This study was undertaken to profile AS patient cytotoxic cells with the hypothesis that an alteration in CD8+ T cells might explain the aberrant cytotoxic profile observed in patients. METHODS: Whole blood was examined for GZM and PRF1 gene expression by quantitative polymerase chain reaction. Serum and synovial fluid (SF) were examined for granzyme and perforin 1 expression by bead array, and blood and SF mononuclear cells were examined for granzyme and perforin 1 expression by fluorescence-activated cell sorting (FACS). RESULTS: GZM and PRF1 gene expression were both reduced in AS patients compared to healthy controls, especially in men. Perforin 1, but not granzyme, protein levels were reduced in AS patient serum. Granzymes were elevated in AS SF, but not in rheumatoid arthritis or osteoarthritis SF. FACS revealed a reduction in granzyme-positive and perforin 1-positive lymphocytes, but not an intrinsic defect in CD8+ T cell granzyme or perforin 1 production. CD8+ T cell frequency was reduced in the blood and increased in the SF of AS patients. CONCLUSION: Our findings indicate that AS patients have an altered cytotoxic T cell profile. These data suggest that CD8+ T cells with a cytotoxic phenotype are recruited to the joints, where they exhibit an activated phenotype. Thus, a central role for CD8+ T cells in AS may have been overlooked and deserves further study.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Citotoxicidade Imunológica/genética , Granzimas/imunologia , Perforina/imunologia , Espondilite Anquilosante/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/genética
16.
Mod Rheumatol ; 30(4): 715-720, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31267817

RESUMO

Background: We aimed to investigate the haplotypes and alleles of two variants (rs2794521 and rs3091244) in AS patients and to examine their relationship with ASDAS-CRP and ASDAS-ESR values.Methods: We evaluated 160 AS patients diagnosed according to the ASAS criteria. ASDAS-CRP and ASDAS-ESR values were calculated. ESR and CRP were examined. The restriction fragment length polymorphism (RFLP) method was used for detecting the rs2794521 and rs3091244 regions on the CRP gene.Results: As a result of the evaluation of rs2794521 gene polymorphism using PCR, TT, TC and CC genotypes were observed in 90, 81 and 9 individuals, respectively. As a result of the evaluation of rs3091244 gene polymorphism, CC, AC and TT genotypes were observed in 104, 51 and 5 individuals, respectively. T allele and C allele were found in rs2794521 gene by 75% and 25%, respectively. In addition, T allele, C allele and A allele were found in rs3091244 gene by 80%, 17% and 3%, respectively. With the help of regression equation, ASDAS-CRP level was 0.34 units higher in cases with rs3091244 C allele than cases without rs3091244 C alleles.Conclusion: CRP rs3091244 C allele may be associated with the increased relative risk for ASDAS-CRP.


Assuntos
Proteína C-Reativa/genética , Polimorfismo de Nucleotídeo Único , Espondilite Anquilosante/genética , Adulto , Feminino , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/patologia
17.
Clin Exp Rheumatol ; 38(2): 275-281, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31287414

RESUMO

OBJECTIVES: To investigate the associations of miR-451 and macrophage migration inhibitory factor (MIF) with disease activity, radiographic progression, and cytokine levels of ankylosing spondylitis (AS). METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated and cultured from 43 AS patients, 11 peripheral spondyloarthritis (pSpA) patients, and 31 healthy controls. ASDAS-CRP and mSASSS were assessed at the time of blood sampling. Expression levels of miR-451 and MIF were determined using quantitative real-time PCR, and the supernatant concentrations of MIF and cytokines were measured using ELISA. After transfection of miR-451 synthetic mimic or FAM-labelled negative control mimic to AS PBMCs, MIF and cytokine levels were determined using quantitative real-time PCR or ELISA. RESULTS: Level of miR-451 expression was lower in AS PBMCs than in pSpA and control PBMCs, while MIF expression was significantly increased in AS PBMCs compared with those in pSpA and control PBMCs. MIF, TNF-α, and IL-6 concentrations in cell supernatants of AS PBMCs were significantly higher than those of pSpA and control PBMCs. miR-451 expression level did not show significant correlation with clinical parameters, but MIF expression level was elevated in PBMCs from AS patients with high mSASSS (12 or more). Treatment of AS PBMCs with the miR-451 synthetic miRNA mimic significantly reduced mRNA expression levels and cell supernatant concentrations of MIF, TNF-α, and IL-6. CONCLUSIONS: The MIF level was elevated in AS patients with greater radiographic damage and overexpression of miR-451 suppressed the MIF and inflammatory cytokine levels. These findings suggest miR-451/MIF may be a novel therapeutic target in the treatment of AS.


Assuntos
Leucócitos Mononucleares , Fatores Inibidores da Migração de Macrófagos/metabolismo , MicroRNAs , Espondilite Anquilosante , Humanos , Fatores Inibidores da Migração de Macrófagos/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Espondilite Anquilosante/genética , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/metabolismo , Fator de Necrose Tumoral alfa
18.
Exp Mol Pathol ; 112: 104355, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31837326

RESUMO

BACKGROUND: Notoginsenoside R1 (NG-R1) exhibits a pharmacological activity against excessive inflammation. Here, we aimed to ascertain the anti-inflammatory role of NG-R1 in ankylosing spondylitis (AS) as well as the possible mechanism which is still under to be elucidated. METHODS: In this study, lipopolysaccharide (LPS) was applied to evoke extreme inflammation in ATDC5 cells. To investigate the anti-inflammatory property of NG-R1, ATDC5 cells were exposed to NG-R1 prior to LPS stimulation. microRNA-301a (miR-301a)-overexpressed ATDC5 cells were established which confirmed by qRT-PCR. Then, inflammatory lesions were indicated by cell viability, apoptosis and inflammatory factors, including interleukin-1 beta (IL-1ß), IL-6 and tumor necrosis factor-alpha (TNF-α). Nuclear factor-kappa B (NF-κB) pathway was determined by Western blotting assay. RESULTS: We found NG-R1 dramatically dampened the decrease of cell viability, facilitation of apoptosis and abundance of inflammatory factors induced by LPS. Additionally, NG-R1 pre-incubation impeded LPS-induced accumulation of miR-301a. However, the protective capacity of NG-R1 was impaired by miR-301a overexpression. Of note, LPS-caused phosphorylation of p65 and inhibitor of nuclear factor kappa-B alpha (IκBα) was repressed by NG-R1, while further enhanced in miR-301-transfected ATDC5 cells. CONCLUSION: NG-R1 relived LPS-elicited inflammatory damages via blocking NF-κB in a miR-301a-silenced manner.


Assuntos
Ginsenosídeos/farmacologia , Inflamação/tratamento farmacológico , MicroRNAs/genética , Espondilite Anquilosante/tratamento farmacológico , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/patologia , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/genética , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Osteoartrite/patologia , Transdução de Sinais/efeitos dos fármacos , Espondilite Anquilosante/induzido quimicamente , Espondilite Anquilosante/genética , Espondilite Anquilosante/patologia
19.
Rheumatology (Oxford) ; 59(7): 1695-1702, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31687771

RESUMO

OBJECTIVES: AS is known to be a highly heritable disease, but previous studies on the magnitude of the familial aggregation and heritability of AS have been small and inconclusive, with familial relative risks ranging from 17 to 94. We aimed to improve estimates of these factors by studying families of all subjects diagnosed with AS in Sweden over a period of 16 years and to investigate if familial risks vary by sex or type of relative. METHODS: In a nested case-control study, we identified AS index patients from the National Patient Register (NPR) and the Swedish Rheumatology Quality Register (SRQ) between 2001 and 2016. Each index patient was matched on age and sex to up to 50 general population controls. First-degree relatives of index patients and controls were identified through the Multi-Generation Register, with disease status ascertained in the NPR and SRQ. Familial risks were defined as odds ratios (ORs) of having AS when exposed to a first-degree relative with AS, using conditional logistic regression. RESULTS: The overall familial OR for AS was 19.4 (95% CI 18.1, 20.8). Estimates were similar for different relative types and by sex, but having more than one affected relative resulted in a higher risk [OR 68.0 (95% CI 51.3, 90.1)]. Heritability, estimated by assuming sibling risks were completely due to genetics, was 77% (95% CI 73, 80). CONCLUSION: Although the familial risk and heritability of AS are higher than for most other diseases, we report estimates that are substantially lower than commonly referenced numbers for AS from other populations.


Assuntos
Predisposição Genética para Doença , Espondilite Anquilosante/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Suécia , Adulto Jovem
20.
Ann Acad Med Singap ; 48(10): 321-329, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31875469

RESUMO

INTRODUCTION: Ankylosing spondylitis (AS) and Behçet's disease are known to be associated with the human leukocyte antigen (HLA)-B27 and HLA-B51 genes, respectively. However, many of their clinical findings-including articular and extra-articular symptoms-are similar, making diagnosis a challenge in the early stage of the disease. The aim of this study was to investigate the differences in clinical findings of AS patients with and without the HLA-B27 gene. MATERIALS AND METHODS: We performed a retrospective chart review of 151 AS patients. The following clinical findings were evaluated: oral ulcer, genital ulcer, skin manifestation, uveitis, peripheral arthritis; and gastrointestinal, cardiac and pulmonary involvement. Patients were divided into 4 groups based on absence or presence of the HLA-B27 and HLA-B51 genes. The number of patients with each clinical finding was subsequently examined in each group. RESULTS: The incidence of uveitis was significantly higher in the HLA-B27-positive group (P = 0.004); however, other clinical findings did not differ significantly according to the absence or presence of the HLA-B27 gene. There were no significant differences in the clinical findings of patients with positive and negative HLA-B51. CONCLUSION: HLA-B27 was associated with the development of uveitis but not with other clinical findings or disease activity in AS patients. HLA-B51 was not associated with the clinical findings or disease activity of AS.


Assuntos
Síndrome de Behçet/diagnóstico , Antígeno HLA-B27/genética , Antígeno HLA-B51/genética , Espondilite Anquilosante/diagnóstico , Adulto , Síndrome de Behçet/genética , Diagnóstico Diferencial , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espondilite Anquilosante/genética
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