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1.
Int J Mol Sci ; 21(24)2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348540

RESUMO

The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet's disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8+ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the "mis-immunopeptidome" that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8+ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases.


Assuntos
Aminopeptidases/genética , Síndrome de Behçet/imunologia , Coriorretinopatia de Birdshot/imunologia , Genes MHC Classe I , Antígenos de Histocompatibilidade Classe I/genética , Imunidade/genética , Antígenos de Histocompatibilidade Menor/genética , Psoríase/imunologia , Espondilite Anquilosante/imunologia , Alelos , Linfócitos T CD8-Positivos/imunologia , Humanos , Polimorfismo de Nucleotídeo Único
2.
PLoS One ; 15(5): e0233781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32459816

RESUMO

OBJECTIVE: Cases of inflammatory bowel disease (IBD) during treatment with interleukin (IL)-17 antagonists have been reported from trials in psoriasis, psoriatic arthritis, and ankylosing spondylitis. The aim of this study was to assess the overall risk for development of IBD due to IL-17 inhibition. DESIGN: Systematic review and meta-analysis of studies conducted 2010-2018 of treatment with IL-17 antagonists in patients with psoriasis, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. We compared risk of IBD development in anti-IL-17 treated patients compared to placebo treatments. We also computed incident rates of IBD overall. A 'worst case scenario' defining subjects ambiguous for prevalent versus incident cases for the latter was also applied. RESULTS: Sixty-six studies of 14,390 patients exposed to induction and 19,380 patients exposed to induction and/or maintenance treatment were included. During induction, 11 incident cases of IBD were reported, whereas 33 cases were diagnosed during the entire treatment period. There was no difference in the pooled risk of new-onset IBD during induction studies for both the best-case [risk difference (RD) 0.0001 (95% CI: -0.0011, 0.0013)] and worst-case scenario [RD 0.0008 (95% CI: -0.0005, 0.0022)]. The risk of IBD was not different from placebo when including data from maintenance and long-term extension studies [RD 0.0007 (95% CI: -0.0023, 0.0036) and RD 0.0022 (95% CI: -0.0010, 0.0055), respectively]. CONCLUSIONS: The risk for development of IBD in patients treated with IL-17 antagonists is not elevated. Prospective surveillance of patients treated with IL-17 antagonists with symptom and biomarker assessments is warranted to assess for onset of IBD in these patients.


Assuntos
Anticorpos Monoclonais , Artrite Psoriásica , Artrite Reumatoide , Doenças Inflamatórias Intestinais , Interleucina-17/antagonistas & inibidores , Espondilite Anquilosante , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/epidemiologia , Artrite Psoriásica/imunologia , Artrite Psoriásica/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/imunologia , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia
3.
Proc Natl Acad Sci U S A ; 117(11): 6056-6066, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123118

RESUMO

T helper (Th) cells are CD4+ effector T cells that play a critical role in immunity by shaping the inflammatory cytokine environment in a variety of physiological and pathological situations. Using a combined chemico-genetic approach, we identify histone H3K27 demethylases KDM6A and KDM6B as central regulators of human Th subsets. The prototypic KDM6 inhibitor GSK-J4 increases genome-wide levels of the repressive H3K27me3 chromatin mark and leads to suppression of the key transcription factor RORγt during Th17 differentiation. In mature Th17 cells, GSK-J4 induces an altered transcriptional program with a profound metabolic reprogramming and concomitant suppression of IL-17 cytokine levels and reduced proliferation. Single-cell analysis reveals a specific shift from highly inflammatory cell subsets toward a resting state upon demethylase inhibition. The root cause of the observed antiinflammatory phenotype in stimulated Th17 cells is reduced expression of key metabolic transcription factors, such as PPRC1. Overall, this leads to reduced mitochondrial biogenesis, resulting in a metabolic switch with concomitant antiinflammatory effects. These data are consistent with an effect of GSK-J4 on Th17 T cell differentiation pathways directly related to proliferation and include regulation of effector cytokine profiles. This suggests that inhibiting KDM6 demethylases may be an effective, even in the short term, therapeutic target for autoimmune diseases, including ankylosing spondylitis.


Assuntos
Benzazepinas/farmacologia , Histona Desmetilases/metabolismo , Histonas/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Pirimidinas/farmacologia , Células Th17/metabolismo , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Benzazepinas/uso terapêutico , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/imunologia , Código das Histonas/efeitos dos fármacos , Histona Desmetilases/antagonistas & inibidores , Humanos , Interleucina-17/metabolismo , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Cultura Primária de Células , Pirimidinas/uso terapêutico , RNA-Seq , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Fatores de Transcrição/metabolismo
4.
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
5.
Pediatr Rheumatol Online J ; 18(1): 6, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31941549

RESUMO

BACKGROUND: Axial SpA and Enthesitis related arthritis (ERA) patients show strong HLA-B27 association, gut dysbiosis, high toll like receptor (TLR)2 and 4 expression on monocytes, pro-inflammatory cytokine production and elevated levels of TLR4 endogenous ligands [tenascin-c (TNC) and myeloid related protein (MRP)8/14] in serum. Hence, we aimed to understand if these diseases have similar or different monocyte response. METHODS: Fifty adult axial SpA, 52 ERA patients and 25 healthy controls (HC) were enrolled. Cytokine-producing monocyte frequency before and after stimulation with lipopolysaccharide (LPS), peptidoglycan (PG), TNC or MRP8 were measured in whole blood (WB) and synovial fluid mononuclear cells (SFMC) by flow cytometry. Also, IL-6, TNF, MMP3, TNC and MRP8/14 levels were measured in unstimulated and TLR ligand stimulated WB cultures supernatant by ELISA. Finally, the mRNA expression levels of TNF and IL-6 were measured post stimulation with LPS, TNC and MRP8. RESULTS: At baseline, ERA and axial SpA patients showed similar TNF-α producing monocyte frequency which was higher than HC. MRP8 simulation led to increased TNF-α producing monocyte frequency in ERA than axial SpA. TNC and MRP8 stimulation led to similar IL-6 producing monocyte frequency in axial SpA and ERA patients. Baseline TNF and IL-6 producing monocyte frequency also modestly correlated with disease activity scores. TNF and IL-6 producing monocyte frequency increased in response to TLR stimulation in SFMC from both patients. In culture supernatants, axial SpA and ERA patients showed similar TNF production at baseline. MRP8 and TNC stimulation led to higher TNF production from ERA. Baseline IL-6 and MMP3 production was higher in ERA while TLR stimulation led to similar IL-6 and MMP3 production from axial SpA and ERA. TNC stimulation led to higher MMP3 production in ERA. mRNA expression in response to TLR stimulation was observed to be similar in axial SpA and ERA. TNC production was higher in ERA at baseline, while MRP8/14 production was higher in axial SpA than ERA post stimulation. CONCLUSION: ERA patients have similar monocyte response to exogenous and endogenous TLR ligands as patients with axial SpA. This suggests that differences between pediatric and adult-onset SpA are minimal and they may have a common pathogenesis.


Assuntos
Artrite Juvenil/imunologia , Vértebra Cervical Áxis , Monócitos/imunologia , Espondilite Anquilosante/imunologia , Adolescente , Adulto , Criança , Citocinas/metabolismo , Citometria de Fluxo , Antígeno HLA-B27/imunologia , Humanos , Interleucina-6/metabolismo , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
6.
Gastroenterology ; 158(6): 1554-1573.e12, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31926171

RESUMO

BACKGROUND & AIMS: Inhibitors of Janus kinases (JAKs) are being developed for treatment of inflammatory bowel diseases and other immune-mediated diseases. Tofacitinib is effective in treatment of ulcerative colitis, but there are safety concerns. We performed a systematic review and meta-analysis to investigate the safety profile of tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with rheumatoid arthritis, inflammatory bowel diseases, psoriasis, or ankylosing spondylitis. METHODS: We searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials from January 1, 1990, through July 1, 2019. We performed a manual review of conference databases from 2012 through 2018. The primary outcome was incidence rates of adverse events (AEs) and serious AEs. We also estimated incidence rates of serious infections, herpes zoster infection, non-melanoma skin cancer, other malignancies, major cardiovascular events, venous thromboembolism, and mortality. We performed a meta-analysis, which included controlled studies, to assess the relative risk of these events. RESULTS: We identified 973 studies; of these, 82 were included in the final analysis, comprising 66,159 patients with immune-mediated diseases who were exposed to a JAK inhibitor. Two-thirds of the included studies were randomized controlled trials. The incidence rate of AEs was 42.65 per 100 person-years and of serious AEs was 9.88 per 100 person-years. Incidence rates of serious infections, herpes zoster infection, malignancy, and major cardiovascular events were 2.81 per 100 person-years, 2.67 per 100 person-years, 0.89 per 100 person-years, and 0.48 per 100 person-years, respectively. Mortality was not increased in patients treated with JAK inhibitors compared with patients given placebo or active comparator (relative risk 0.72; 95% confidence interval 0.40-1.28). The meta-analysis showed a significant increase in risk of herpes zoster infection among patients who received JAK inhibitors (relative risk 1.57; 95% confidence interval 1.04-2.37). CONCLUSIONS: In a systematic review and meta-analysis, we found an increased risk of herpes zoster infection among patients with immune-mediated diseases treated with JAK inhibitors. All other AEs were not increased among patients treated with JAK inhibitors.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Herpes Zoster/epidemiologia , Doenças Inflamatórias Intestinais/tratamento farmacológico , Inibidores de Janus Quinases/efeitos adversos , Psoríase/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/mortalidade , Azetidinas/efeitos adversos , Herpes Zoster/induzido quimicamente , Herpes Zoster/imunologia , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Incidência , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/mortalidade , Inibidores de Janus Quinases/administração & dosagem , Janus Quinases/antagonistas & inibidores , Janus Quinases/imunologia , Janus Quinases/metabolismo , Piperidinas/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Psoríase/imunologia , Psoríase/mortalidade , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Pirróis/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/mortalidade , Sulfonamidas/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento , Triazóis/efeitos adversos
7.
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
8.
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
9.
Clin Exp Rheumatol ; 38(2): 267-274, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31365335

RESUMO

OBJECTIVES: To evaluate the long-term drug retention, efficacy, and safety of the infliximab biosimilar CT-P13 in Korean patients with ankylosing spondylitis (AS) in clinical practice. The primary outcome was drug retention (i.e. time to treatment discontinuation or changing to another biologic) in Korean patients with AS. Additional outcomes included efficacy and safety. METHODS: Data were collected through the Korean College of Rheumatology Biologics (KOBIO) registry (ClinicalTrials.gov identifier: NCT01965132). CT-P13 efficacy was assessed using standard disease activity parameters, and safety was evaluated by adverse events (AEs). RESULTS: Between December 2012 and December 2017, 244 patients with AS treated with CT-P13 were enrolled. Of those, 203 (83.2%) received CT-P13 as first-line therapy. The median duration of treatment was 2.05 years. After 4 years' follow-up, the retention rate of CT-P13 in the overall patient population was 66%. Treatment changes or discontinuations occurred in 38 (15.6%) and 32 (13.1%) patients, respectively. Lack of efficacy was the most common reason for treatment changes, whereas AEs were the most common single cause of discontinuation. Disease activity decreased markedly from baseline following initiation of CT-P13 treatment, and thereafter remained stable. A total of 313 AEs occurred in 118 patients (48.4%); the majority (94.6%) were mild or moderate in severity. The most common treatment-related AEs were infusion or injection-site reactions (4.1% of patients), uveitis (3.7%), and skin rash (3.7%). CONCLUSIONS: In this real-world study, CT-P13 demonstrated encouraging drug retention rates and times, together with reasonable long-term efficacy and safety, in Korean patients with AS.


Assuntos
Antirreumáticos , Medicamentos Biossimilares , Infliximab , Espondilite Anquilosante , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/uso terapêutico , Humanos , Infliximab/efeitos adversos , Infliximab/uso terapêutico , Sistema de Registros , República da Coreia , Reumatologia , Índice de Gravidade de Doença , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/imunologia , Resultado do Tratamento
10.
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
11.
Ann Rheum Dis ; 79(1): 132-140, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31662318

RESUMO

OBJECTIVES: Diverse evidence including clinical, genetic and microbiome studies support a major role of the gut microbiome in the common immune-mediated arthropathy, ankylosing spondylitis (AS). We set out to (1) further define the key microbial characteristics driving disease, and (2) examine the effects of tumour necrosis factor-inhibitor (TNFi) therapy upon the microbiome. METHODS: The stools from a case-control cohort of 250 Han-Chinese subjects underwent shotgun metagenomic sequencing. All subjects were genotyped using the Illumina CoreExome SNP microarray. RESULTS: Previous reports of gut dysbiosis in AS were reconfirmed and several notable bacterial species and functional categories were differentially abundant. TNFi therapy was correlated with a restoration the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. Enrichment of bacterial peptides homologous to HLA-B27-presented epitopes was observed in the stools of patients with AS, suggesting that either HLA-B27 fails to clear these or that they are involved in driving HLA-B27-associated immune reactions. TNFi therapy largely restored the perturbed microbiome observed in untreated AS cases to that of healthy controls, including several important bacterial species that have been previously associated with AS and other related diseases. TNFi therapy of patients with AS was also associated with a reduction of potentially arthritogenic bacterial peptides, relative to untreated patients. CONCLUSION: These findings emphasise the key role that the gut microbiome plays in driving the pathogenesis of AS and highlight potential therapeutic and/or preventative targets.


Assuntos
Disbiose/microbiologia , Microbioma Gastrointestinal/genética , Metagenoma , Espondilite Anquilosante/microbiologia , Adulto , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , China , Reações Cruzadas , Disbiose/imunologia , Epitopos/imunologia , Feminino , Microbioma Gastrointestinal/imunologia , Antígeno HLA-B27/imunologia , Humanos , Masculino , Metagenômica , Pessoa de Meia-Idade , Peptídeos/imunologia , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/imunologia , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto Jovem
12.
Sci Rep ; 9(1): 18000, 2019 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-31784598

RESUMO

To prevent spinal progression in ankylosing spondylitis, initiating TNF-inhibitor treatment as early as possible is suggested. However, the outcomes are inconsistent in previous clinical studies. Here, we investigated the effect of TNF inhibition alone on spinal progression when used during arthritis development in a murine model. We injected 8-week-old SKG mice with curdlan (curdlan group). We injected adalimumab at 3 and 9 weeks after the first curdlan injection (ADA group). The clinical scores of peripheral arthritis decreased in the ADA group at 3 weeks after first adalimumab injection. Using positron emission tomography-magnetic resonance imaging and histologic examination, spinal inflammation was observed in the curdlan group, and was significantly deceased in the ADA group. However, spinal osteoblast activities by imaging using OsteoSense 680 EX and bone metabolism-related cytokines such as receptor activator of nuclear factor-kappa B ligand, osteoprotegerin, Dickkopf-1, and sclerostin levels except IL-17A level were not different between the two groups. We conclude that treating TNF inhibitor alone reduced peripheral arthritis score and spinal inflammation in curdlan-injected SKG mice but did not decrease the spinal osteoblast activity, suggesting little effect on spinal ankylosis.


Assuntos
Adalimumab/administração & dosagem , Artrite Experimental/tratamento farmacológico , Coluna Vertebral/efeitos dos fármacos , Espondilite Anquilosante/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Artrite Experimental/diagnóstico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Progressão da Doença , Feminino , Humanos , Injeções Intraperitoneais , Camundongos , Índice de Gravidade de Doença , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/imunologia , Coluna Vertebral/patologia , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Tomografia Computadorizada por Raios X , beta-Glucanas/administração & dosagem , beta-Glucanas/imunologia
13.
Arthritis Res Ther ; 21(1): 239, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31722720

RESUMO

BACKGROUND: Bone marrow mesenchymal stem cells (BM-MSCs) can dampen inflammation in animal models of inflammatory rheumatisms and human osteoarthritis. They are expected to be a solution for numerous human conditions. However, in rheumatoid arthritis (RA) and spondyloarthritis (SpA), subsets of subchondral BM-MSCs might conversely fuel synovitis and enthesitis. MAIN TEXT: Abnormal behaviour of BM-MSCs and/or their progeny has been found in RA and SpA. BM-MSCs also contribute to the ossifying processes observed in ankylosing spondylitis. Some synovial fibroblastic stem cells probably derive from BM-MSCs, but some stem cells can also migrate through the bare zone area of joints, not covered by cartilage, into the synovium. BM-MSCs can also migrate in the synovium over tendons. Sub-populations of bone marrow stem cells also invade the soft tissue side of enthesis via small holes in the bone cortex. The present review aims (1) to make a focus on these two aspects and (2) to put forward the hypothesis that lasting epigenetic changes of some BM-MSCs, induced by transient infections of the bone marrow close to the synovium and/or entheses (i.e. trained immunity of BM-MSCs and/or their progeny), contribute to the pathogenesis of inflammatory rheumatisms. Such hypothesis would fit with (1) the uneven distribution and/or flares of arthritis and enthesitis observed at the individual level in RA and SpA (reminiscent of what is observed following reactive arthritis and/or in Whipple's disease); (2) the subchondral bone marrow oedema and erosions occurring in many RA patients, in the bare zone area; and (3) the frequent relapses of RA and SpA despite bone marrow transplantation, whereas most BM-MSCs resist graft preconditioning. CONCLUSION: Some BM-MSCs might be more the problem than the solution in inflammatory rheumatisms. Subchondral bone marrow BM-MSCs and their progeny trafficking through the bare zone area of joints or holes in the bone cortex of entheses should be thoroughly studied in RA and SpA respectively. This may be done first in animal models. Mini-arthroscopy of joints could also be used in humans to specifically sample tissues close to the bare zone and/or enthesis areas.


Assuntos
Artrite Reumatoide/imunologia , Células-Tronco Mesenquimais/imunologia , Espondilartrite/imunologia , Espondilite Anquilosante/imunologia , Animais , Artrite Reumatoide/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Espondilartrite/metabolismo , Espondilite Anquilosante/metabolismo
14.
Int J Mol Sci ; 20(21)2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683793

RESUMO

Rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA) make up a group of chronic immune-mediated inflammatory diseases (IMIDs). The course of these diseases involves chronic inflammation of joints and enthesopathies, which can result in joint damage and disability. Microparticles (MPs) are a group of small spherical membranous vesicles. The structure and cellular origin of MPs, mechanisms that stimulate their secretion and the place of their production, determine their biological properties, which could become manifest in the pathogenesis of immune-mediated inflammatory diseases. Microparticles can stimulate synovitis with proinflammatory cytokines and chemokines. MPs may also contribute to the pathogenesis of rheumatic diseases by the formation of immune complexes and complement activation, pro-coagulation activity, activation of vascular endothelium cells, and stimulation of metalloproteinase production. It seems that in the future, microparticles can become a modern marker of disease activity, a response to treatment, and, possibly, they can be used in the prognosis of the course of arthritis. The knowledge of the complexity of MPs biology remains incomplete and it requires further comprehensive studies to explain how they affect the development of rheumatic diseases. This review focuses on the immunopathogenic and therapeutic role of MPs in chronic immune-mediated inflammatory joint diseases.


Assuntos
Micropartículas Derivadas de Células/imunologia , Entesopatia/imunologia , Inflamação/imunologia , Artropatias/imunologia , Artrite Juvenil/imunologia , Artrite Juvenil/metabolismo , Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Micropartículas Derivadas de Células/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Entesopatia/metabolismo , Humanos , Inflamação/metabolismo , Artropatias/metabolismo , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/metabolismo
15.
Int J Rheum Dis ; 22(12): 2206-2212, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31721427

RESUMO

INTRODUCTION: The Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) are commonly used instruments for measuring disease activity. However, few studies have assessed their psychometric properties in patients with axial spondyloarthritis (axSpA). We aimed to assess the validity and reliability of ASDAS-CRP and BASDAI in patients with axSpA in Singapore. METHODS: Cross-sectional data from 280 patients with axSpA from a dedicated axSpA clinic in a Singapore tertiary referral hospital from 2011 to 2019 were used. Internal consistency was assessed using Cronbach's alpha. Construct validity was assessed through 12 a priori hypotheses by correlation of overall ASDAS-CRP and BASDAI score with other patient-reported outcomes measures (PROMs). Structural validity was evaluated via confirmatory factor analysis using maximum-likelihood method, where Comparative Fit Index (CFI) >0.95, Tucker-Lewis Index (TLI) >0.95, Root Mean Square Error of Approximation (RMSEA) <0.06 and Standardized Root Mean Residuals (SRMR) <0.08 were indicative of good fit. RESULTS: Among 280 patients (78.2% Male; 92.5% Chinese), ASDAS-CRP showed poor internal consistency of 0.33, while BASDAI showed high internal consistency of 0.87. Convergent and divergent construct validity were demonstrated by fulfillment of 11 out of 12 a priori hypotheses when ASDAS-CRP and BASDAI were compared with other PROMs. Our proposed ASDAS-CRP and BASDAI model showed good fit for a 1-factor structure respectively (CFI = 0.993, TLI = 0.984, RMSEA = 0.036, SRMR = 0.026 for ASDAS-CRP; CFI = 0.993, TLI = 0.985, RMSEA = 0.057, SRMR = 0.022 for BASDAI), demonstrating structural validity. CONCLUSION: This study supports the use of both ASDAS-CRP and BASDAI in measuring disease activity in patients with axSpA in Singapore.


Assuntos
Proteína C-Reativa/análise , Indicadores Básicos de Saúde , Mediadores da Inflamação/sangue , Espondilite Anquilosante/diagnóstico , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Singapura , Espondilite Anquilosante/sangue , Espondilite Anquilosante/imunologia , Adulto Jovem
16.
Nat Commun ; 10(1): 4575, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594933

RESUMO

IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases.


Assuntos
Autoimunidade/genética , Subunidade alfa de Receptor de Interleucina-7/genética , Interleucina-7/imunologia , Monócitos/imunologia , Espondilite Anquilosante/genética , Alelos , RNA Helicases DEAD-box/imunologia , RNA Helicases DEAD-box/metabolismo , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Voluntários Saudáveis , Humanos , Interleucina-7/metabolismo , Subunidade alfa de Receptor de Interleucina-7/imunologia , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Lipopolissacarídeos/imunologia , Monócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de RNA , Análise de Célula Única , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Líquido Sinovial/citologia , Líquido Sinovial/imunologia , Regulação para Cima/imunologia
17.
Int J Rheum Dis ; 22(11): 2073-2079, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31647182

RESUMO

We describe a previously unreported association of ankylosing spondylitis with synovial chondromatosis, and briefly review previously reported cases and treatment of synovial chondromatosis in patients with other immune-mediated inflammatory arthritides. A 20-year-old man with ankylosing spondylitis whose axial disease was in remission with nonsteroidal anti-inflammatory drugs and oral disease-modifying anti-rheumatic drugs developed recurrent right knee pain and swelling. Magnetic resonance imaging of his right knee revealed calcified loose bodies, suggestive of synovial chondromatosis. While waiting for the surgical intervention and other invasive therapy previously reported in patients with synovial chondromatosis, a trial of etanercept eliminated the pain and swelling of the knee; however, the loose bodies have persisted during the 2-year follow-up. Thus, synovial chondromatosis should be considered in the differential diagnoses of a refractory monoarticular pain and swelling in patients with otherwise controlled inflammatory arthritis. Our report advocates a trial of anti-tumor necrosis factor drugs, which might delay the need for invasive therapy in patients with synovial chondromatosis.


Assuntos
Condromatose Sinovial/tratamento farmacológico , Etanercepte/uso terapêutico , Espondilite Anquilosante/tratamento farmacológico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Condromatose Sinovial/diagnóstico , Condromatose Sinovial/imunologia , Humanos , Masculino , Espondilite Anquilosante/diagnóstico , Espondilite Anquilosante/imunologia , Resultado do Tratamento , Adulto Jovem
18.
Mol Med Rep ; 20(4): 3565-3572, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485664

RESUMO

Ankylosing spondylitis (AS) is a common chronic inflammatory autoimmune disease. Toll­like receptors (TLRs) are involved in non­specific immunity. In the present study, the roles of TLRs in AS were investigated. The levels of inflammatory cytokines were detected by ELISA and reverse transcription­quantitative polymerase chain reaction (RT­qPCR). The expression levels of TLRs and nuclear factor­κB (NF­κB) signaling­associated factors were determined via RT­qPCR and western blot analyses. It was observed that the levels of interleukin (IL)­6, tumor necrosis factor­α (TNF­α), C­reactive protein, TLR4 and TLR5 were increased in patients with AS, whereas those of IL­10 and TLR3 were decreased. Pomalidomide, a TNF­α release inhibitor, reduced the expression of IL­6, TNF­α, TLR4, TLR5 and phosphorylated­p65, and upregulated that of IL­10, TLR3 and p65 in peripheral blood mononuclear cells from patients with AS. Treatment of patients with infliximab, an anti­TNF­α monoclonal antibody, induced similar effects in vivo. In conclusion, it was revealed that inhibition of TNF­α suppressed inflammatory responses in patients with AS, increased the expression of TLR3 and decreased NF­κB signaling, and the expression of TLR4 and TLR5. The results indicated that TLRs and the NF­κB signaling pathway were involved in the regulation of inflammatory responses in AS. These findings provided insight into the mechanisms underlying the development of AS and potential novel therapeutic approaches.


Assuntos
Leucócitos Mononucleares/patologia , Espondilite Anquilosante/genética , Receptores Toll-Like/genética , Adulto , Idoso , Regulação para Baixo , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/genética , NF-kappa B/imunologia , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia , Receptores Toll-Like/imunologia , Regulação para Cima
19.
Stem Cells Dev ; 28(20): 1398-1412, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31456484

RESUMO

The pathogenesis of ankylosing spondylitis (AS), an immune-mediated inflammatory disease, remains largely unknown. We previously reported that the immunoregulatory function of mesenchymal stem cells (MSCs) was dysfunctional in AS. Furthermore, it has been demonstrated that TLR3 and TLR4 could regulate the immunoregulatory function of MSCs. Therefore, this study aimed to investigate the effect of TLR3 and TLR4 activation on the immunoregulatory function of AS-MSCs. By gene expression and western blot analyses, we found that both TLR3 and TLR4 in AS-MSCs to be downregulated when compared with MSCs derived from healthy donors (HDs). Despite the lower basal expression of TLRs, AS-MSCs were as sensitive or more sensitive to TLR agonists as compared with HD-MSCs in terms of activation of p38 and ERK MAPK signaling pathways. Furthermore, TLR4-primed AS-MSCs were observed to possess enhanced immunoregulatory effects against the proliferation of naive CD4+ T cells than HD-MSCs due to elevated IL-10 production. However, TLR activation or the source of MSCs did not affect MSC-induced differentiation of naive CD4+ T cells to Th17 cells. Similarly, the MSC-induced inhibition of Treg cell differentiation of naive CD4+ T cells was not affected by TLR activation or MSC source. MSC-induced Th17 differentiation was likely mediated by the elevated secretion of proinflammatory cytokines, IL-6 and IL-17, and reduced expression of IL-2, IL-4, and IFN-γ, which were not affected by TLR activation. Taken together, our results suggest that TLR3 and TLR4 may play an important role in the immunoregulatory function of MSCs in AS patients.


Assuntos
Comunicação Celular/imunologia , Regulação da Expressão Gênica/imunologia , Células-Tronco Mesenquimais/imunologia , Espondilite Anquilosante/imunologia , Receptor 3 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Estudos de Casos e Controles , Comunicação Celular/genética , Diferenciação Celular , Proliferação de Células , Técnicas de Cocultura , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Sistema de Sinalização das MAP Quinases , Células-Tronco Mesenquimais/patologia , Espondilite Anquilosante/genética , Espondilite Anquilosante/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th17/imunologia , Células Th17/patologia , Receptor 3 Toll-Like/genética , Receptor 4 Toll-Like/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
20.
Mol Med Rep ; 20(4): 3388-3394, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432140

RESUMO

Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease. MicroRNAs (miRNAs) are a group of endogenous small non­coding RNAs that regulate target genes, and play a critical role in many biological processes. However, the underlying mechanism of specific miRNA, miR­130a­3p, in AS remains largely unknown. Therefore, the present study aimed to explore the underlying mechanism of miR­130a­3p in the development of AS. In the present study, it was revealed that miR­130a­3p was downregulated in T cells from HLA­B27­positive AS patients compared with the HLA­B27­negative healthy controls. Next, bioinformatics software TargetScan 7.2 was used to predict the target genes of miR­130a­3p, and a luciferase reporter assay indicated that HOXB1 was the direct target gene of miR­130a­3p. Furthermore, it was determined that HOXB1 expression was upregulated in T cells from HLA­B27­positive AS patients. In addition, the results of the present study indicated that miR­130a­3p inhibitor significantly inhibited cell proliferation ability and induced cell apoptosis of Jurkat T cells, while the miR­130a­3p mimic promoted proliferation ability and inhibited cell apoptosis of Jurkat T cells. Notably, all the effects of the miR­130a­3p mimic on Jurkat T cells were reversed by HOXB1­plasmid. Collectively, our data indicated that miR­130a­3p was decreased in T cells from AS patients and it could regulate T­cell survival by targeting HOXB1.


Assuntos
Apoptose/imunologia , Regulação para Baixo/imunologia , MicroRNAs/imunologia , Espondilite Anquilosante/imunologia , Linfócitos T/imunologia , Adulto , Sobrevivência Celular/imunologia , Feminino , Antígeno HLA-B27/imunologia , Proteínas de Homeodomínio/imunologia , Humanos , Células Jurkat , Masculino , Pessoa de Meia-Idade , Espondilite Anquilosante/patologia , Linfócitos T/patologia
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