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1.
Psychiatry Res ; 317: 114812, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36058039

RESUMO

The negative relationship between schizophrenia (SCZ) and rheumatoid arthritis (RA) has been observed for 85 years, but the mechanisms driving this association are unknown. This study analyzed differences in profiles of cytokines (IL-1ß, IL-Ra, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFNγ, TNFα), selected genes (HLA-DRB1, IL1RN, HP2), and antibodies related to gluten sensitivity (AGA-IgG, AGA-IgA), celiac disease (tTG), and systemic autoimmunity (ANA, anti-CCP, RF) in 40 subjects with SCZ, 40 with RA, and 40 healthy controls (HC). HLA-DRB1*04:01 alleles were enriched in persons with SCZ and RA compared with HC, and the HP2/HP2 genotype was 2-fold more prevalent in AGA/tTG-positive versus negative SCZ patients. Patients with SCZ demonstrated 52.5% positivity for any of the antibodies tested, compared to 90% of RA patients and 30% of HC. Cluster analysis of the cytokines revealed three clusters: one associated with SCZ marked by high levels of IL-1Ra, one associated with HC, and one associated with both SCZ and RA marked by elevated levels of IFNγ, TNFα, and IL-6. These analyses suggest that stratification of SCZ patients by cytokine profile may identify unique SCZ subgroups and enable the use of currently available cytokine-targeted treatment strategies.


Assuntos
Artrite Reumatoide , Esquizofrenia , Humanos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos , Citocinas , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Interleucina-6 , Peptídeos Cíclicos , Esquizofrenia/genética , Esquizofrenia/imunologia , Fator de Necrose Tumoral alfa
2.
Front Immunol ; 13: 980805, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091038

RESUMO

Observations from numerous clinical, epidemiological and serological studies link periodontitis with severity and progression of rheumatoid arthritis. The strong association is observed despite totally different aetiology of these two diseases, periodontitis being driven by dysbiotic microbial flora on the tooth surface below the gum line, while rheumatoid arthritis being the autoimmune disease powered by anti-citrullinated protein antibodies (ACPAs). Here we discuss genetic and environmental risk factors underlying development of both diseases with special emphasis on bacteria implicated in pathogenicity of periodontitis. Individual periodontal pathogens and their virulence factors are argued as potentially contributing to putative causative link between periodontal infection and initiation of a chain of events leading to breakdown of immunotolerance and development of ACPAs. In this respect peptidylarginine deiminase, an enzyme unique among prokaryotes for Porphyromonas gingivalis, is elaborated as a potential mechanistic link between this major periodontal pathogen and initiation of rheumatoid arthritis development.


Assuntos
Anticorpos Anti-Proteína Citrulinada , Artrite Reumatoide , Periodontite , Desiminases de Arginina em Proteínas , Anticorpos Anti-Proteína Citrulinada/genética , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/genética , Autoanticorpos/imunologia , Humanos , Periodontite/complicações , Periodontite/genética , Periodontite/imunologia , Periodontite/microbiologia , Porphyromonas gingivalis/enzimologia , Porphyromonas gingivalis/genética , Desiminases de Arginina em Proteínas/genética , Desiminases de Arginina em Proteínas/imunologia
3.
Front Immunol ; 13: 913830, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967391

RESUMO

Objective: MALT1 regulates immunity and inflammation in multiple ways, while its role in rheumatoid arthritis (RA) is obscure. This study aimed to investigate the relationship of MALT1 with disease features, treatment outcome, as well as its effect on Th1/2/17 cell differentiation and underlying molecule mechanism in RA. Methods: Totally 147 RA patients were enrolled. Then their blood Th1, Th2, and Th17 cells were detected by flow cytometry. Besides, PBMC MALT1 expression was detected before treatment (baseline), at week (W) 6, W12, and W24. PBMC MALT1 in 30 osteoarthritis patients and 30 health controls were also detected. Then, blood CD4+ T cells were isolated from RA patients, followed by MALT1 overexpression or knockdown lentivirus transfection and Th1/2/17 polarization assay. In addition, IMD 0354 (NF-κB antagonist) and SP600125 (JNK antagonist) were also added to treat CD4+ T cells. Results: MALT1 was increased in RA patients compared to osteoarthritis patients and healthy controls. Meanwhile, MALT1 positively related to CRP, ESR, DAS28 score, Th17 cells, negatively linked with Th2 cells, but did not link with other features or Th1 cells in RA patients. Notably, MALT1 decreased longitudinally during treatment, whose decrement correlated with RA treatment outcome (treatment response, low disease activity, or disease remission). In addition, MALT1 overexpression promoted Th17 differentiation, inhibited Th2 differentiation, less affected Th1 differentiation, activated NF-κB and JNK pathways in RA CD4+ T cells; while MALT1 knockdown exhibited the opposite effect. Besides, IMD 0354 and SP600125 addition attenuated MALT1's effect on Th2 and Th17 differentiation. Conclusion: MALT1 regulates Th2 and Th17 differentiation via NF-κB and JNK pathways, as well as correlates with disease activity and treatment outcome in RA.


Assuntos
Artrite Reumatoide , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , NF-kappa B , Osteoartrite , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Diferenciação Celular , Humanos , Leucócitos Mononucleares/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Osteoartrite/metabolismo , Células Th17/imunologia , Células Th2/imunologia , Resultado do Tratamento
4.
Front Immunol ; 13: 932627, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35967356

RESUMO

Background: Despite immune cell dysregulation being an important event preceding the onset of rheumatoid arthritis (RA), the phenotype of T and B cells in preclinical RA is less understood. The aim of this study was to characterize T and B cell populations in RA patients and their autoantibody (aAb) negative and positive first-degree relatives (FDR). Methods: Cryopreserved peripheral blood mononuclear cells (PBMCs) collected at scheduled visits from aAb-(n=25), and aAb+ FDR (n=10) and RA patients (n=13) were thawed and stained using optimized antibody cocktails as per a specific 13-color T or B cell panel. Immunophenotyping was performed using a Cytoflex LX (Beckman-Coulter) flow cytometer and FlowJo software was used for analyzing the frequency of immune cell populations. Results: Multicolor flow cytometry experiments identified an increased TIGIT expression in circulating lymphocytes of aAb+ FDR and RA patients, relative to aAb- FDR (P<0.01). These TIGIT+ T cells exhibited a memory phenotype and expressed high levels of PD-1, ICOS, HLA-DR, CXCR3 and CXCR5. Moreover, increased TIGIT+ CD4 T cell frequency correlated with the frequency of PD-1+ CD4 T cells (r = 0.4705: P = 0.0043) and circulating levels of ACPA and RF. We also identified a decreased frequency of CD27+IgD- switched memory B cells in RA patients (P < 0.01), while increased frequency of TIGIT+ CD4 T cells in FDR correlated with the frequency of PD1+PTEN+ B cells (r = 0.6838, P = 0.0004) and autoantibody positivity (P = 0.01). Conclusion: We demonstrate TIGIT as a distinct CD4 T cell marker for differentiating aAb- FDR from aAb+FDR and might play a critical role in regulating T and B cell crosstalk in preclinical RA.


Assuntos
Artrite Reumatoide , Linfócitos T CD4-Positivos , Receptores Imunológicos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/genética , Autoanticorpos/imunologia , Linfócitos T CD4-Positivos/imunologia , Humanos , Leucócitos Mononucleares/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Subpopulações de Linfócitos T/imunologia
5.
Front Immunol ; 13: 930112, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35774784

RESUMO

The risk to develop ACPA positive rheumatoid arthritis (RA), the most destructive type of autoimmune arthritis, is carried by HLA-DRB1 alleles containing a 5 amino acid motif: the shared epitope (SE). RA is preceded by the emergence of disease specific anti citrullinated protein antibodies (ACPA). SE positive HLA-DRB1 alleles are associated with ACPA and ACPA positive RA, not with ACPA negative RA, suggesting that ACPA contribute to the pathogenesis of RA. Understanding how HLA-DRB1 genotypes influence ACPA could lead to a curative or preventive treatment of RA. The "Shared epitope binds citrullinated peptides " hypothesis suggests that RA associated HLA-DR alleles present citrullinated peptides to T cells that help ACPA producing B cells. The "Hapten carrier model" suggests that PAD4 is the target of the T cells which help ACPA specific B cells through a hapten carrier mechanism in which PAD4 is the carrier and citrullinated peptides are the haptens. Direct binding assay of citrullinated peptides to purified HLA-DR molecules does not support the "shared epitope binds citrullinated peptides" hypothesis. The Odds Ratios to develop ACPA positive RA associated with each of 12 common HLA-DRB1 genotypes match the probability that the two HLA-DR molecules they encode can bind at least one peptide from PAD4, not from citrullinated fibrinogen. Thus, PAD4 tolerization might stop the carrier effect and switch off production of ACPA.


Assuntos
Artrite Reumatoide , Autoanticorpos , Citrulinação , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Autoanticorpos/biossíntese , Epitopos , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Haptenos/genética , Haptenos/imunologia , Humanos , Peptídeos/genética , Peptídeos/imunologia , Peptídeos Cíclicos/genética , Peptídeos Cíclicos/imunologia
6.
Adv Rheumatol ; 62(1): 25, 2022 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-35820936

RESUMO

BACKGROUND: Phospholipase C-like 1 (PLCL1), a protein that lacks catalytic activity, has similar structures to the PLC family. The aim of this research was to find the function and underlying mechanisms of PLCL1 in fibroblast-like synoviocyte (FLS) of rheumatoid arthritis (RA). METHODS: In this study, we first analyzed the expression of PLCL1 in the synovial tissue of RA patients and K/BxN mice by immunohistochemical staining. Then silencing or overexpressing PLCL1 in FLS before stimulating by TNF-α. The levels of IL-6, IL-1ß and CXCL8 in FLS and supernatants were detected by Western Blot (WB), Real-Time Quantitative PCR and Enzyme Linked Immunosorbent Assay. We used INF39 to specifically inhibit the activation of NLRP3 inflammasomes, and detected the expression of NLRP3, Cleaved Caspase-1, IL-6 and IL-1ß in FLS by WB. RESULT: When PLCL1 was silenced, the level of IL-6, IL-1ß and CXCL8 were down-regulated. When PLCL1 was overexpressed, the level of IL-6, IL-1ß and CXCL8 were unregulated. The previous results demonstrated that the mechanism of PLCL1 regulating inflammation in FLS was related to NLRP3 inflammasomes. INF39 could counteract the release of inflammatory cytokines caused by overexpression of PLCL1. CONCLUSION: Result showed that the function of PLCL1 in RA FLS might be related to the NLRP3 inflammasomes. We finally confirmed our hypothesis with the NLRP3 inhibitor INF39. Our results suggested that PLCL1 might promote the inflammatory response of RA FLS by regulating the NLRP3 inflammasomes.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Artrite Reumatoide , Proteína 3 que Contém Domínio de Pirina da Família NLR , Fosfoinositídeo Fosfolipase C , Sinoviócitos , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Fibroblastos/metabolismo , Humanos , Inflamassomos/metabolismo , Inflamação , Interleucina-6/imunologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fosfoinositídeo Fosfolipase C/imunologia , Sinoviócitos/imunologia , Sinoviócitos/patologia
7.
Nat Commun ; 13(1): 4046, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831277

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease affecting synovial joints where different CD4+ T cell subsets may contribute to pathology. Here, we perform single cell sequencing on synovial CD4+ T cells from anti-citrullinated protein antibodies (ACPA)+ and ACPA- RA patients and identify two peripheral helper T cell (TPH) states and a cytotoxic CD4+ T cell subset. We show that the adhesion G-protein coupled receptor 56 (GPR56) delineates synovial CXCL13high TPH CD4+ T cells expressing LAG-3 and the tissue-resident memory receptors CXCR6 and CD69. In ACPA- SF, TPH cells display lower levels of GPR56 and LAG-3. Further, most expanded T cell clones in the joint are within CXCL13high TPH CD4+ T cells. Finally, RNA-velocity analyses suggest a common differentiation pathway between the two TPH clusters and effector CD4+ T cells. Our study provides comprehensive immunoprofiling of the synovial CD4+ T cell subsets in ACPA+ and ACPA- RA.


Assuntos
Artrite Reumatoide , Receptores Acoplados a Proteínas G , Linfócitos T Auxiliares-Indutores , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Humanos , Articulações/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia
8.
Int J Mol Sci ; 23(10)2022 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-35628640

RESUMO

Anti-citrullinated protein antibodies (ACPAs) are involved in the pathogenesis of rheumatoid arthritis. N-glycosylation pattern of ACPA-IgG and healthy IgG Fc differs. The aim of this study is to determine the relative sialylation and galactosylation level of ACPAs and control IgG to assess their capability of inducing TNFα production, and furthermore, to analyze the correlations between the composition of Fc glycans and inflammatory markers in RA. We isolated IgG from sera of healthy volunteers and RA patients, and purified ACPAs on a citrulline-peptide column. Immunocomplexes (IC) were formed by adding an F(ab)2 fragment of anti-human IgG. U937 cells were used to monitor the binding of IC to FcγR and to trigger TNFα release determined by ELISA. To analyze glycan profiles, control IgG and ACPA-IgG were digested with trypsin and the glycosylation patterns of glycopeptides were analyzed by determining site-specific N-glycosylation using nano-UHPLC-MS/MS. We found that both sialylation and galactosylation levels of ACPA-IgG negatively correlate with inflammation-related parameters such as CRP, ESR, and RF. Functional assays show that dimerized ACPA-IgG significantly enhances TNFα release in an FcγRI-dependent manner, whereas healthy IgG does not. TNFα production inversely correlates with the relative intensities of the G0 glycoform, which lacks galactose and terminal sialic acid moieties.


Assuntos
Artrite Reumatoide , Imunoglobulina G , Fator de Necrose Tumoral alfa , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Glicosilação , Humanos , Imunoglobulina G/imunologia , Receptores Fc/imunologia , Espectrometria de Massas em Tandem , Fator de Necrose Tumoral alfa/imunologia
9.
Sci Data ; 9(1): 196, 2022 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534493

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.


Assuntos
Artrite Reumatoide , Bancos de Espécimes Biológicos , Vacinas , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Autoanticorpos , Humanos , Monócitos/imunologia , Proteômica
10.
Immunol Invest ; 51(6): 1804-1819, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35404706

RESUMO

OBJECTIVE: This study aims to elucidate the changes in the percentage of GPR56 and/or granzyme B (GZMB) positive cells in rheumatoid arthritis (RA) CD4 and CD8 T lymphocytes, and to explore their clinical value in diagnosing and reflecting the progression of RA. METHODS: The percentages of GPR56 and/or GZMB positive cells were analyzed in peripheral blood (PB) and spleen T cells in a collagen-induced arthritis (CIA) model established in DBA/1 mice. The percentages of GPR56+ and/or GZMB+ cells were further analyzed in PBs from RA patients and healthy controls. Correlation analysis was performed between clinical indicators and GPR56+, GZMB+, and GPR56+ GZMB+ T cells. Receiver operating characteristic (ROC) curves were used to evaluate the value of GPR56 and GZMB in differentiating active and stable remitting RA. RESULTS: GPR56+ levels were increased in CD4 and CD8 T cells in the PB of CIA mice. The percentages of GPR56+ and GZMB+ cells were increased in both CD4 and CD8 T cell subsets in patients with active RA. GPR56+, GZMB+, and GPR56+ GZMB+ cells were positively correlated with rheumatoid factor and DAS28. ROC analysis revealed that AUCs for GPR56+, GZMB+, and GPR56+ GZMB+ cell percentages to distinguish active RA from stable remission RA were 0.7106, 0.6941, 0.7024, with cut-off values of 16.35, 16.40, 14.80 in CD4 + T cells, and 0.8031, 0.8086, 0.8196 with cut-off values 60.25, 62.15, 40.15 in CD8 + T cells, respectively. CONCLUSIONS: GPR56+ and/or GZMB+ T cells are up-regulated in patients with active RA and reflect their condition. The detection of GPR56 and GZMB is helpful for RA disease assessment.


Assuntos
Artrite Reumatoide , Linfócitos T Citotóxicos , Animais , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos , Progressão da Doença , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos DBA , Receptores Acoplados a Proteínas G
11.
J Intern Med ; 292(3): 477-491, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35411981

RESUMO

BACKGROUND: Anti-drug antibodies (ADAb) frequently form early in the treatment course of infliximab and other tumour necrosis factor (TNF) inhibitors, leading to treatment failure and adverse events. OBJECTIVE: To identify risk factors for ADAb in the early phase of infliximab treatment. METHODS: Patients (n = 410) with immune-mediated inflammatory diseases who initiated infliximab treatment were included in the 38-week Norwegian Drug Monitoring Trial (NOR-DRUM) A and randomised 1:1 to therapeutic drug monitoring (TDM) or standard therapy. Serum levels of infliximab and ADAb were measured at each infusion. Possible risk factors for ADAb formation were assessed using logistic regression, adjusting for potential confounders. RESULTS: ADAb were detected in 78 (19%) patients. A diagnosis of rheumatoid arthritis (RA) (odds ratio [OR], 1.9 [95% confidence interval [CI] 1.0-3.6]) and lifetime smoking (OR, 2.0 [CI 1.1-3.6]) were baseline risk factors, while baseline use of concomitant immunosuppressors (OR, 0.4 [CI 0.2-0.8]) and a diagnosis of spondyloarthritis (SpA) (OR, 0.4 [CI 0.2-0.8]) reduced the risk of ADAb. Higher disease activity during follow-up (OR, 1.1 [CI 1.0-1.1]) and "drug holidays" of more than 11 weeks (OR, 4.1 [CI 1.2-13.8]) increased the risk of ADAb, whereas higher infliximab doses (OR, 0.1 [CI 0.0-0.3) and higher serum infliximab concentrations (OR, 0.7 [CI 0.6-0.8]) reduced the risk of immunogenicity. CONCLUSION: Several risk factors for ADAb formation during early-phase infliximab treatment were identified. This knowledge provides a basis for treatment strategies to mitigate the formation of ADAb and identify patients in whom these measures are of particular importance.


Assuntos
Anticorpos , Antirreumáticos , Artrite Reumatoide , Infliximab , Formação de Anticorpos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Humanos , Infliximab/efeitos adversos , Fatores de Risco
12.
Front Immunol ; 13: 835625, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35185927

RESUMO

TH1-mediated diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA) improve during pregnancy, coinciding with increasing levels of the pregnancy hormone progesterone (P4), highlighting P4 as a potential mediator of this immunomodulation. Here, we performed detailed characterization of how P4 affects the chromatin and transcriptomic landscape during early human TH1 differentiation, utilizing both ATAC-seq and RNA-seq. Time series analysis of the earlier events (0.5-24 hrs) during TH1 differentiation revealed that P4 counteracted many of the changes induced during normal differentiation, mainly by downregulating key regulatory genes and their upstream transcription factors (TFs) involved in the initial T-cell activation. Members of the AP-1 complex such as FOSL1, FOSL2, JUN and JUNB were particularly affected, in both in promoters and in distal regulatory elements. Moreover, the changes induced by P4 were significantly enriched for disease-associated changes related to both MS and RA, revealing several shared upstream TFs, where again JUN was highlighted to be of central importance. Our findings support an immune regulatory role for P4 during pregnancy by impeding T-cell activation, a crucial checkpoint during pregnancy and in T-cell mediated diseases, and a central event prior to T-cell lineage commitment. Indeed, P4 is emerging as a likely candidate involved in disease modulation during pregnancy and further studies evaluating P4 as a potential treatment option are needed.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Cromatina/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Ativação Linfocitária/imunologia , Progesterona/farmacologia , Artrite Reumatoide/imunologia , Células Cultivadas , Sequenciamento de Cromatina por Imunoprecipitação , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Esclerose Múltipla/imunologia , Gravidez , RNA-Seq , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
13.
Scand J Immunol ; 95(1): e13116, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35213743

RESUMO

Rheumatoid arthritis (RA) is a chronic multisystem disease with a complex immunopathology. Its inflammatory state is dominated by pro-inflammatory cytokines such as TNFα and activated Th1/Th17. Only proportion of patients achieve clinical remission despite potent biologics targeting these pathways. This study investigated the resolution of inflammation in RA patients (naïve for biologics) receiving TNFα inhibitors (TNFi) and evaluated the biological mechanisms behind treatment response and assessed them using clinical scoring systems. The majority showed a good clinical response after six months (6M) and a significant drop in DAS28-CRP (P ≤ .002), CDAI (P ≤ .0001) and RheumXpert (P ≤ .0001). Before treatment, the patients demonstrated a chronic innate and adaptive inflammatory state. The improved clinical condition was reflected with a decrease in Th17/Tc17 (P ≤ .05) and an increase in Tregs after 6M (P ≤ .05). Using a logistic regression model on serum data, IL-6, IL-18, IL-21, IL-22, IFNγ and TNFα were identified as the main contributing biomarkers in the chronic inflammatory state of RA. A specific test score (STS) was defined and converted to a single cytokine composite test score (CCTS), which showed the disease outcome on a scale 0-100, providing sensitivity and specificity of ≥90%. Thus, the immunological complexity in RA is driven by a complex interplay of pro-inflammatory cytokines and effector T-cell response dominated by Th17/Tc17. In addition, the resolution of inflammation could be linked to a partially Treg-driven homeostatic innate immune response. Therefore, a more complex therapeutic approach against the above markers might be of value to obtain full clinical remission in the future.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Citocinas/sangue , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/induzido quimicamente , Biomarcadores/sangue , Feminino , Humanos , Islândia , Inflamação/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Células Th1/imunologia , Resultado do Tratamento
14.
Int J Mol Sci ; 23(3)2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35163420

RESUMO

Monocytes and their tissue counterpart macrophages (MP) constitute the front line of the immune system. Indeed, they are able to rapidly and efficiently detect both external and internal danger signals, thereby activating the immune system to eradicate the disturbing biological, chemical, or physical agents. They are also in charge of the control of the immune response and account for the repair of the damaged tissues, eventually restoring tissue homeostasis. The balance between these dual activities must be thoroughly controlled in space and time. Any sustained unbalanced response of MP leads to pathological disorders, such as chronic inflammation, or favors cancer development and progression. In this review, we take advantage of our expertise in chronic inflammation, especially in rheumatoid arthritis, and in cancer, to highlight the pivotal role of MP in the physiopathology of these disorders and to emphasize the repolarization of unbalanced MP as a promising therapeutic strategy to control these diseases.


Assuntos
Artrite Reumatoide/imunologia , Macrófagos/imunologia , Neoplasias/imunologia , Animais , Polaridade Celular , Humanos , Macrófagos/patologia , Neoplasias/patologia
15.
PLoS Pathog ; 18(2): e1010185, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35143591

RESUMO

Arthritogenic alphaviruses are mosquito-borne viruses that are a major cause of infectious arthropathies worldwide, and recent outbreaks of chikungunya virus and Ross River virus (RRV) infections highlight the need for robust intervention strategies. Alphaviral arthritis can persist for months after the initial acute disease, and is mediated by cellular immune responses. A common strategy to limit inflammation and pathology is to dampen the overwhelming inflammatory responses by modulating proinflammatory cytokine pathways. Here, we investigate the contribution of interleukin-17 (IL-17), a cytokine involved in arthropathies such as rheumatoid arthritis, in the development RRV-induced arthritis and myositis. IL-17 was quantified in serum from RRV-infected patients, and mice were infected with RRV and joints and muscle tissues collected to analyse cellular infiltrates, tissue mRNA, cytokine expression, and joint and muscle histopathology. IL-17 expression was increased in musculoskeletal tissues and serum of RRV-infected mice and humans, respectively. IL-17-producing T cells and neutrophils contributed to the cellular infiltrate in the joint and muscle tissue during acute RRV disease in mice. Blockade of IL-17A/F using a monoclonal antibody (mAb) reduced disease severity in RRV-infected mice and led to decreased proinflammatory proteins, cellular infiltration in synovial tissues and cartilage damage, without affecting viral titers in inflamed tissues. IL-17A/F blockade triggered a shift in transcriptional profile of both leukocyte infiltrates and musculoskeletal stromal cells by downregulating proinflammatory genes. This study highlights a previously uncharacterized role for an effector cytokine in alphaviral pathology and points towards potential therapeutic benefit in targeting IL-17 to treat patients presenting with RRV-induced arthropathy.


Assuntos
Artrite Reumatoide/imunologia , Imunidade Celular , Inflamação/imunologia , Interleucina-17/imunologia , Miosite/imunologia , Vírus do Rio Ross/imunologia , Infecções por Alphavirus/imunologia , Infecções por Alphavirus/virologia , Animais , Artrite Reumatoide/virologia , Chlorocebus aethiops , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miosite/virologia , Células Vero , Carga Viral
16.
J Immunol Res ; 2022: 6839356, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35224112

RESUMO

Intestinal bacterial compositions of rheumatoid arthritis (RA) patients have been reported to be different from those of healthy people. Dysbiosis, imbalance of the microbiota, is widely known to cause gut barrier damage, resulting in an influx of bacteria and their substances into host bloodstreams in animal studies. However, few studies have investigated the effect of bacterial substances on the pathophysiology of RA. In this study, eighty-seven active RA patients who had inadequate responses to conventional synthetic disease-modifying antirheumatic drugs or severe comorbidities were analyzed for correlations between many factors such as disease activities, disease biomarkers, intestinal bacterial counts, fecal and serum lipopolysaccharide (LPS), LPS-binding protein (LBP), endotoxin neutralizing capacity (ENC), and serum antibacterial substance IgG and IgA antibody levels by multiple regression analysis with consideration for demographic factors such as age, sex, smoking, and methotrexate treatment. Serum LBP levels, fecal LPS levels, total bacteria counts, serum anti-LPS from Porphyromonas gingivalis (Pg-LPS) IgG antibody levels, and serum anti-Pg-LPS IgA antibody levels were selected for multiple regression analysis using Spearman's correlation analysis. Serum LBP levels were correlated with disease biomarker levels, such as erythrocyte sedimentation rate (p < 0.001), C-reactive protein (p < 0.001), matrix metalloproteinase-3 (p < 0.001), and IL-6 (p = 0.001), and were inversely correlated with hemoglobin (p = 0.005). Anti-Pg-LPS IgG antibody levels were inversely correlated with activity indices such as patient global assessments using visual analogue scale (VAS) (p = 0.002) and painVAS (p < 0.001). Total bacteria counts were correlated with ENC (p < 0.001), and inversely correlated with serum LPS (p < 0.001) and anti-Pg-LPS IgA antibody levels (p < 0.001). These results suggest that substances from oral and gut microbiota may influence disease activity in RA patients.


Assuntos
Artrite Reumatoide/microbiologia , Infecções por Bacteroidaceae/microbiologia , Disbiose/microbiologia , Boca/microbiologia , Porphyromonas gingivalis/fisiologia , Proteínas de Fase Aguda/metabolismo , Idoso , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Carga Bacteriana , Infecções por Bacteroidaceae/imunologia , Biomarcadores/metabolismo , Proteínas de Transporte/metabolismo , Estudos Transversais , Disbiose/imunologia , Feminino , Microbioma Gastrointestinal , Humanos , Imunoglobulina A/metabolismo , Lipopolissacarídeos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade
17.
Comput Math Methods Med ; 2022: 6783659, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35140805

RESUMO

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease for which there is a lack of therapeutic options. Genome-wide association studies (GWASs) have identified over 100 genetic loci associated with RA susceptibility; however, the most causal risk genes (RGs) associated with, and molecular mechanism underlying, RA remain unknown. In this study, we collected 95 RA-associated loci from multiple GWASs and detected 87 candidate high-confidence risk genes (HRGs) from these loci via integrated multiomics data (the genome-scale chromosome conformation capture data, enhancer-promoter linkage data, and gene expression data) using the Bayesian integrative risk gene selector (iRIGS). Analysis of these HRGs indicates that these genes were indeed, markedly associated with different aspects of RA. Among these, 36 and 46 HRGs have been reported to be related to RA and autoimmunity, respectively. Meanwhile, most novel HRGs were also involved in the significantly enriched RA-related biological functions and pathways. Furthermore, drug repositioning prediction of the HRGs revealed three potential targets (ERBB2, IL6ST, and MAPK1) and nine possible drugs for RA treatment, of which two IL-6 receptor antagonists (tocilizumab and sarilumab) have been approved for RA treatment and four drugs (trastuzumab, lapatinib, masoprocol, and arsenic trioxide) have been reported to have a high potential to ameliorate RA. In summary, we believe that this study provides new clues for understanding the pathogenesis of RA and is important for research regarding the mechanisms underlying RA and the development of therapeutics for this condition.


Assuntos
Artrite Reumatoide/genética , Antirreumáticos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Autoimunidade/genética , Teorema de Bayes , Biologia Computacional , Desenvolvimento de Medicamentos/estatística & dados numéricos , Reposicionamento de Medicamentos/estatística & dados numéricos , Redes Reguladoras de Genes , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Fatores de Risco
18.
J Immunol ; 208(5): 1115-1127, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35165166

RESUMO

Purinergic signaling plays a major role in T cell activation leading to IL-2 production and proliferation. However, it is unclear whether purinergic signaling contributes to the differentiation and activation of effector T cells. In this study, we found that the purinergic receptor P2X4 was associated with human Th17 cells but not with Th1 cells. Inhibition of P2X4 receptor with the specific antagonist 5-BDBD and small interfering RNA inhibited the development of Th17 cells and the production of IL-17 by effector Th17 cells stimulated via the CD3/CD28 pathway. Our results showed that P2X4 was required for the expression of retinoic acid-related orphan receptor C, which is the master regulator of Th17 cells. In contrast, inhibition of P2X4 receptor had no effect on Th1 cells and on the production of IFN-γ and it did not affect the expression of the transcription factor T-bet (T-box transcription factor). Furthermore, inhibition of P2X4 receptor reduced the production of IL-17 but not of IFN-γ by effector/memory CD4+ T cells isolated from patients with rheumatoid arthritis. In contrast to P2X4, inhibition of P2X7 and P2Y11 receptors had no effects on Th17 and Th1 cell activation. Finally, treatment with the P2X4 receptor antagonist 5-BDBD reduced the severity of collagen-induced arthritis in mice by inhibiting Th17 cell expansion and activation. Our findings provide novel insights into the role of purinergic signaling in T cell activation and identify a critical role for the purinergic receptor P2X4 in Th17 activation and in autoimmune arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/imunologia , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X4/metabolismo , Células Th17/imunologia , Animais , Artrite Reumatoide/patologia , Benzodiazepinonas/farmacologia , Diferenciação Celular/imunologia , Células Cultivadas , Humanos , Memória Imunológica/imunologia , Interferon gama/biossíntese , Interleucina-17/biossíntese , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Receptores Nucleares Órfãos , Interferência de RNA , RNA Interferente Pequeno/genética , Receptores Purinérgicos P2X4/genética , Proteínas com Domínio T/biossíntese , Células Th1/citologia , Células Th1/imunologia , Células Th17/citologia
19.
Comput Math Methods Med ; 2022: 7843990, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35211187

RESUMO

Interactions between genetic variants (epistasis) are ubiquitous in the model system and can significantly affect evolutionary adaptation, genetic mapping, and precision medical efforts. In this paper, we proposed a method for epistasis detection, called EpiMIC (epistasis detection through a maximal information coefficient (MIC)). MIC is a promising bivariate dependence measure explicitly designed for rapidly exploring various function types equally and for interpreting and comparing them on the same scale. Most epistasis detection approaches make assumptions about the form of the association between genetic variants, resulting in limited statistical performance. Based on the notion that if two SNPs do not interact, their joint distribution in all samples and in only cases should not be substantially different. We developed a statistic that utilizes the difference of MIC as a signal of epistasis and combined it with a permutation resampling strategy to estimate the empirical distribution of our statistic. Results of simulation and real-world data set showed that EpiMIC outperformed previous approaches for identifying epistasis at varying degrees of heredity.


Assuntos
Epistasia Genética , Modelos Genéticos , Algoritmos , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Biologia Computacional , Simulação por Computador , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Humanos , Polimorfismo de Nucleotídeo Único
20.
Sci Immunol ; 7(68): eabf2846, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35148199

RESUMO

Macrophages regulate protective immune responses to infectious microbes, but aberrant macrophage activation frequently drives pathological inflammation. To identify regulators of vigorous macrophage activation, we analyzed RNA-seq data from synovial macrophages and identified SLAMF7 as a receptor associated with a superactivated macrophage state in rheumatoid arthritis. We implicated IFN-γ as a key regulator of SLAMF7 expression and engaging SLAMF7 drove a strong wave of inflammatory cytokine expression. Induction of TNF-α after SLAMF7 engagement amplified inflammation through an autocrine signaling loop. We observed SLAMF7-induced gene programs not only in macrophages from rheumatoid arthritis patients but also in gut macrophages from patients with active Crohn's disease and in lung macrophages from patients with severe COVID-19. This suggests a central role for SLAMF7 in macrophage superactivation with broad implications in human disease pathology.


Assuntos
Inflamação/imunologia , Ativação de Macrófagos/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Transcriptoma/imunologia , Doença Aguda , Adulto , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , COVID-19/genética , COVID-19/imunologia , COVID-19/metabolismo , COVID-19/virologia , Células Cultivadas , Doença Crônica , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/metabolismo , Feminino , Humanos , Inflamação/genética , Inflamação/metabolismo , Ativação de Macrófagos/genética , RNA-Seq/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Análise de Célula Única/métodos , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Transcriptoma/genética
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