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1.
Arthritis Res Ther ; 26(1): 117, 2024 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-38845046

RESUMO

BACKGROUND: The objective of this study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF­06835375, a potent selective afucosyl immunoglobulin G1 antibody targeting C-X-C chemokine receptor type 5 (CXCR5) that potentially depletes B cells, follicular T helper (Tfh) cells, and circulating Tfh-like (cTfh) cells, in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: This first-in-human, multicenter, double-blind, sponsor-open, placebo-controlled Phase 1 study recruited patients aged 18-70 years with SLE or RA. In Part A, patients received single doses of intravenous PF-06835375 (dose range: 0.03-6 mg) or placebo in six sequential single ascending dose (SAD) cohorts. In Part B, patients received repeat doses of subcutaneous PF-06835375 (dose range: 0.3-10 mg) or placebo on Days 1 and 29 in five multiple ascending dose (MAD) cohorts. Tetanus/Diphtheria (Td) and Meningococcal B (MenB/Trumenba™) vaccines were administered at Day 4 (Td and MenB) and Week 8 (MenB only) to assess PF-06835375 functional effects. Endpoints included treatment-emergent adverse events (TEAEs), pharmacokinetic parameters, pharmacodynamic effects on B and cTfh cells, and biomarker counts, vaccine response, and exploratory differential gene expression analysis. Safety, pharmacokinetic, and pharmacodynamic endpoints are summarized descriptively. The change from baseline of B and Tfh cell-specific genes over time was calculated using a prespecified mixed-effects model, with a false discovery rate < 0.05 considered statistically significant. RESULTS: In total, 73 patients were treated (SAD cohorts: SLE, n = 17; RA, n = 14; MAD cohorts: SLE, n = 22; RA, n = 20). Mean age was 53.3 years. Sixty-two (84.9%) patients experienced TEAEs (placebo n = 17; PF-06835375 n = 45); most were mild or moderate. Three (9.7%) patients experienced serious adverse events. Mean t1/2 ranged from 3.4-121.4 h (SAD cohorts) and 162.0-234.0 h (MAD cohorts, Day 29). B and cTfh cell counts generally showed dose-dependent reductions across cohorts (range of mean maximum depletion: 67.3-99.3%/62.4-98.7% [SAD] and 91.1-99.6%/89.5-98.1% [MAD], respectively). B cell-related genes and pathways were significantly downregulated in patients treated with PF-06835375. CONCLUSIONS: These data support further development of PF-06835375 to assess the clinical potential for B and Tfh cell depletion as a treatment for autoimmune diseases. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03334851.


Assuntos
Artrite Reumatoide , Lúpus Eritematoso Sistêmico , Receptores CXCR5 , Humanos , Pessoa de Meia-Idade , Adulto , Método Duplo-Cego , Feminino , Masculino , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Idoso , Adulto Jovem , Relação Dose-Resposta a Droga , Adolescente , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/farmacocinética , Antirreumáticos/administração & dosagem , Antirreumáticos/uso terapêutico , Antirreumáticos/efeitos adversos
2.
Front Immunol ; 15: 1352251, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38840915

RESUMO

Objective: Antigen-presenting dendritic cells (DCs) and monocytes play an essential role in rheumatoid arthritis (RA) pathogenesis, however, their tolerogenic potential remains unclear. Herein, the tolerogenic profiles of DCs are characterized in treatment-naïve RA patients to determine their role to inflammatory arthritis management. Methods: Thirty-six treatment-naïve RA patients were enrolled, of which 62% were non-responders to methotrexate (MTX) monotherapy based on disease activity score (DAS) after 6-months of therapy. DC and monocyte subset frequencies, activation (CD40, CD86, CD209 expression), and tolerogenic profile (intracellular indoleamine-2,3-dioxygenase [IDO1] and cytotoxic T lymphocyte antigen 4 [CTLA-4] expression) were examined in the baseline peripheral blood by multicolor flow-cytometry. Soluble CTLA-4 (sCTLA-4) levels in plasma were measured. Results: DC subsets were decreased in RA compared to healthy controls (HC), and the frequency of conventional DCs (cDC) inversely correlated with inflammatory markers and improvement in disease activity. CD141+ cDC1s were the major IDO1-expressing cells. IDO1+cDC1s were reduced in RA patients compared to HC. The baseline frequency of IDO1+cDC1s inversely correlated with improvement in disease activity. CTLA-4 expression in CD1c+ cDC2s and monocytes was lower in RA patients compared to HC. Moreover, MTX-responders had a significantly lower frequency of IDO1+cDC1 cells and higher level of sCTLA-4 in the plasma compared to MTX non-responders. There was a strong predictive association of low IDO1+cDC1 cells, low sCTLA-4 and non-response to MTX. Conclusions: Our findings reveal altered DC and monocytes immunophenotypes that are associated with RA pathology and treatment response. The frequencies of tolerogenic IDO1+cDC1s and the low level of sCTLA-4 are strongly associated with MTX non-responsiveness and therapeutic outcome. These results suggest that investigation of the association IDO1+cDC1 and sCTLA-4 with response to treatment may be more generalizable to other autoimmune diseases.


Assuntos
Artrite Reumatoide , Antígeno CTLA-4 , Células Dendríticas , Indolamina-Pirrol 2,3,-Dioxigenase , Metotrexato , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/sangue , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Metotrexato/uso terapêutico , Metotrexato/farmacologia , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Antirreumáticos/uso terapêutico , Antirreumáticos/farmacologia , Idoso , Monócitos/imunologia , Monócitos/metabolismo , Resultado do Tratamento , Biomarcadores
3.
Front Immunol ; 15: 1356314, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38840924

RESUMO

Introduction: Outbreaks of coronaviruses and especially the recent COVID-19 pandemic emphasize the importance of immunological research in this area to mitigate the effect of future incidents. Bioinformatics approaches are capable of providing multisided insights from virus sequencing data, although currently available software options are not entirely suitable for a specific task of mutation surveillance within immunogenic epitopes of SARS-CoV-2. Method: Here, we describe the development of a mutation tracker, EpitopeScan, a Python3 package with command line and graphical user interface tools facilitating the investigation of the mutation dynamics in SARS-CoV-2 epitopes via analysis of multiple-sequence alignments of genomes over time. We provide an application case by examining three Spike protein-derived immunodominant CD4+ T-cell epitopes restricted by HLA-DRB1*04:01, an allele strongly associated with susceptibility to rheumatoid arthritis (RA). Mutations in these peptides are relevant for immune monitoring of CD4+ T-cell responses against SARS-CoV-2 spike protein in patients with RA. The analysis focused on 2.3 million SARS-CoV-2 genomes sampled in England. Results: We detail cases of epitope conservation over time, partial loss of conservation, and complete divergence from the wild type following the emergence of the N969K Omicron-specific mutation in November 2021. The wild type and the mutated peptide represent potential candidates to monitor variant-specific CD4+ T-cell responses. EpitopeScan is available via GitHub repository https://github.com/Aleksandr-biochem/EpitopeScan.


Assuntos
COVID-19 , Epitopos de Linfócito T , Mutação , SARS-CoV-2 , Software , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/imunologia , SARS-CoV-2/genética , Humanos , COVID-19/imunologia , COVID-19/genética , COVID-19/virologia , Epitopos de Linfócito T/imunologia , Epitopos de Linfócito T/genética , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/genética , Linfócitos T CD4-Positivos/imunologia , Biologia Computacional/métodos , Epitopos Imunodominantes/imunologia , Epitopos Imunodominantes/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/genética , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia
4.
Ter Arkh ; 96(5): 494-499, 2024 Jun 03.
Artigo em Russo | MEDLINE | ID: mdl-38829811

RESUMO

AIM: To study the association of bone mineral density (BMD) with serum biochemical and immunological markers in postmenopausal women with rheumatoid arthritis (RA). MATERIALS AND METHODS: The study included 173 women with RA (age 61.0 [56.0; 66.0] years). A survey, dual-energy X-ray absorptiometry to measure the BMD of the lumbar spine (LI-LIV), femoral neck (FN) and total hip (TH), routine blood chemistry, measurement of C-reactive protein (CRP), rheumatoid factor, cyclic citrullinated peptide antibodies (CCPA), parathyroid hormone (PTH), vitamin D3, myostatin, follistatin, interleukin-6 (IL-6), IL-6 receptors, insulin-like growth factor 1, adiponectin, leptin, fibroblast growth factor 23, and tumor necrosis factor SF12 were performed. RESULTS: PTH (ß=-0.22, -0.35 and -0.30 for LI-LIV, FN and TH, respectively), CRP (ß=-0.18, 0.23 and -0.22 for LI-LIV, FN and TH, respectively) and leptin (ß=0.35, 0.32 and 0.42 for LI-LIV, FN and TH, respectively) were shown a significant association with BMD in all sites of measurement. It was independent of age, body mass index and postmenopause duration. Associations were also found between adiponectin and BMD of LI-LIV and TH (ß=-0.36 and -0.28, respectively), CCPA and BMD of FN and TH (ß=-0.21, -0.24, respectively) and IL-6 and BMD of FN (ß=0.37). CONCLUSION: The study of biochemical and immunological markers in women with RA demonstrated that CRP, CCPA, PTH, IL-6, adiponectin, and leptin influenced BMD.


Assuntos
Artrite Reumatoide , Biomarcadores , Densidade Óssea , Humanos , Feminino , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Densidade Óssea/fisiologia , Pessoa de Meia-Idade , Biomarcadores/sangue , Absorciometria de Fóton/métodos , Idoso , Pós-Menopausa/sangue , Pós-Menopausa/imunologia , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Adiponectina/sangue , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/imunologia , Osteoporose Pós-Menopausa/fisiopatologia , Osteoporose Pós-Menopausa/etiologia , Leptina/sangue
6.
BMC Cancer ; 24(1): 714, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38858644

RESUMO

BACKGROUND: Our study aims to explore the relationship, shared gene signature, and the underlying mechanisms that connect rheumatoid arthritis (RA) to colorectal cancer (CRC). METHODS: Mendelian randomization (MR) analysis was conducted to assess the causality between RA and CRC. Summary statistic data-based Mendelian randomization (SMR) leveraging eQTL data was employed to identify the CRC-related causal genes. Integrated analyses of single-cell RNA sequencing and bulk RNA sequencing were employed to comprehensively investigate the shared gene signature and potential mechanisms underlying the pathogenesis of both RA and CRC. Predictive analysis of the shared hub gene in CRC immunotherapy response was performed. Pan-cancer analyses were conducted to explore the potential role of MYO9A in 33 types of human tumors. RESULTS: MR analysis suggested that RA might be associated with a slight increased risk of CRC (Odds Ratio = 1.04, 95% Confidence Interval = 1.01-1.07, P = 0.005). SMR analysis combining transcriptome analyses identified MYO9A as a causal gene in CRC and a shared gene signature in both RA and CRC. MYO9A may contribute to tumor suppression, while downregulation of MYO9A may impact CRC tumorigenesis by disrupting epithelial polarity and architecture, resulting in a worse prognosis in CRC. Additionally, MYO9A shows promise as a powerful predictive biomarker for cancer prognosis and immunotherapy response in CRC. Pan-cancer analyses demonstrated MYO9A may have a protective role in the occurrence and progression of various human cancers. CONCLUSION: RA might be associated with a slight increased risk of CRC. MYO9A is a shared gene signature and a potential immune-related therapeutic target for both CRC and RA. Targeting the MYO9A-mediated loss of polarity and epithelial architecture could be a novel therapeutic approach for CRC.


Assuntos
Artrite Reumatoide , Neoplasias Colorretais , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Análise da Randomização Mendeliana , Miosinas/genética , Perfilação da Expressão Gênica , Transcriptoma , Locos de Características Quantitativas , Prognóstico , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Multiômica
7.
Autoimmunity ; 57(1): 2358069, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38869013

RESUMO

Rheumatoid arthritis (RA) is the predominant manifestation of inflammatory arthritis, distinguished by an increasing burden of morbidity and mortality. The intricate interplay of genes and signalling pathways involved in synovial inflammation in patients with RA remains inadequately comprehended. This study aimed to ascertain the role of necroptosis in RA, as along with their associations with immune cell infiltration. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were employed to identify central genes for RA. In this study, identified total of 28 differentially expressed genes (DEGs) were identified in RA. Utilising WGCNA, two co-expression modules were generated, with one module demonstrating the strongest correlation with RA. Through the integration of differential gene expression analysis, a total of 5 intersecting genes were discovered. These 5 hub genes, namely fused in sarcoma (FUS), transformer 2 beta homolog (TRA2B), eukaryotic translation elongation factor 2 (EEF2), cleavage and polyadenylation specific factor 6 (CPSF6) and signal transducer and activator of transcription 3 (STAT3) were found to possess significant diagnostic value as determined by receiver operating characteristic (ROC) curve analysis. The close association between the concentrations of various immune cells is anticipated to contribute to the diagnosis and treatment of RA. Furthermore, the infiltration of immune cells mentioned earlier is likely to exert a substantial influence on the initiation of this disease.


Assuntos
Artrite Reumatoide , Redes Reguladoras de Genes , Necroptose , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/genética , Humanos , Necroptose/imunologia , Perfilação da Expressão Gênica , Transcriptoma , Biologia Computacional/métodos , Regulação da Expressão Gênica , Transdução de Sinais/imunologia , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genética , Biomarcadores , Curva ROC
8.
Nat Commun ; 15(1): 4991, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862501

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease involving antigen-specific T and B cells. Here, we perform single-cell RNA and repertoire sequencing on paired synovial tissue and blood samples from 12 seropositive RA patients. We identify clonally expanded CD4 + T cells, including CCL5+ cells and T peripheral helper (Tph) cells, which show a prominent transcriptomic signature of recent activation and effector function. CD8 + T cells show higher oligoclonality than CD4 + T cells, with the largest synovial clones enriched in GZMK+ cells. CD8 + T cells with possibly virus-reactive TCRs are distributed across transcriptomic clusters. In the B cell compartment, NR4A1+ activated B cells, and plasma cells are enriched in the synovium and demonstrate substantial clonal expansion. We identify synovial plasma cells that share BCRs with synovial ABC, memory, and activated B cells. Receptor-ligand analysis predicted IFNG and TNFRSF members as mediators of synovial Tph-B cell interactions. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate the synovium of patients with RA.


Assuntos
Artrite Reumatoide , Linfócitos B , Membrana Sinovial , Humanos , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/patologia , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Feminino , Masculino , Pessoa de Meia-Idade , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Análise de Célula Única , Transcriptoma , Plasmócitos/imunologia , Plasmócitos/metabolismo , Idoso , Ativação Linfocitária , Adulto
9.
Front Immunol ; 15: 1355824, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38799447

RESUMO

Objectives: IL26 levels are elevated in the blood and synovial fluid of patients with inflammatory arthritis. IL26 can be produced by Th17 cells and locally within joints by tissue-resident cells. IL26 induces osteoblast mineralization in vitro. As osteoproliferation and Th17 cells are important factors in the pathogenesis of axial spondyloarthritis (axSpA), we aimed to clarify the cellular sources of IL26 in spondyloarthritis. Methods: Serum, peripheral blood mononuclear cells (n = 15-35) and synovial tissue (n = 3-9) of adult patients with axSpA, psoriatic arthritis (PsA) and rheumatoid arthritis (RA) and healthy controls (HCs, n = 5) were evaluated by ELISA, flow cytometry including PrimeFlow assay, immunohistochemistry and immunofluorescence and quantitative PCR. Results: Synovial tissue of axSpA patients shows significantly more IL26-positive cells than that of HCs (p < 0.01), but numbers are also elevated in PsA and RA patients. Immunofluorescence shows co-localization of IL26 with CD68, but not with CD3, SMA, CD163, cadherin-11, or CD90. IL26 is elevated in the serum of RA and PsA (but not axSpA) patients compared with HCs (p < 0.001 and p < 0.01). However, peripheral blood CD4+ T cells from axSpA and PsA patients show higher positivity for IL26 in the PrimeFlow assay compared with HCs. CD4+ memory T cells from axSpA patients produce more IL26 under Th17-favoring conditions (IL-1ß and IL-23) than cells from PsA and RA patients or HCs. Conclusion: IL26 production is increased in the synovial tissue of SpA and can be localized to CD68+ macrophage-like synoviocytes, whereas circulating IL26+ Th17 cells are only modestly enriched. Considering the osteoproliferative properties of IL26, this offers new therapeutic options independent of Th17 pathways.


Assuntos
Antígenos CD , Artrite Psoriásica , Interleucinas , Sinoviócitos , Humanos , Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Sinoviócitos/metabolismo , Sinoviócitos/imunologia , Sinoviócitos/patologia , Masculino , Adulto , Feminino , Antígenos CD/metabolismo , Interleucinas/metabolismo , Interleucinas/sangue , Pessoa de Meia-Idade , Antígenos de Diferenciação Mielomonocítica/metabolismo , Espondiloartrite Axial/imunologia , Células Th17/imunologia , Células Th17/metabolismo , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Articulações/patologia , Articulações/imunologia , Articulações/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/sangue , Artrite Reumatoide/patologia
10.
Nat Commun ; 15(1): 4650, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38821936

RESUMO

Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution in 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identify 24 chromatin classes and predict their associated transcription factors, including a CD8 + GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating with an RA tissue transcriptional atlas, we propose that these chromatin classes represent 'superstates' corresponding to multiple transcriptional cell states. Finally, we demonstrate the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance, as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.


Assuntos
Artrite Reumatoide , Cromatina , Membrana Sinovial , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Artrite Reumatoide/imunologia , Humanos , Cromatina/metabolismo , Cromatina/genética , Membrana Sinovial/metabolismo , Membrana Sinovial/patologia , Proteínas com Domínio T/metabolismo , Proteínas com Domínio T/genética , Epigênese Genética , Análise de Célula Única , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fibroblastos/metabolismo , Fator de Transcrição AP-1/metabolismo , Fator de Transcrição AP-1/genética , Transcrição Gênica , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo
12.
J Autoimmun ; 146: 103238, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38754239

RESUMO

BACKGROUND: Women are more likely to develop autoimmune diseases than men. Contribution from microchimerism (Mc) has been proposed, as women naturally acquire Mc from more sources than men because of pregnancy. Women with Rheumatoid Arthritis (RA) who lack RA-associated HLA alleles have been found to harbor Mc with RA-associated HLA alleles in higher amounts than healthy women in prior work. However, an immunological impact of Mc remains to be elucidated. OBJECTIVES: To test the hypothesis that Mc with RA-risk associated HLA alleles can result in the production of RA-associated autoantibodies, when host genetic risk is absent. METHODS: DBA/2 mice are unable to produce RA-specific anti-citrullinated autoantibodies (ACPAs) after immunization with the enzyme peptidyl arginine deiminase (PAD) in a previously developed model. DBA/2 females were mated with C57BL/6 males humanized to express HLA-DR4, which is associated with RA-risk and production of ACPAs, to evaluate DR4+ fetal Mc contribution. Next, DBA/2 females born of heterozygous DR4+/- mothers were evaluated for DR4+ Mc of maternal or littermate origin. Finally, DBA/2 females from DR4+/- mothers were crossed with DR4+ males, to evaluate the contribution of any Mc source to ACPA production. RESULTS: After PAD immunization, between 20 % and 43 % of DBA/2 females (otherwise unable to produce ACPAs) had detectable ACPAs (CCP2 kit) after exposure to sources of Mc with RA-associated HLA alleles, compared to 0 % of unmated/unexposed DBA/2 females. Further the microchimeric origin of the autoantibodies was confirmed by detecting a C57BL/6-specific immunoglobulin isotype in the DBA/2 response. CONCLUSION: Our study demonstrates that Mc cells can produce "autoantibodies" and points to a role of Mc in the biology of autoimmune diseases, including RA.


Assuntos
Artrite Reumatoide , Autoanticorpos , Quimerismo , Camundongos Endogâmicos DBA , Artrite Reumatoide/imunologia , Animais , Camundongos , Feminino , Autoanticorpos/imunologia , Masculino , Humanos , Modelos Animais de Doenças , Alelos , Camundongos Endogâmicos C57BL , Anticorpos Antiproteína Citrulinada/imunologia , Gravidez
13.
J Control Release ; 370: 747-762, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38740094

RESUMO

Rheumatoid arthritis (RA) is a progressive autoimmune disease and drug therapy has been restricted due to poor therapeutic efficacy and adverse effects. In RA synovium, dendritic cells present self-antigens to activate cascade immune pathway. Furthermore, downstream macrophages secrete high levels of pro-inflammatory cytokines; Hyperplasia of activated synovial fibroblasts (FLS) is responsible for hypoxic synovium microenvironment, secretion of cytokines/chemokines and erosion of bone/cartilage tissues. Positive feedback loop of inflammation between macrophages and FLS independent of antigen-presentation is constructed. Herein, an injectable pH-sensitive peptide hydrogel encapsulating siRNA/Methotrexate-polyethyleneimine (siMP, including sip65MP, sip38MP, siCD86MP) and Bismuthene nanosheet/Methotrexate-polyethyleneimine (BiMP) is successfully developed. Among them, siCD86MP reduces protein level of co-stimulatory molecule CD86 while sip65MP and sip38MP separately inhibit NF-κB and MAPK-p38 pathways of macrophages and FLS to suppress secretion of cytokines and MMPs. Meanwhile, reduction in anti-apoptotic property of FLS induced by inhibition of NF-κB pathway has a synergistic effect with photodynamic therapy (PDT) and photothermal therapy (PTT) mediated by BiMP for FLS elimination, effectively ameliorating hypoxic synovium microenvironment. After being injected into synovium, hydrogel responds to acidic microenvironment and serves as a reservoir for sustained drug release and inherent retention capacity of which enables cationic nanoparticles to bypass tissue barrier for precise synovium targeting. This brand-new drug delivery system combines modulating cascade immune pathway from beginning to end by RNAi and eliminating FLS for improving synovium microenvironment by phototherapy together, providing a robust strategy for clinical RA treatment.


Assuntos
Artrite Reumatoide , Fibroblastos , Hidrogéis , Metotrexato , Membrana Sinovial , Fibroblastos/efeitos dos fármacos , Artrite Reumatoide/imunologia , Artrite Reumatoide/terapia , Hidrogéis/administração & dosagem , Membrana Sinovial/imunologia , Animais , Metotrexato/administração & dosagem , Metotrexato/farmacologia , RNA Interferente Pequeno/administração & dosagem , Fotoquimioterapia/métodos , Camundongos , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Células RAW 264.7 , Citocinas/metabolismo , Antirreumáticos/administração & dosagem , Microambiente Celular/efeitos dos fármacos , NF-kappa B/metabolismo , Fototerapia/métodos , Peptídeos/administração & dosagem
14.
Aging (Albany NY) ; 16(10): 8687-8696, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38761178

RESUMO

Rheumatoid arthritis (RA) is one of the most common autoimmune joint disorders that leads to cartilage degradation. However, its specific correlation with immune cells has not been thoroughly clarified. Based on the two-sample Mendelian randomization (MR) analysis, the association between RA and 731 immune phenotypes which include morphological parameters (MP), relative cell (RC), median fluorescence intensities (MFI), and absolute cells (AC) was comprehensively determined. After false discovery rate correction, RA and immunophenotypes were statistically associated with each other. It was observed that four immune phenotypes, including 1 MPs, 8 RCs, 15 MFIs, and 10 ACs were causally associated with the risk of RA. Meanwhile, several identified immune traits could serve as independent factors for RA and be robust against pleiotropy. While considering the role of RA in immune traits, the involvement of RA in multiple immunophenotypes including CD62L- myeloid DC AC, CD3 on secreting Treg, CD3 on activated and secreting Treg, and CD3 on CD4 Treg was revealed. This study is the first comprehensive evaluation of the interaction between immune response and RA risk, thus providing therapeutic strategies for RA from an immunological perspective.


Assuntos
Artrite Reumatoide , Análise da Randomização Mendeliana , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Humanos , Predisposição Genética para Doença , Fenótipo , Imunofenotipagem , Polimorfismo de Nucleotídeo Único
15.
Scand J Clin Lab Invest ; 84(3): 211-217, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38767606

RESUMO

PsoP27 is an antigen expressed in psoriatic lesions. It plays an inflammatory role in psoriasis. This study objective was to characterize antibodies (Abs) against PsoP27 in patients with psoriatic arthritis (PsA) and rheumatoid arthritis (RA). Levels of Abs against native and citrullinated PsoP27 in PsA and RA patients' synovial fluid (SF) and sera were determined by ELISA. SF of osteoarthritis (OA) patients and sera of healthy donors were used as controls. Levels of Abs against PsoP27 were correlated with disease activity scores. Abs against native and citrullinated PsoP27 levels in SF of PsA (n = 48; 0.38 ± 0.03 and 0.44 ± 0.04, respectively) and RA (n = 22; 0.57 ± 0.1 and 0.62 ± 0.09, respectively) were significantly higher than in OA patients (n = 23; 0.14 ± 0.01 and 0.15 ± 0.01, respectively) (p < .0001). For both Abs, there were no significant differences between their level in PsA and RA patients. There was no difference in the level of Abs against citrullinated PsoP27 in SF of seronegative versus seropositive RA patients. Levels of Abs against both native and citrullinated PsoP27 in the SF and level of systemic C-reactive protein in PsA correlated positively, while in RA there were no significant correlations with disease activity scores. No differences in level of Abs against PsoP27 were found in the sera of all three study groups. Abs against native and citrullinated PsoP27 are present in PsA and RA SF but not in those of OA patients, suggesting a potential role of those Abs in inflammatory joint diseases.


Assuntos
Artrite Psoriásica , Artrite Reumatoide , Autoanticorpos , Líquido Sinovial , Humanos , Artrite Psoriásica/imunologia , Artrite Psoriásica/sangue , Artrite Psoriásica/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/sangue , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Autoanticorpos/sangue , Autoanticorpos/imunologia , Masculino , Pessoa de Meia-Idade , Feminino , Adulto , Idoso , Estudos de Casos e Controles , Osteoartrite/imunologia , Osteoartrite/sangue , Ensaio de Imunoadsorção Enzimática
16.
Kaohsiung J Med Sci ; 40(6): 520-529, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38712483

RESUMO

Autoimmune disease is characterized by the proliferation of harmful immune cells, inducing tissue inflammation and ultimately causing organ damage. Current treatments often lack specificity, necessitating high doses, prolonged usage, and high recurrence rates. Therefore, the identification of innovative and safe therapeutic strategies is urgently required. Recent preclinical studies and clinical trials on inflammatory and autoimmune diseases have evidenced the immunosuppressive properties of mesenchymal stromal cells (MSCs). Studies have demonstrated that extracellular vesicles (EV) derived from MSCs can mitigate abnormal autoinflammation while maintaining safety within the diseased microenvironment. This study conducted a systematic review to elucidate the crucial role of MSC-EVs in alleviating autoimmune diseases, particularly focusing on their impact on the underlying mechanisms of autoimmune conditions such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD). By specifically examining the regulatory functions of microRNAs (miRNAs) derived from MSC-EVs, the comprehensive study aimed to enhance the understanding related to disease mechanisms and identify potential diagnostic markers and therapeutic targets for these diseases.


Assuntos
Doenças Autoimunes , Vesículas Extracelulares , Células-Tronco Mesenquimais , MicroRNAs , Humanos , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/imunologia , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/transplante , Doenças Autoimunes/terapia , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Lúpus Eritematoso Sistêmico/terapia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Artrite Reumatoide/terapia , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Animais , Doenças Inflamatórias Intestinais/terapia , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/patologia , Imunomodulação
17.
Medicine (Baltimore) ; 103(19): e38115, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38728509

RESUMO

Platelets are increasingly recognized for their multifaceted roles in inflammation beyond their traditional involvement in haemostasis. This review consolidates knowledge on platelets as critical players in inflammatory responses. This study did an extensive search of electronic databases and identified studies on platelets in inflammation, focusing on molecular mechanisms, cell interactions, and clinical implications, emphasizing recent publications. Platelets contribute to inflammation via surface receptors, release of mediators, and participation in neutrophil extracellular trap formation. They are implicated in diseases like atherosclerosis, rheumatoid arthritis, and sepsis, highlighting their interaction with immune cells as pivotal in the onset and resolution of inflammation. Platelets are central to regulating inflammation, offering new therapeutic targets for inflammatory diseases. Future research should explore specific molecular pathways of platelets in inflammation for therapeutic intervention.


Assuntos
Plaquetas , Inflamação , Humanos , Plaquetas/imunologia , Inflamação/imunologia , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/metabolismo , Sepse/imunologia , Sepse/sangue , Artrite Reumatoide/imunologia , Artrite Reumatoide/sangue , Neutrófilos/imunologia
18.
Clin Immunol ; 264: 110238, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38729230

RESUMO

OBJECTIVE: Rheumatoid Arthritis (RA) is a systemic autoimmune disease involving pro-inflammatory cytokines that can be therapeutically targeted by antibodies or kinase inhibitors. Nevertheless, these drugs fail in a subset of patients independent of the abundance of the targeted cytokines. We aim to explore the cellular basis of this phenomenon by analyzing the relation of cytokine abundance and activation of downstream signaling pathways in RA. METHODS: The study included 62 RA patients and 9 healthy controls (HC). Phosphorylation of STAT 1-6 in various immune cell subsets was determined ex vivo using a novel robust flow cytometry-based protocol. Serum concentrations of IL-6, IL-10, IL-12p70, IL-17 A, interferon gamma, and TNFα in the same samples were measured using highly sensitive single molecule array (SIMOA). RESULTS: We found an increase in circulating cytokines in RA patients, while STAT activity was lower in RA patients compared to HC. Based on STAT activity we determined three endotypes in active RA patients (cDAI>10, n = 28): 1) those with active STAT5a/b signaling in T cells (n = 7/28), 2) those with a low STAT activity in all assessed cell types (n = 14/28), and 3) those with active STAT1 and STAT3 signaling mainly in myeloid cells (n = 7/28). Integrating intracellular STAT activation and cytokine analysis revealed diminished JAK/STAT signaling in a subset of patients (n = 8/20) despite elevated serum cytokine concentrations. CONCLUSION: Diminished JAK/STAT signaling in active RA may partly explain unresponsiveness to therapy targeting cytokine signaling. Analysis of JAK/STAT phosphorylation may identify patients at risk for non-response to these therapies.


Assuntos
Artrite Reumatoide , Citocinas , Janus Quinases , Fatores de Transcrição STAT , Transdução de Sinais , Humanos , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Pessoa de Meia-Idade , Feminino , Masculino , Citocinas/sangue , Janus Quinases/metabolismo , Adulto , Fatores de Transcrição STAT/metabolismo , Idoso , Fosforilação , Fator de Transcrição STAT5/metabolismo , Leucócitos/metabolismo , Leucócitos/imunologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT1/sangue
19.
Int Immunopharmacol ; 136: 112357, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38810303

RESUMO

Rheumatoid Arthritis (RA) is an autoimmune condition responsible for the impairment of synovia and joints, endangering the functionality of individuals and contributing to mortality. Currently, obesity is increasing worldwide, and recent studies have suggested an association between such condition and RA. In this sense, obese individuals present a lower capacity for achieving remission and present more intense symptoms of the disease, demonstrating a link between both disorders. Different studies aim to understand the possible connection between the conditions; however, few is known in this sense. Therefore, knowing that obesity can alter the activity of multiple body systems, this work's objective is to evaluate the main modifications caused by obesity, which can be linked to the pathophysiology of RA, highlighting as relevant topics obesity's negative impact triggering systemic inflammation, intestinal dysbiosis, endocrine disbalances. Furthermore, the relationship between oxidative stress and obesity also deserves to be highlighted, considering the influence of reactive oxygen species (ROS) accumulation in RA exacerbation. Additionally, many of those characteristics influenced by obesity, along with the classic peculiarities of RA pathophysiology, can also be associated with purinergic signaling. Hence, this work suggests possible connections between the purinergic system and RA, proposing potential therapeutic targets against RA to be studied.


Assuntos
Artrite Reumatoide , Obesidade , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Humanos , Obesidade/metabolismo , Obesidade/imunologia , Animais , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Receptores Purinérgicos/metabolismo , Disbiose , Transdução de Sinais
20.
Int Immunopharmacol ; 136: 112264, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38810308

RESUMO

BACKGROUND: Chemotaxis and trafficking of dendritic cells (DCs) induced by cytokine receptors are crucial steps in rheumatoid arthritis (RA) pathogenesis. C-C chemokine receptor type 5 (CCR5) plays a key role in DC movement and has been implicated in multitudinous inflammatory and immunology diseases. Thus, targeting CCR5 to suppress DC chemotaxis is considered as a potential strategy for the management of RA. METHODS: Herein, we first synthesized a new hybrid named CT3-1 which based on artesunate and isatin. Besides, we studied the regulating effectiveness of CT3-1 on bone marrow-derived DCs (BMDCs) and on collagen-induced arthritis (CIA) through RNA-seq analysis, cell function experiments in vitro and mice model in vivo. RESULTS: The results shown that CT3-1 mainly reduced CCR5 expression of immature BMDCs and importantly inhibited immature BMDC migration induced by CCR5 in vitro, with no or minor influence on other functions of DCs, such as phagocytosis and maturation. In the mouse model, CT3-1 relieved arthritis severity and inhibited CIA development. Furthermore, CT3-1 intervention decreased the expression of CCR5 in DCs and reduced the proportion of DCs in the peripheral blood of CIA mice. CONCLUSIONS: Our findings suggest that CCR5-induced chemotaxis and trafficking of immature DCs are important in RA. Targeting CCR5 and inhibiting immature DC chemotaxis may provide a novel choice for the treatment of RA and other similar autoimmune diseases. Moreover, we synthesized a new hybrid compound CT3-1 that could inhibit immature DC trafficking and effectively relieve RA by directly reducing the CCR5 expression of immature DCs.


Assuntos
Artesunato , Artrite Experimental , Artrite Reumatoide , Quimiotaxia , Células Dendríticas , Receptores CCR5 , Animais , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Receptores CCR5/metabolismo , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Quimiotaxia/efeitos dos fármacos , Artesunato/farmacologia , Artesunato/uso terapêutico , Camundongos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Camundongos Endogâmicos DBA , Masculino , Células Cultivadas , Humanos
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