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1.
Nat Immunol ; 20(7): 928-942, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31061532

RESUMEN

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.


Asunto(s)
Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Perfilación de la Expresión Génica , Membrana Sinovial/metabolismo , Transcriptoma , Artritis Reumatoide/patología , Autoinmunidad/genética , Biomarcadores , Biología Computacional/métodos , Estudios Transversales , Citocinas/metabolismo , Fibroblastos/metabolismo , Citometría de Flujo , Expresión Génica , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Leucocitos/inmunología , Leucocitos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Transducción de Señal , Análisis de la Célula Individual/métodos , Membrana Sinovial/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Flujo de Trabajo
2.
J Immunol ; 206(6): 1194-1203, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33579724

RESUMEN

We described a human regulatory T cell (Treg) population activated by IgG+ B cells presenting peptides of the heavy C region (Fc) via processing of the surface IgG underlying a model for B cell-Treg cooperation in the human immune regulation. Functionally, Treg inhibited the polarization of naive T cells toward a proinflammatory phenotype in both a cognate and a noncognate fashion. Their fine specificities were similar in healthy donors and patients with rheumatoid arthritis, a systemic autoimmune disease. Four immunodominant Fc peptides bound multiple HLA class II alleles and were recognized by most subjects in the two cohorts. The presentation of Fc peptides that stimulate Treg through the processing of IgG by dendritic cells (DC) occurred in myeloid DC classical DC 1 and classical DC 2. Different routes of Ag processing of the IgG impacted Treg expansion in rheumatoid arthritis patients.


Asunto(s)
Artritis Reumatoide/inmunología , Epítopos de Linfocito B/inmunología , Fragmentos Fc de Inmunoglobulinas/inmunología , Inmunoglobulina G/inmunología , Linfocitos T Reguladores/inmunología , Adulto , Anciano , Presentación de Antígeno , Artritis Reumatoide/sangre , Células Dendríticas/inmunología , Femenino , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Fragmentos Fc de Inmunoglobulinas/metabolismo , Inmunoglobulina G/metabolismo , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , Adulto Joven
3.
Ann Rheum Dis ; 78(5): 600-609, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30808624

RESUMEN

OBJECTIVE: We aimed to understand the role of the tyrosine phosphatase PTPN14-which in cancer cells modulates the Hippo pathway by retaining YAP in the cytosol-in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS: Gene/protein expression levels were measured by quantitative PCR and/or Western blotting. Gene knockdown in RA FLS was achieved using antisense oligonucleotides. The interaction between PTPN14 and YAP was assessed by immunoprecipitation. The cellular localisation of YAP and SMAD3 was examined via immunofluorescence. SMAD reporter studies were carried out in HEK293T cells. The RA FLS/cartilage coimplantation and passive K/BxN models were used to examine the role of YAP in arthritis. RESULTS: RA FLS displayed overexpression of PTPN14 when compared with FLS from patients with osteoarthritis (OA). PTPN14 knockdown in RA FLS impaired TGFß-dependent expression of MMP13 and potentiation of TNF signalling. In RA FLS, PTPN14 formed a complex with YAP. Expression of PTPN14 or nuclear YAP-but not of a non-YAP-interacting PTPN14 mutant-enhanced SMAD reporter activity. YAP promoted TGFß-dependent SMAD3 nuclear localisation in RA FLS. Differences in epigenetic marks within Hippo pathway genes, including YAP, were found between RA FLS and OA FLS. Inhibition of YAP reduced RA FLS pathogenic behaviour and ameliorated arthritis severity. CONCLUSION: In RA FLS, PTPN14 and YAP promote nuclear localisation of SMAD3. YAP enhances a range of RA FLS pathogenic behaviours which, together with epigenetic evidence, points to the Hippo pathway as an important regulator of RA FLS behaviour.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteínas Tirosina Fosfatasas no Receptoras/fisiología , Transducción de Señal/fisiología , Sinoviocitos/metabolismo , Factores de Transcripción/fisiología , Factor de Crecimiento Transformador beta/fisiología , Animales , Artritis Reumatoide/metabolismo , Proteínas de Ciclo Celular/fisiología , Humanos , Ratones , Proteínas Señalizadoras YAP
4.
Inflamm Res ; 68(4): 261-274, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30739130

RESUMEN

OBJECTIVE/DESIGN: In a double-blind, placebo-controlled, multiple-dose study, we assessed the molecular mechanism of action of the selective histamine-4-receptor antagonist toreforant. PATIENTS/TREATMENT: Patients with active rheumatoid arthritis (RA) despite methotrexate were randomized (3:1) to toreforant 30 mg/day (weeks 0-52) or placebo (weeks 0-12) followed by toreforant 30 mg/day (weeks 12-52). METHODS: Primary biomarker analyses comprised 39 different proteins/mRNA transcripts measured in synovial biopsy (n = 39) and/or time-matched serum (n = 15) samples collected at baseline and week 6. Clinical response was assessed using C-reactive protein-based 28-joint disease activity scores. Data were summarized using descriptive statistics. RESULTS: Among 21 randomized, treated patients (toreforant-16, placebo-5), 18 (toreforant-13, placebo-5) completed the 12-week double-blind period (none completed open-label treatment) prior to the early study termination. Biomarker profiling indicated potential modest effects of toreforant on gene expression of histamine-1-receptor, tumor necrosis factor-alpha, and interleukin-8 in synovium. Potential trends between biomarkers and clinical response were observed with synovial monocyte chemoattractant protein-4 and phosphorylated extracellular-signal-regulated kinases and serum matrix metalloproteinase-3. Minimal synovial gene expression of interleukins-17A and 17F was detected. CONCLUSIONS: While clear biomarker signals associated with toreforant pharmacology in RA patients were not identified, modest associations between biomarkers and clinical response were noted. Synovial expression of interleukins-17A/17F was minimal. Limited sample size warrants cautious interpretation.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Bencimidazoles/uso terapéutico , Antagonistas de los Receptores Histamínicos/uso terapéutico , Piperidinas/uso terapéutico , Pirimidinas/uso terapéutico , Receptores Histamínicos H4/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Antirreumáticos/farmacología , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Bencimidazoles/farmacología , Método Doble Ciego , Femenino , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Interleucina-17/inmunología , Masculino , Metotrexato/farmacología , Metotrexato/uso terapéutico , Persona de Mediana Edad , Piperidinas/farmacología , Pirimidinas/farmacología , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Resultado del Tratamiento , Adulto Joven
5.
J Immunol ; 199(7): 2316-2322, 2017 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-28807995

RESUMEN

Rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) display unique aggressive behavior, invading the articular cartilage and promoting inflammation. Using an integrative analysis of RA risk alleles, the transcriptome and methylome in RA FLS, we recently identified the limb bud and heart development (LBH) gene as a key dysregulated gene in RA and other autoimmune diseases. Although some evidence suggests that LBH could modulate the cell cycle, the precise mechanism is unknown and its impact on inflammation in vivo has not been defined. Our cell cycle analysis studies show that LBH deficiency in FLS leads to S-phase arrest and failure to progress through the cell cycle. LBH-deficient FLS had increased DNA damage and reduced expression of the catalytic subunit of DNA polymerase α. Decreased DNA polymerase α was followed by checkpoint arrest due to phosphorylation of checkpoint kinase 1. Because DNA fragments can increase arthritis severity in preclinical models, we then explored the effect of LBH deficiency in the K/BxN serum transfer model. Lbh knockout exacerbated disease severity, which is associated with elevated levels of IL-1ß and checkpoint kinase 1 phosphorylation. These studies indicate that LBH deficiency induces S-phase arrest that, in turn, exacerbates inflammation. Because LBH gene variants are associated with type I diabetes mellitus, systemic lupus erythematosus, RA, and celiac disease, these results suggest a general mechanism that could contribute to immune-mediated diseases.


Asunto(s)
Artritis Reumatoide/genética , Ciclo Celular/genética , Proteínas Nucleares/genética , Sinoviocitos/inmunología , Animales , Artritis Experimental , Artritis Reumatoide/inmunología , Artritis Reumatoide/fisiopatología , Proteínas de Ciclo Celular , Células Cultivadas , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/genética , Daño del ADN , ADN Polimerasa I/genética , ADN Polimerasa I/metabolismo , Regulación de la Expresión Génica , Genes cdc , Humanos , Interleucina-1beta/biosíntesis , Ratones , Ratones Noqueados , Proteínas Nucleares/deficiencia , Proteínas Nucleares/metabolismo , Fosforilación , Transducción de Señal , Factores de Transcripción
6.
Immunity ; 30(6): 875-87, 2009 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-19501000

RESUMEN

NLRP3 nucleates the inflammasome, a protein complex responsible for cleavage of prointerleukin-1beta (IL-1beta) to its active form. Mutations in the NLRP3 gene cause the autoinflammatory disease spectrum cryopyrin-associated periodic syndromes (CAPS). The central role of IL-1beta in CAPS is supported by the response to IL-1-targeted therapy. We developed two Nlrp3 mutant knockin mouse strains to model CAPS to examine the role of other inflammatory mediators and adaptive immune responses in an innate immune-driven disease. These mice had systemic inflammation and poor growth, similar to some human CAPS patients, and demonstrated early mortality, primarily mediated by myeloid cells. Mating these mutant mice to various gene mutant backgrounds showed that the mouse disease phenotype required an intact inflammasome, was only partially dependent on IL-1beta, and was independent of T cells. These data suggest that CAPS are true inflammasome-mediated diseases and provide insight for more common inflammatory disorders.


Asunto(s)
Proteínas Portadoras/metabolismo , Citocinas/metabolismo , Inmunidad Innata/genética , Inflamación/genética , Interleucina-1beta/metabolismo , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Inmunidad Activa , Inflamación/inmunología , Interleucina-18 , Interleucina-1beta/inmunología , Ratones , Ratones Mutantes , Mutación/genética , Mutación/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR , Linfocitos T/inmunología , Linfocitos T/metabolismo
7.
Ann Rheum Dis ; 75(1): 295-302, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25378349

RESUMEN

OBJECTIVE: In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) that line joint synovial membranes aggressively invade the extracellular matrix, destroying cartilage and bone. As signal transduction in FLS is mediated through multiple pathways involving protein tyrosine phosphorylation, we sought to identify protein tyrosine phosphatases (PTPs) regulating the invasiveness of RA FLS. We describe that the transmembrane receptor PTPκ (RPTPκ), encoded by the transforming growth factor (TGF) ß-target gene, PTPRK, promotes RA FLS invasiveness. METHODS: Gene expression was quantified by quantitative PCR. PTP knockdown was achieved using antisense oligonucleotides. FLS invasion and migration were assessed in transwell or spot assays. FLS spreading was assessed by immunofluorescence microscopy. Activation of signalling pathways was analysed by Western blotting of FLS lysates using phosphospecific antibodies. In vivo FLS invasiveness was assessed by intradermal implantation of FLS into nude mice. The RPTPκ substrate was identified by pull-down assays. RESULTS: PTPRK expression was higher in FLS from patients with RA versus patients with osteoarthritis, resulting from increased TGFB1 expression in RA FLS. RPTPκ knockdown impaired RA FLS spreading, migration, invasiveness and responsiveness to platelet-derived growth factor, tumour necrosis factor and interleukin 1 stimulation. Furthermore, RPTPκ deficiency impaired the in vivo invasiveness of RA FLS. Molecular analysis revealed that RPTPκ promoted RA FLS migration by dephosphorylation of the inhibitory residue Y527 of SRC. CONCLUSIONS: By regulating phosphorylation of SRC, RPTPκ promotes the pathogenic action of RA FLS, mediating cross-activation of growth factor and inflammatory cytokine signalling by TGFß in RA FLS.


Asunto(s)
Artritis Reumatoide/patología , Fibroblastos/patología , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/fisiología , Membrana Sinovial/patología , Factor de Crecimiento Transformador beta1/fisiología , Animales , Artritis Reumatoide/metabolismo , Movimiento Celular/genética , Movimiento Celular/fisiología , Fibroblastos/metabolismo , Fibroblastos/fisiología , Fibroblastos/trasplante , Regulación Enzimológica de la Expresión Génica/fisiología , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Ratones Desnudos , Proteínas Tirosina Fosfatasas/genética , Proteínas Tirosina Fosfatasas/fisiología , ARN Mensajero/genética , Proteínas Tirosina Fosfatasas Clase 2 Similares a Receptores/genética , Membrana Sinovial/metabolismo , Membrana Sinovial/trasplante , Regulación hacia Arriba
8.
J Immunol ; 190(3): 1297-303, 2013 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-23277489

RESUMEN

Rheumatoid arthritis (RA) is a chronic inflammatory disease in which fibroblast-like synoviocytes (FLS) exhibit an aggressive phenotype. Although the mechanisms responsible are not well defined, epigenetic determinants such as DNA methylation might contribute. DNA methyltransferases (DNMTs) are critical enzymes that establish and maintain DNA methylation. We evaluated whether proinflammatory cytokines might contribute to differential DNA methylation previously described in RA FLS through altered DNMT expression. FLS were obtained from RA and osteoarthritis (OA) synovium at the time of total joint replacement. Gene expression was determined by quantitative real-time PCR and protein expression by Western blot analysis. DNMT activity was measured with a functional assay, and global methylation was determined by an immunoassay that detects methylcytosine. Resting expression of DNMT1, -3a, and -3b mRNA were similar in RA and OA FLS. Western blot showed abundant DNMT1 and DNMT3a protein. Exposure to IL-1 decreased DNMT1 and DNMT3a mRNA expression in FLS. Dose responses demonstrated decreased DNMT expression at concentrations as low as 1 pg/ml of IL-1. DNMT mRNA levels decreased rapidly, with significant suppression after 2-8 h of IL-1 stimulation. IL-1 stimulation of OA FLS did not affect methylation of LINE1 sites but led to demethylation of a CHI3L1 locus that is hypomethylated in RA FLS. Chronic IL-1 stimulation also mimicked the effect of a DNMT inhibitor on FLS gene expression. Exposure to proinflammatory mediators reversibly alters DNA methylation in FLS by decreasing DNMT expression and function. These data suggest that IL-1 can potentially imprint cells in chronic inflammatory diseases.


Asunto(s)
Artritis Reumatoide/genética , Metilación de ADN , Membrana Sinovial/metabolismo , Adipoquinas , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Azacitidina/farmacología , Proteína 1 Similar a Quitinasa-3 , Colágeno Tipo I , Cadena alfa 1 del Colágeno Tipo I , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/biosíntesis , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Relación Dosis-Respuesta a Droga , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1beta/farmacología , Lectinas , Elementos de Nucleótido Esparcido Largo , Osteoartritis/genética , Osteoartritis/metabolismo , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Membrana Sinovial/patología , ADN Metiltransferasa 3B
9.
J Pharmacol Exp Ther ; 348(2): 271-80, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24244039

RESUMEN

Phosphoinositide 3-kinases γ and δ (PI3Kγ and PI3Kδ) are expressed in rheumatoid arthritis (RA) synovium and regulate innate and adaptive immune responses. We determined the effect of a potent PI3Kδ,γ inhibitor, IPI-145, in two preclinical models of RA. IPI-145 was administered orally in rat adjuvant-induced arthritis (AA) and intraperitoneally in mouse collagen-induced arthritis (CIA). Efficacy was assessed by paw swelling, clinical scores, histopathology and radiography, and microcomputed tomography scanning. Gene expression and Akt phosphorylation in joint tissues were determined by quantitative real-time polymerase chain reaction and Western blot analysis. Serum concentrations of anti-type II collagen (CII) IgG and IgE were measured by immunoassay. T-cell responses to CII were assayed using thymidine incorporation and immunoassay. IPI-145 significantly reduced arthritis severity in both RA models using dosing regimens initiated before onset of clinical disease. Treatment of established arthritis with IPI-145 in AA, but not CIA, significantly decreased arthritis progression. In AA, histology scores, radiographic joint damage, and matrix metalloproteinase (MMP)-13 expression were reduced in IPI-145-treated rats. In CIA, joint histology scores and expression of MMP-3 and MMP-13 mRNA were lower in the IPI-145 early treatment group than in the vehicle group. The ratio of anti-CII IgG2a to total IgG in CIA was modestly reduced. Interleukin-17 production in response to CII was decreased in the IPI-145-treated group, suggesting an inhibitory effect on T-helper cell 17 differentiation. These data show that PI3Kδ,γ inhibition suppresses inflammatory arthritis, as well as bone and cartilage damage, through effects on innate and adaptive immunity and that IPI-145 is a potential therapy for RA.


Asunto(s)
Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Modelos Animales de Enfermedad , Drogas en Investigación/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Articulaciones/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3 , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/uso terapéutico , Antirreumáticos/administración & dosificación , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Células Cultivadas , Drogas en Investigación/administración & dosificación , Inhibidores Enzimáticos/administración & dosificación , Inyecciones Intraperitoneales , Interleucina-17/antagonistas & inhibidores , Interleucina-17/genética , Interleucina-17/metabolismo , Isoenzimas/antagonistas & inhibidores , Isoenzimas/metabolismo , Isoquinolinas/administración & dosificación , Isoquinolinas/uso terapéutico , Articulaciones/inmunología , Articulaciones/metabolismo , Articulaciones/patología , Masculino , Ratones , Ratones Endogámicos DBA , Fosfatidilinositol 3-Quinasas/metabolismo , Purinas/administración & dosificación , Purinas/uso terapéutico , Distribución Aleatoria , Ratas , Ratas Endogámicas Lew , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/enzimología , Membrana Sinovial/inmunología , Membrana Sinovial/patología , Células Th17/efectos de los fármacos , Células Th17/inmunología , Células Th17/metabolismo
10.
Arthritis Rheum ; 65(5): 1194-202, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23335302

RESUMEN

OBJECTIVE: Through its location on nociceptors, acid-sensing ion channel 3 (ASIC-3) is activated by decreases in pH and plays a significant role in musculoskeletal pain. We recently showed that decreases in pH activate ASIC-3 located on fibroblast-like synoviocytes (FLS), which are key cells in the inflammatory process. The purpose of this study was to test whether ASIC-3-deficient mice with arthritis have altered inflammation and pain relative to controls. METHODS: Collagen antibody-induced arthritis (CAIA) was generated by injection of an anti-type II collagen antibody cocktail. Inflammation and pain parameters in ASIC-3(-/-) and ASIC-3(+/+) mice were assessed. Disease severity was assessed by determining clinical arthritis scores, measuring joint diameters, analyzing joint histology, and assessing synovial gene expression by quantitative polymerase chain reaction analysis. Cell death was assessed with a Live/Dead assay of FLS in response to decreases in pH. Pain behaviors in the mice were measured by examining withdrawal thresholds in the joints and paws and by measuring their physical activity levels. RESULTS: Surprisingly, ASIC-3(-/-) mice with CAIA demonstrated significantly increased joint inflammation, joint destruction, and expression of interleukin-6 (IL-6), matrix metalloproteinase 3 (MMP-3), and MMP-13 in joint tissue as compared to ASIC-3(+/+) mice. ASIC-3(+/+) FLS showed enhanced cell death when exposed to pH 6.0 in the presence of IL-1ß, which was abolished in ASIC-3(-/-) FLS. Despite enhanced disease severity, ASIC-3(-/-) mice did not develop mechanical hypersensitivity of the paw and showed greater levels of physical activity. CONCLUSION: Our findings are consistent with the hypothesis that ASIC-3 plays a protective role in the inflammatory arthritides by limiting inflammation through enhanced synoviocyte cell death, which reduces disease severity, and through the production of pain, which reduces joint use.


Asunto(s)
Canales Iónicos Sensibles al Ácido/deficiencia , Artritis Experimental/patología , Artritis Reumatoide/patología , Dolor/patología , Sinovitis/patología , Animales , Artritis Experimental/complicaciones , Artritis Experimental/fisiopatología , Artritis Reumatoide/complicaciones , Artritis Reumatoide/fisiopatología , Conducta Animal , Muerte Celular , Supervivencia Celular , Femenino , Expresión Génica , Miembro Posterior , Hiperalgesia , Interleucina-6/genética , Interleucina-6/metabolismo , Articulaciones/metabolismo , Articulaciones/patología , Articulaciones/fisiopatología , Masculino , Metaloproteinasas de la Matriz/genética , Metaloproteinasas de la Matriz/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Dolor/etiología , Dolor/fisiopatología , Dimensión del Dolor , Umbral del Dolor , Índice de Severidad de la Enfermedad , Sinovitis/etiología , Sinovitis/fisiopatología
11.
Arthritis Rheum ; 65(5): 1171-80, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23335101

RESUMEN

OBJECTIVE: The fibroblast-like synoviocytes (FLS) in the synovial intimal lining of the joint are key mediators of inflammation and joint destruction in rheumatoid arthritis (RA). In RA, these cells aggressively invade the extracellular matrix, producing cartilage-degrading proteases and inflammatory cytokines. The behavior of FLS is controlled by multiple interconnected signal transduction pathways involving reversible phosphorylation of proteins on tyrosine residues. However, little is known about the role of the protein tyrosine phosphatases (PTPs) in FLS function. This study was undertaken to explore the expression of all of the PTP genes (the PTPome) in FLS. METHODS: A comparative screening of the expression of the PTPome in FLS from patients with RA and patients with osteoarthritis (OA) was conducted. The functional effect on RA FLS of SH2 domain-containing phosphatase 2 (SHP-2), a PTP that was up-regulated in RA, was then analyzed by knockdown using cell-permeable antisense oligonucleotides. RESULTS: PTPN11 was overexpressed in RA FLS compared to OA FLS. Knockdown of PTPN11, which encodes SHP-2, reduced the invasion, migration, adhesion, spreading, and survival of RA FLS. Additionally, signaling in response to growth factors and inflammatory cytokines was impaired by SHP-2 knockdown. RA FLS that were deficient in SHP-2 exhibited decreased activation of focal adhesion kinase and mitogen-activated protein kinases. CONCLUSION: These findings indicate that SHP-2 has a novel role in mediating human FLS function and suggest that it promotes the invasiveness and survival of RA FLS. Further investigation may reveal SHP-2 to be a candidate therapeutic target for RA.


Asunto(s)
Artritis Reumatoide/enzimología , Fibroblastos/enzimología , Osteoartritis/enzimología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Proteínas Tirosina Fosfatasas/metabolismo , Membrana Sinovial/enzimología , Artritis Reumatoide/genética , Línea Celular , Movimiento Celular , Fibroblastos/patología , Regulación Enzimológica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Oligonucleótidos Antisentido/farmacología , Osteoartritis/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Tirosina Fosfatasas/genética , Transducción de Señal , Membrana Sinovial/patología , Regulación hacia Arriba
12.
Arthritis Rheumatol ; 76(8): 1252-1262, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38566346

RESUMEN

OBJECTIVE: Fibroblast-like synoviocytes (FLS) contribute to the pathogenesis of rheumatoid arthritis (RA), in part due to activation of the proinflammatory transcription factor NF-κB. Neddylation is modulated by the negative regulator of ubiquitin-like protein (NUB) 1. We determined whether NUB1 and neddylation are aberrant in the models with RA FLS, thereby contributing to their aggressive phenotype. METHODS: Models with RA or osteoarthritis (OA) FLS were obtained from arthroplasty synovia. Real-time quantitative polymerase chain reaction and Western blot analysis assessed gene and protein expression, respectively. NUB1 was overexpressed using an expression vector. NF-κB activation was assessed by stimulating FLS with interleukin (IL)-1ß. Neddylation inhibitor (MLN4924) and proteasome inhibitor were used in migration and gene expression assays. MLN4924 was used in the model with K/BxN serum-transfer arthritis. RESULTS: Enhanced H3K27ac and H3K27me3 peaks were observed in the NUB1 promoter in the OA FLS compared with the RA FLS. NUB1 was constitutively expressed by FLS, but induction by IL-1ß was significantly greater in the OA FLS. The ratio of neddylated cullin (CUL) 1 to nonneddylated CUL1 was lower in the OA FLS than the RA FLS. NUB1 overexpression decreased NF-κB nuclear translocation and IL-6 messenger RNA (mRNA) in IL-1ß-stimulated the RA FLS. MLN4924 decreased CUL1 neddylation, NF-κB nuclear translocation, and IL-6 mRNA in IL-1ß-stimulated the RA FLS. MLN4924 significantly decreased arthritis severity in the model with K/BxN serum-transfer arthritis. CONCLUSION: CUL1 neddylation and NUB1 induction is dysregulated in the models with RA, which increases FLS activation. Inhibition of neddylation is an effective therapy in an animal model of arthritis. These data suggest that the neddylation system contributes to the pathogenesis of RA and that regulation of neddylation could be a novel therapeutic approach.


Asunto(s)
Artritis Reumatoide , Ciclopentanos , Fibroblastos , FN-kappa B , Sinoviocitos , Artritis Reumatoide/metabolismo , Sinoviocitos/metabolismo , Sinoviocitos/efectos de los fármacos , Humanos , Ciclopentanos/farmacología , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , FN-kappa B/metabolismo , Osteoartritis/metabolismo , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacología , Pirimidinas/farmacología , Animales , Ubiquitinas/metabolismo , Ubiquitinas/genética , Inflamación/metabolismo , Proteínas Cullin/metabolismo , Proteínas Cullin/genética , Proteína NEDD8/metabolismo , Proteína NEDD8/genética , Ratones
13.
PLoS One ; 19(6): e0304530, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38829908

RESUMEN

Rheumatoid arthritis (RA) is a systemic immune-mediated disease characterized by joint inflammation and destruction. The disease typically affects small joints in the hands and feet, later progressing to involve larger joints such as the knees, shoulders, and hips. While the reasons for these joint-specific differences are unclear, distinct epigenetic patterns associated with joint location have been reported. In this study, we evaluated the unique epigenetic landscapes of fibroblast-like synoviocytes (FLS) from hip and knee synovium in RA patients, focusing on the expression and regulation of Homeobox (HOX) transcription factors. These highly conserved genes play a critical role in embryonic development and are known to maintain distinct expression patterns in various adult tissues. We found that several HOX genes, especially HOXD10, were differentially expressed in knee FLS compared with hip FLS. Epigenetic differences in chromatin accessibility and histone marks were observed in HOXD10 promoter between knee and hip FLS. Histone modification, particularly histone acetylation, was identified as an important regulator of HOXD10 expression. To understand the mechanism of differential HOXD10 expression, we inhibited histone deacetylases (HDACs) with small molecules and siRNA. We found that HDAC1 blockade or deficiency normalized the joint-specific HOXD10 expression patterns. These observations suggest that epigenetic differences, specifically histone acetylation related to increased HDAC1 expression, play a crucial role in joint-specific HOXD10 expression. Understanding these mechanisms could provide insights into the regional aspects of RA and potentially lead to therapeutic strategies targeting specific patterns of joint involvement during the course of disease.


Asunto(s)
Artritis Reumatoide , Epigénesis Genética , Fibroblastos , Proteínas de Homeodominio , Sinoviocitos , Humanos , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Artritis Reumatoide/genética , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Sinoviocitos/metabolismo , Sinoviocitos/patología , Fibroblastos/metabolismo , Fibroblastos/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 1/genética , Regiones Promotoras Genéticas , Articulación de la Rodilla/patología , Articulación de la Rodilla/metabolismo , Regulación de la Expresión Génica , Histonas/metabolismo , Acetilación , Articulación de la Cadera/patología , Articulación de la Cadera/metabolismo
14.
Nat Commun ; 15(1): 4991, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38862501

RESUMEN

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.


Asunto(s)
Artritis Reumatoide , Linfocitos B , Membrana Sinovial , Humanos , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Artritis Reumatoide/genética , Artritis Reumatoide/patología , Membrana Sinovial/inmunología , Membrana Sinovial/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Femenino , Masculino , Persona de Mediana Edad , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Análisis de la Célula Individual , Transcriptoma , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Anciano , Activación de Linfocitos , Adulto
15.
Ann Rheum Dis ; 72(1): 110-7, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22736089

RESUMEN

OBJECTIVES: Epigenetics can influence disease susceptibility and severity. While DNA methylation of individual genes has been explored in autoimmunity, no unbiased systematic analyses have been reported. Therefore, a genome-wide evaluation of DNA methylation loci in fibroblast-like synoviocytes (FLS) isolated from the site of disease in rheumatoid arthritis (RA) was performed. METHODS: Genomic DNA was isolated from six RA and five osteoarthritis (OA) FLS lines and evaluated using the Illumina HumanMethylation450 chip. Cluster analysis of data was performed and corrected using Benjamini-Hochberg adjustment for multiple comparisons. Methylation was confirmed by pyrosequencing and gene expression was determined by qPCR. Pathway analysis was performed using the Kyoto Encyclopedia of Genes and Genomes. RESULTS: RA and control FLS segregated based on DNA methylation, with 1859 differentially methylated loci. Hypomethylated loci were identified in key genes relevant to RA, such as CHI3L1, CASP1, STAT3, MAP3K5, MEFV and WISP3. Hypermethylation was also observed, including TGFBR2 and FOXO1. Hypomethylation of individual genes was associated with increased gene expression. Grouped analysis identified 207 hypermethylated or hypomethylated genes with multiple differentially methylated loci, including COL1A1, MEFV and TNF. Hypomethylation was increased in multiple pathways related to cell migration, including focal adhesion, cell adhesion, transendothelial migration and extracellular matrix interactions. Confirmatory studies with OA and normal FLS also demonstrated segregation of RA from control FLS based on methylation pattern. CONCLUSIONS: Differentially methylated genes could alter FLS gene expression and contribute to the pathogenesis of RA. DNA methylation of critical genes suggests that RA FLS are imprinted and implicate epigenetic contributions to inflammatory arthritis.


Asunto(s)
Artritis Reumatoide/genética , Metilación de ADN/genética , Regulación de la Expresión Génica , Transcriptoma , Anciano , Análisis por Conglomerados , Femenino , Fibroblastos/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Membrana Sinovial/citología , Membrana Sinovial/metabolismo
16.
Am J Pathol ; 180(5): 1906-16, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22433439

RESUMEN

Class I phosphoinositide 3 kinase (PI3K) δ is a promising therapeutic target for rheumatoid arthritis (RA) because of its contribution to leukocyte biology. However, its contribution in fibroblasts has not been studied as a mechanism that contributes to efficacy. We investigated the expression and function of PI3Kδ in synovium and cultured fibroblast-like synoviocytes (FLS). Immunohistochemistry demonstrated that PI3Kδ is highly expressed in RA synovium, especially in the synovial lining. Using quantitative PCR and Western blot analysis, we found that PI3Kδ mRNA and protein expression is higher in RA than in osteoarthritis (OA) synovium. PI3Kδ was also expressed in cultured FLS, along with PI3Kα and PI3Kß, whereas PI3Kγ was not detectable. PI3Kδ mRNA expression was selectively induced by inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) but not by growth factors platelet-derived growth factor (PDGF) and transforming growth factor ß (TGFß). The use of inhibitors that block individual PI3K isoforms, including the novel selective PI3Kδ inhibitor INK007, showed that PI3Kδ is required for PDGF- and TNF-induced Akt activation. PI3Kδ inhibition also diminished PDGF-mediated synoviocyte growth and sensitized cells to H(2)O(2)-induced apoptosis. These data are the first documentation of increased PI3Kδ expression in both RA synovium and cultured synoviocytes. Furthermore, these are the first data demonstrating that PI3Kδ is a major regulator of PDGF-mediated fibroblast growth and survival via Akt. Thus, targeting PI3Kδ in RA could modulate synoviocyte function via anti-inflammatory and disease-altering mechanisms.


Asunto(s)
Artritis Reumatoide/enzimología , Fosfatidilinositol 3-Quinasas/fisiología , Membrana Sinovial/enzimología , Apoptosis/fisiología , Artritis Reumatoide/patología , División Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Fosfatidilinositol 3-Quinasa Clase I , Citocinas/farmacología , Inhibidores Enzimáticos/farmacología , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Humanos , Mediadores de Inflamación/farmacología , Osteoartritis/enzimología , Fosfatidilinositol 3-Quinasas/biosíntesis , Fosfatidilinositol 3-Quinasas/genética , Inhibidores de las Quinasa Fosfoinosítidos-3 , Factor de Crecimiento Derivado de Plaquetas/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/genética , Membrana Sinovial/patología , Factor de Crecimiento Transformador beta/farmacología
17.
Arthritis Rheum ; 64(9): 2887-95, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22488549

RESUMEN

OBJECTIVE: Inhibitors of p38 demonstrate limited benefit in rheumatoid arthritis (RA), perhaps due to the antiinflammatory functions of p38α. This study was performed to determine if selective deletion of p38α in macrophages affects the severity of arthritis and whether blocking upstream kinases in the p38 pathway, such as MKK-3 or MKK-6, avoids some of the limitations of p38 blockade. METHODS: Wild-type (WT) mice and mice with selective deletion of p38α in macrophages (p38α(ΔLysM) ) were injected with K/BxN sera. Antigen-induced arthritis was also induced in p38α(ΔLysM) mice. Mouse joint extracts were evaluated by enzyme-linked immunosorbent assay, quantitative polymerase chain reaction (qPCR), and Western blot analysis. Bone marrow-derived macrophages (BMMs) were stimulated with lipopolysaccharide (LPS) and were evaluated by qPCR and Western blotting. Bone marrow chimeras were generated using MKK-3(-/-) and MKK-6(-/-) mice, and K/BxN serum was administered to induce arthritis. RESULTS: Compared to WT mice, p38α(ΔLysM) mice had increased disease severity and delayed resolution of arthritis, which correlated with higher synovial inflammatory mediator expression and ERK phosphorylation. In contrast to WT BMMs cultured in the presence of a p38α/ß inhibitor, LPS-stimulated MKK-6- and MKK-3-deficient BMMs had suppressed LPS-mediated interleukin-6 (IL-6) expression but had normal IL-10 production, dual-specificity phosphatase 1 expression, and MAPK phosphorylation. WT chimeric mice with MKK-6- and MKK-3-deficient bone marrow had markedly decreased passive K/BxN arthritis severity. CONCLUSION: Inhibiting p38α in a disease that is dominated by macrophage cytokines, such as RA, could paradoxically suppress antiinflammatory functions and interfere with clinical efficacy. Targeting an upstream kinase that regulates p38 could be more effective by suppressing proinflammatory cytokines while preventing decreased IL-10 expression and increased MAPK activation.


Asunto(s)
Artritis Experimental/metabolismo , Artritis Reumatoide/metabolismo , MAP Quinasa Quinasa 3/metabolismo , MAP Quinasa Quinasa 6/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Artritis Experimental/genética , Artritis Reumatoide/genética , Humanos , Inflamación/genética , Inflamación/metabolismo , Interferón gamma/metabolismo , Articulaciones/metabolismo , MAP Quinasa Quinasa 3/genética , MAP Quinasa Quinasa 6/genética , Macrófagos/metabolismo , Ratones , Ratones Noqueados , Fosforilación , Bazo/metabolismo , Membrana Sinovial/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética
18.
Arthritis Rheum ; 64(3): 678-87, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21953132

RESUMEN

OBJECTIVE: The MAPK kinases MKK-3 and MKK-6 regulate p38 MAPK activation in inflammatory diseases such as rheumatoid arthritis (RA). Previous studies demonstrated that MKK-3 or MKK-6 deficiency inhibits K/BxN serum-induced arthritis. However, the role of these kinases in adaptive immunity-dependent models of chronic arthritis is not known. The goal of this study was to evaluate MKK-3 and MKK-6 deficiency in the collagen-induced arthritis (CIA) model. METHODS: Wild-type (WT), MKK-3(-/-) , and MKK-6(-/-) mice were immunized with bovine type II collagen. Disease activity was evaluated by semiquantitative scoring, histologic assessment, and micro-computed tomography. Serum anticollagen antibody levels were quantified by enzyme-linked immunosorbent assay. In vitro T cell cytokine response was measured by flow cytometry and multiplex analysis. Expression of joint cytokines and matrix metalloproteinases (MMPs) was determined by quantitative polymerase chain reaction. RESULTS: MKK-6 deficiency markedly reduced arthritis severity compared with that in WT mice, while the absence of MKK-3 had an intermediate effect. Joint damage was minimal in arthritic MKK-6(-/-) mice and intermediate in MKK-3(-/-) mice compared with WT mice. MKK-6(-/-) mice had modestly lower levels of pathogenic anticollagen antibodies than did WT or MKK-3(-/-) mice. In vitro T cell assays showed reduced proliferation and interleukin-17 (IL-17) production by lymph node cells from MKK-6(-/-) mice in response to type II collagen. Gene expression of synovial IL-6, MMP-3, and MMP-13 was significantly inhibited in MKK-6-deficient mice. CONCLUSION: Reduced disease severity in MKK-6(-/-) mice correlated with decreased anticollagen antibody responses, indicating that MKK-6 is a crucial regulator of inflammatory joint destruction in CIA. MKK-6 is a potential therapeutic target in complex diseases involving adaptive immune responses, such as RA.


Asunto(s)
Inmunidad Adaptativa/inmunología , Artritis Experimental/inmunología , Artritis Experimental/patología , MAP Quinasa Quinasa 6/deficiencia , Animales , Artritis Experimental/fisiopatología , Bovinos , Colágeno/inmunología , Colágeno/farmacología , Femenino , Endogamia , Interleucina-6/genética , Interleucina-6/metabolismo , Articulaciones/metabolismo , Articulaciones/patología , Articulaciones/fisiopatología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , MAP Quinasa Quinasa 3/genética , MAP Quinasa Quinasa 3/metabolismo , MAP Quinasa Quinasa 6/genética , MAP Quinasa Quinasa 6/metabolismo , Masculino , Metaloproteinasa 13 de la Matriz/genética , Metaloproteinasa 13 de la Matriz/metabolismo , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/metabolismo , Ratones , Ratones Endogámicos DBA , Ratones Noqueados , Membrana Sinovial/efectos de los fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/patología
19.
bioRxiv ; 2023 Mar 21.
Artículo en Inglés | MEDLINE | ID: mdl-36993527

RESUMEN

Rheumatoid arthritis (RA) is an autoimmune disease initiated by antigen-specific T cells and B cells, which promote synovial inflammation through a complex set of interactions with innate immune and stromal cells. To better understand the phenotypes and clonal relationships of synovial T and B cells, we performed single-cell RNA and repertoire sequencing on paired synovial tissue and peripheral blood samples from 12 donors with seropositive RA ranging from early to chronic disease. Paired transcriptomic-repertoire analyses highlighted 3 clonally distinct CD4 T cells populations that were enriched in RA synovium: T peripheral helper (Tph) and T follicular helper (Tfh) cells, CCL5+ T cells, and T regulatory cells (Tregs). Among these cells, Tph cells showed a unique transcriptomic signature of recent T cell receptor (TCR) activation, and clonally expanded Tph cells expressed an elevated transcriptomic effector signature compared to non-expanded Tph cells. CD8 T cells showed higher oligoclonality than CD4 T cells, and the largest CD8 T cell clones in synovium were highly enriched in GZMK+ cells. TCR analyses revealed CD8 T cells with likely viral-reactive TCRs distributed across transcriptomic clusters and definitively identified MAIT cells in synovium, which showed transcriptomic features of TCR activation. Among B cells, non-naive B cells including age-associated B cells (ABC), NR4A1+ activated B cells, and plasma cells, were enriched in synovium and had higher somatic hypermutation rates compared to blood B cells. Synovial B cells demonstrated substantial clonal expansion, with ABC, memory, and activated B cells clonally linked to synovial plasma cells. Together, these results reveal clonal relationships between functionally distinct lymphocyte populations that infiltrate RA synovium.

20.
Nat Commun ; 14(1): 7637, 2023 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-37993439

RESUMEN

Molecular markers of autoimmunity, such as antibodies to citrullinated protein antigens (ACPA), are detectable prior to inflammatory arthritis (IA) in rheumatoid arthritis (RA) and may define a state that is 'at-risk' for future RA. Here we present a cross-sectional comparative analysis among three groups that include ACPA positive individuals without IA (At-Risk), ACPA negative individuals and individuals with early, ACPA positive clinical RA (Early RA). Differential methylation analysis among the groups identifies non-specific dysregulation in peripheral B, memory and naïve T cells in At-Risk participants, with more specific immunological pathway abnormalities in Early RA. Tetramer studies show increased abundance of T cells recognizing citrullinated (cit) epitopes in At-Risk participants, including expansion of T cells reactive to citrullinated cartilage intermediate layer protein I (cit-CILP); these T cells have Th1, Th17, and T stem cell memory-like phenotypes. Antibody-antigen array analyses show that antibodies targeting cit-clusterin, cit-fibrinogen and cit-histone H4 are elevated in At-Risk and Early RA participants, with the highest levels of antibodies detected in those with Early RA. These findings indicate that an ACPA positive at-risk state is associated with multifaceted immune dysregulation that may represent a potential opportunity for targeted intervention.


Asunto(s)
Artritis Reumatoide , Autoanticuerpos , Humanos , Estudios Transversales , Epítopos
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