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1.
Isr Med Assoc J ; 21(7): 454-459, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507120

RESUMO

BACKGROUND: Platelets have the ability to influence the immune system and the inflammatory process and may be strongly involved in the whole pathogenic process of chronic inflammatory joint diseases, such as rheumatoid arthritis. They may play a significant role even before the clinical onset of the disease, contributing to the loss of tolerance of the immune system and the induction of autoimmunity. Subsequently, they can interact with the most important cellular players involved in autoimmunity and inflammation, namely innate immunity cells and T cells and eventually contribute to the building of inflammation in the synovium, thus inducing the activation, migration, and proliferation of fibroblasts that eventually lead to joint damage. Due to their peculiar features, studying the behavior of platelets is a challenging task; however, platelets may prove to be valuable therapeutic targets in the future.


Assuntos
Artrite Reumatoide/imunologia , Plaquetas/imunologia , Sinovite/imunologia , Artrite Reumatoide/patologia , Autoimunidade/imunologia , Fibroblastos/imunologia , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Inflamação/patologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/patologia , Linfócitos T/imunologia
2.
Autoimmun Rev ; 18(11): 102397, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520798

RESUMO

BACKGROUND AND AIM: Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease; the clinical manifestations are correlated with continuum multiarticular synovitis, cartilage and bone damage, and defeat of joint function, that causes disability. Involvement of internal organs is also frequent. Between the inflammatory cells involved in RA, macrophages play a key role. These cells can polarize in different phenotype and mediate the immune/inflammatory reaction as well as the reparatory phase when possible. The properties of these cells are mediate by the body's environmental factors. In this systematic review, all English-speaking articles concerning the role of M1 (pro-inflammatory) or M2 (anti-inflammatory) macrophages in RA were systematically reviewed and categorized according to their polarized-function in RA, especially in the synovial tissue. Analyses of the endogenous molecules and the drugs that could modulate M1 and M2 activity in RA were achieved. METHODS: A sensitive search was developed in Pubmed, Web of Science, Ovid Med-Line, Embase Database and Science Direct Database (la both from Elsevier) to identify articles to increase the highlighting on the role of macrophages M1 and M2 in RA using the following terms: ((M1 AND M2) AND Rheumatoid Arthritis). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Relevant data were extracted and analyzed using a standardized template designed for this review. RESULTS: In total 39 resulting articles were selected and categorized according to description of M1/M2's role in RA. Data from humans, mice and rats were subcategorized, thus in every section were highlighted the contribute, in peripheral blood and synovial tissue, of both polarized macrophages; section for endogenous molecules and drugs that favor the switch from M1 to M2 macrophages were carried out. The most evinced relevant results, were that in RA blood and in the synovial tissue, there isn't a clear distinction phase with M1 or M2 macrophages (by membrane marker analysis); rather there is M1 and M2 subset disequilibrium and by deeply analyses of mRNA gene and cytokine produced, it emerged that a non-coherent expression inner marker match with membrane molecules, and also the tissue section can define the marker expressed. CONCLUSION: This systematic review emphasizes that the rigid classical subdivision of M1 and M2 macrophages, as well as the different samples' results comparison, might be questionable. In addition, it is suggested, when taking samples from RA patients, to carefully consider their therapies in order to analyze the M1 and M2 macrophages behavior without drug influence. In line with the advances in M1 and M2 knowledge, and the progression in the single-cell methodologies by identification of individual cell molecular markers, therapeutic approaches seem possible to favor the anti-inflammatory macrophage response in RA (e.g. M2 polarization).


Assuntos
Artrite Reumatoide/imunologia , Macrófagos/imunologia , Animais , Humanos
3.
Egypt J Immunol ; 26(1): 43-54, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31332995

RESUMO

Different cytokines play roles in the pathogenesis and tissue damage of Rheumatoid Arthritis (RA) including, Tumor necrosis factor superfamily (TNFSF) and their receptors particularly TNF-like ligand 1A (TL1A), and its decoy receptor DcR3. This study included 150 subjects, of them 50 patients having Rheumatoid Arthritis (RA), 50 patients with Osteoarthritis (OA), and 50 normal controls. Clinical examination was done and data was collected from patient's sheets, routine laboratory investigations included, rheumatoid factor (RF) antibody, anti-cyclic citrullinated peptide (anti-CCP) antibody, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Disease activity score 28 was calculated and used to measure the activity of RA. Serum and synovial fluid (SF) TL1A and DcR3 levels were measured by (ELISA), while IL-17 was measured in supernatant fluid of PBMC culture after stimulation with recombinant human (rh) TL1A. Results showed significantly higher levels of TL1A and its decoy receptor DcR3 in RA patients than the other two groups. It was also found that TL1A is significantly related to the disease activity and enhances IL-17 production after stimulation of PBMC. These results can guide scientists to the future substitutions in the way of treatment of various inflammatory and autoimmune diseases.


Assuntos
Artrite Reumatoide/fisiopatologia , Autoanticorpos/imunologia , Membro 6b de Receptores do Fator de Necrose Tumoral/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Células Cultivadas , Humanos , Interleucina-17/imunologia , Leucócitos Mononucleares
4.
J Agric Food Chem ; 67(24): 6773-6784, 2019 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-31154759

RESUMO

The aim of this study was to evaluate the immunomodulatory effects of atractylodin, a polyethylene alkyne, on the maturation of bone marrow-derived dendritic cells (BM-DC) as well as its antirheumatic effect on collagen-induced arthritis (CIA) in DBA/1 mice. Our results indicate that atractylodin effectively suppressed the secretion of pro-inflammatory cytokines, expression of costimulatory molecules, and p38 MAPK, ERK, and NF-κBp65 signaling pathways in LPS-incubated dendritic cells (DCs). Additionally, the proliferation and cytokine secretion (IFN-γ and IL-17A) of CD8+ and CD4+ T cells were reduced. In a murine CIA model, intraperitoneal injection of atractylodin significantly alleviated the severity of the disease progression, as indicated by reduced paw swelling, clinical arthritis scores, and pathological changes of joint tissues. In addition, the overall proliferation of T cells stimulated by type II collagen and the abundance of Th1 and Th17 in the spleens were also significantly decreased with atractylodin treatments. Furthermore, atractylodin significantly downregulated the expression levels of CD40, CD80, and CD86 of DCs in the spleens. In conclusion, this study shows for the first time that atractylodin has potential to manipulate the maturation of BM-DCs and should be further explored as a therapeutic agent in the treatment of rheumatoid arthritis (RA).


Assuntos
Artrite Reumatoide/tratamento farmacológico , Atractylodes/química , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo II/efeitos adversos , Células Dendríticas/citologia , Furanos/administração & dosagem , Animais , Artrite Reumatoide/induzido quimicamente , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Células Th17/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia
5.
APMIS ; 127(8): 588-593, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31233243

RESUMO

Microfibrillar-associated protein 4 (MFAP4) is a non-structural matrix protein with cell regulatory activities and a potential as seromarker for fibrosis. We aimed to study the occurrence of MFAP4 in the synovial membrane from patients with rheumatoid arthritis (RA) vs osteoarthritis (OA). Formaldehyde-fixed synovial tissue sections, from patients with RA (N = 6) and OA (N = 6) undergoing total hip arthroplasty, were deparaffinized and immunostained with monoclonal antibodies against MFAP4. Elastin was detected using ElastiKit. MFAP4 in serum (sMFAP4) and synovial fluid was measured by an immunoassay. MFAP4 was present in synovial biopsies from both RA and OA patients, particularly prominent in deep arterioles where it colocalized with elastin. Notably however, MFAP4 was absent from the internal elastic lamina in RA arterioles irrespective of disease duration and synovitis activity, while present although with irregular staining patterns in OA specimens. sMFAP4 was increased in RA and OA serum vs healthy controls: median (interquartile range) 29.8 (25.3-39.1) and 25.5 U/L (18.1-43.3) vs 17.7 U/L (13.7-21.2), p = 0.006 and p = 0.02, respectively The concentration of synovial fluid was lower than in serum in both RA and OA. These findings may suggest that MFAP4 is involved in adaptive vessel wall remodeling associated with chronic joint disease.


Assuntos
Artrite Reumatoide/imunologia , Proteínas de Transporte/análise , Proteínas da Matriz Extracelular/análise , Glicoproteínas/análise , Osteoartrite/imunologia , Membrana Sinovial/imunologia , Idoso , Anticorpos Monoclonais/imunologia , Biomarcadores/análise , Proteínas de Transporte/imunologia , Estudos de Casos e Controles , Proteínas da Matriz Extracelular/imunologia , Feminino , Glicoproteínas/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Líquido Sinovial/química , Membrana Sinovial/patologia
6.
Mol Immunol ; 112: 188-197, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176198

RESUMO

Rheumatoid arthritis (RA) is a chronic, systemic, synovitis-based inflammatory disease with unknown etiology. Neutrophils play important roles in the pathogenesis of RA. Apoptosis and NETosis of neutrophils are two major mechanisms of programmed cell death that differ in their morphological characteristics and effects on the immune system. In rheumatoid arthritis, delayed neutrophil apoptosis amplifies the inflammatory response; and massive release of NETs and their components may cause tissue damage and provide self-antigens. Emodin is a natural anthraquinone derivative that occurs in many widely used Chinese medicinal herbs. In this study, we evaluated the effect of emodin on a murine adjuvant-induced arthritis (AA) model of RA in vivo and on neutrophil apoptosis and NETosis in vitro. Our results show that emodin alleviated AA by reducing neutrophil infiltration and proinflammatory cytokine (interleukin-6, interferon-gamma and tumor necrosis factor-α) release. Emodin promoted apoptosis and inhibited autophagy and NETosis in neutrophils. These findings indicate that emodin represents a potential therapeutic agent for RA.


Assuntos
Apoptose/imunologia , Artrite Reumatoide/imunologia , Emodina/imunologia , Armadilhas Extracelulares/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Animais , Artrite Experimental/imunologia , Autoantígenos/imunologia , Autofagia/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/imunologia
7.
Mol Immunol ; 112: 256-265, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31207549

RESUMO

Rheumatoid arthritis (RA) is a complex autoimmune disease with an etiology that is not yet well understood, disproportionally affects women and also varies in incidence and prevalence by population. The presence of anti-citrullinated protein antibodies (ACPA) is a highly specific biomarker for the diagnosis of clinically apparent RA. ACPA are also present in the serum for an average of 3-5 years prior to the onset of RA during an asymptomatic period characterized by mucosal inflammation and local ACPA production at these sites. We hypothesized that systemic complement activation products might be generated during the pre-clinical initiation of RA and/or provide a second hit that promotes subsequent arthritis development in the joints. In addition, we evaluated which demographic and genetic features and environmental exposures could influence the complement activation process. We analyzed plasma from healthy subjects, subjects at-risk for the development of RA based on serum ACPA positivity in absence of inflammatory arthritis (IA), and ACPA positive RA subjects by Multiplex Assay and ELISA for eighteen complement system components, factors and activation products belonging to the classical, lectin and alternative pathways. By using regression models, associations between complement proteins and various demographic, genetic, and environmental factors previously found to be associated with RA, including sex, smoking, shared epitope, and oral contraceptive use, were examined. We found no evidence of systemic complement activation in ACPA positive subjects without IA, but in contrast found evidence of systemic involvement of the both classical and alternative pathways during the stage of the disease where classified RA is present, (i.e. during joint inflammation and damage). With regard to the demographic, genetic, and environmental variables, females who reported current or past oral contraceptive use and subjects with current tobacco exposure demonstrated alterations of the alternative pathway of complement. Furthermore, RA subjects with established disease who have a body mass index categorized as obese demonstrated higher levels of C2 compared to RA subjects who are not considered obese. In sum, the complement system may be involved in the pathogenesis of RA, with only localized mucosal effects during the preclinical period in those at-risk for RA but in the joint as well as systemically in those who have developed clinically apparent arthritis.


Assuntos
Artrite Reumatoide/imunologia , Proteínas do Sistema Complemento/imunologia , Anticorpos Anti-Proteína Citrulinada/imunologia , Índice de Massa Corporal , Estudos de Casos e Controles , Ativação do Complemento/imunologia , Progressão da Doença , Epitopos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/imunologia , Tabaco/imunologia
8.
Isr Med Assoc J ; 5(21): 345-352, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31140228

RESUMO

BACKGROUND: Angiogenesis is the outgrowth of new blood vessels from existing ones and is an early occurrence in inflamed joint tissue. It is governed by a tightly controlled balance of pro- and anti-angiogenic stimuli, which promote or inhibit generation and proliferation of new endothelial cells, vascular morphogenesis, and vessel remodeling. At the beginning, capillary formation is crucial in maintaining the supply of various nutrients as well as oxygen to the inflamed tissue. Local and systemic expression of angiogenic factors may indicate a constant remodeling of synovial vasculature. Redox signaling is closely related to angiogenesis and can alter angiogenic responses of synovial cells. In this review we discuss key issues about the endothelial pathology in inflammatory arthritis followed by a review of angiogenic processes and main angiogenic mediators. We discuss the hypoxia-vascular endothelial growth factor (VEGF)-Ang/Tie2 system and its related therapeutic implications in detail with further review of various mediator protein targets and intracellular regulatory pathway targets with their current and potential future role in preclinical or clinical setting whilst ameliorating inflammation.


Assuntos
Artrite Reumatoide , Neovascularização Patológica , Membrana Sinovial , Proteínas Angiogênicas/metabolismo , Anti-Inflamatórios/farmacologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/imunologia , Membrana Sinovial/irrigação sanguínea , Membrana Sinovial/imunologia , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/imunologia
9.
Clin Exp Rheumatol ; 37(3): 347-357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31111823

RESUMO

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease influenced by both genetic and environmental factors. Over the last few years, particular attention has been given to novel genes and to the close interaction between genetic factors and epigenetic mechanisms. Research has also focused on the influence of environmental factors on disease development, and on new mechanisms of the innate and adaptive immune system that can influence the different stages of RA. However, there are still several aspects of the disease that need further investigation. Shedding some light on the different aspects of RA pathogenesis will help to improve the current diagnostic tools and to identify new targets for the development of disease-modifying therapies. Thus, in this review we summarise the new insights in RA pathogenesis, resulting from literature research data published in the last year.


Assuntos
Artrite Reumatoide , Meio Ambiente , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Humanos , Fatores de Risco
10.
Scand J Immunol ; 90(2): e12792, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31141193

RESUMO

Depletion of B cells is beneficial in rheumatoid arthritis (RA) patients with autoantibodies to citrullinated proteins (ACPA) and/or the Fc portion of immunoglobulins (rheumatoid factor [RF]), suggesting a role for B cells in disease pathogenesis. To date, however, the identity of specifically pathogenic B cell subsets has not been discovered. One candidate population is identified by the low expression or absence of complement receptor 2 (CD21-/low B cells). In this study, we sought to determine whether there was any correlation between CD21-/low B cells and clinical outcome in patients with established RA, either ACPA+ /RF+ (n = 27) or ACPA- /RF- (n = 10). Healthy donors (n = 17) were included as controls. The proportion of the CD21-/low CD27- IgD- memory B cell subset in peripheral blood (PB) was significantly increased in ACPA+ /RF+ RA patients compared with healthy donors, and the frequency of this subset correlated with joint destruction (r = 0.57, P < 0.04). The levels of the chemokines CXCL-9 and CXCL-10 were higher in synovial fluid than in plasma, and PB CD21-/low cells expressed the receptor, CXCR3. In synovial fluid, most of the B cells were CD21-/low , approximately 40% of that population was CD27- IgD- , and a third of those expressed the pro-osteoclastogenic factor receptor activator of the nuclear factor κB ligand (RANKL). This subset also secreted RANKL, in addition to other factors such as IL-6, even in the absence of stimulation. We interpret these data as reason to propose the hypothesis that the CD27- IgD- subset of CD21-/low B cells may mediate joint destruction in patients with ACPA+ /RF+ RA.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Subpopulações de Linfócitos B/imunologia , Imunoglobulina D/metabolismo , Receptores de Complemento 3d/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Adulto , Quimiocina CXCL10/sangue , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/sangue , Quimiocina CXCL9/metabolismo , Feminino , Humanos , Articulações/imunologia , Articulações/patologia , Masculino , Pessoa de Meia-Idade , Ligante RANK/biossíntese , Receptores CXCR3/biossíntese , Líquido Sinovial/metabolismo
11.
Inflamm Res ; 68(7): 597-611, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31119302

RESUMO

OBJECTIVE: The present study was undertaken to validate whether TNF-α and calreticulin (CRT) serve as dual signaling to activate nucleotide-binding oligomerization domain-, leucine-rich repeat- and pyrin domain-containing 3 (NLRP3) inflammasome in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and HUVECs. The effect of human antigen R (HuR) in NLRP3 inflammasome activation was also explored in RA FLS. METHODS: Immunofluorescence was used to determine the expression of NLRP3 and adaptor protein apoptosis associated speck-like protein containing a CARD (ASC) in RA synovial tissue and HuR location in RA FLS. Western blot and quantitative real-time PCR were employed to measure the priming effect of NLRP3 inflammasome in cells and HuR expression in synovial tissue. The concentrations of IL-1ß and IL-18 were detected by enzyme linked immunosorbent assay. Immunohistochemistry was used to visualize the expression of HuR in synovial tissue. HuR knockdown in RA FLS was achieved by siRNA-mediated gene silencing. RESULTS: Higher expression of NLRP3 and ASC in RA synovial tissue than those in osteoarthritis was detected. The staining of NLRP3, ASC and cleaved IL-1ß were observed in FLS and vascular endothelial cells in RA synovium. Expression of NLRP3 and pro-IL-1ß in RA FLS and HUVECs treated with TNF-α was increased. The pro-IL-18 expression was also enhanced in HUVECs, but not in RA FLS. TNF-α/CRT dual stimulation of cells gave rise to caspase-1 p20 expression and the secretion of IL-1ß. The secreted IL-18 was also elevated in HUVECs but not in RA FLS. HuR expression was significantly elevated in RA synovial tissue. TNF-α initiated the nucleocytoplasmic shuttling of HuR in both FLS and HUVECs. The knockdown of HuR in FLS incubated with TNF-α led to reduced caspase-1 p20 protein expression and further resulted in decreased secretion of IL-1ß in the presence of CRT. CONCLUSIONS: TNF-α/CRT dual signaling induced NLRP3 inflammasome activation, which could be suppressed by HuR knockdown presumably due to the block of HuR translocating from nucleus to cytoplasma.


Assuntos
Artrite Reumatoide/imunologia , Calreticulina/imunologia , Proteína Semelhante a ELAV 1/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Fator de Necrose Tumoral alfa/imunologia , Células Endoteliais da Veia Umbilical Humana/imunologia , Humanos , Transdução de Sinais , Membrana Sinovial/imunologia , Sinoviócitos/imunologia
12.
Immunopharmacol Immunotoxicol ; 41(2): 185-191, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31072166

RESUMO

Rheumatoid arthritis (RA) is an autoimmune, chronic inflammatory disease and is characterized by destruction of the articular cartilage. A number of pro-inflammatory cytokines work sequentially and in concert with one another to induce the development of RA. IL-23, a member of IL-12 family, is composed of p19 and p40 subunits and it interacts with IL-23 receptor complex to trigger plethora of biochemical actions. A number of preclinical studies have shown the role of IL-23 in the development of RA in rodents. IL-23 receptor signaling is primarily linked to the activation of JAK-STAT, tyrosine kinase 2, NF-kB, and retinoic acid receptor-related orphan receptors. IL-23 produces its osteoclastogenic effects, mainly through IL-17 and Th17 cells suggesting the importance of IL-23/IL-17/Th17 in the joint inflammation and destruction in RA. Monoclonal antibodies targeted against IL-23, including tildrakizumab and guselkumab have been developed and evaluated in clinical trials. However, there are very limited clinical studies regarding the use of IL-23 modulators in RA patients. The present review discusses the different aspects of IL-23 including its structural features, signal transduction pathway, preclinical, and clinical role in RA.


Assuntos
Artrite Reumatoide/imunologia , Interleucina-23/imunologia , Receptores de Interleucina/imunologia , Transdução de Sinais/imunologia , Células Th17/imunologia , Animais , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Ensaios Clínicos como Assunto , Humanos , Interleucina-17/imunologia , Transdução de Sinais/efeitos dos fármacos , Células Th17/patologia
13.
Analyst ; 144(11): 3613-3619, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31070614

RESUMO

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic joint inflammation and one of the main causes of chronic disability worldwide with high prevalence in the ageing population. RA is characterized by autoantibody production, synovial inflammation and bone destruction, and the most accepted biomarker is rheumatoid factor (RF) autoantibodies. In this work, we developed a low-cost approach for the detection and quantification of the RF marker. This colorimetric immunosensor is based on gold nanoprobe crosslinking that results in extensive aggregation in the presence of the pentameric IgM RF. Aggregation of the nanoconjugates yields a color change from red to purple that can be easily observed by the naked eye. The interaction between nanoconjugates and the specific target was confirmed via dynamic light scattering (DLS), Raman spectroscopy and atomic force microscopy (AFM) imaging. This conceptual system shows a LOD of 4.15 UA mL-1 IgM RF (clinical threshold is set for 20 IU mL-1). The one-step biosensor strategy herein proposed is much faster than conventional detection techniques, without the need for secondary antibodies, additional complex washing or signal amplification protocols. To the best of our knowledge this is the first report on target induced aggregation of gold nanoprobes for quantitative colorimetric autoantibody detection.


Assuntos
Artrite Reumatoide/diagnóstico , Ouro/química , Imunoglobulina M/sangue , Nanopartículas Metálicas/química , Fator Reumatoide/sangue , Artrite Reumatoide/imunologia , Biomarcadores , Técnicas Biossensoriais/métodos , Colorimetria/métodos , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Limite de Detecção , Tamanho da Partícula , Fator Reumatoide/imunologia
14.
Cell Physiol Biochem ; 52(5): 1178-1192, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30990587

RESUMO

BACKGROUND/AIMS: Rheumatoid arthritis (RA) is a progressive, chronic, even disabling systemic autoimmune disease. Imbalance between pathogenic immune cells and immunosuppressive cells is associated with the pathogenesis and development of RA and other autoimmune diseases. As Foxp3 is also expressed on activated CD4+ cells in the presence of inflammation, the identification of Treg cells in patients with RA remains a challenge. METHODS: Comprehensive analyses were carried out by Flow cytometry. Expression of Helios, CD226, T cell immunoreceptor with Ig and ITIM domains clinical samples and healthy controls. RESULTS: We have systemically examined three potential markers, Helios, CD226 and TIGIT, that are possibly related to Treg identification, and found that Helios expression on CD4+Foxp3+cells was decreased and negatively correlated with the disease activity of RA patients, while CD226 and TIGIT both showed elevated expression levels in CD4+Foxp3+cells in RA patients and they were not associated with disease activity of RA patients. CONCLUSION: Taken together, our findings indicate that CD4+CD25hiCD127low/-Foxp3+Helios+ may represent the real Treg cell population in patients with RA.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos de Diferenciação/imunologia , Artrite Reumatoide/imunologia , Fatores de Transcrição Forkhead/imunologia , Fator de Transcrição Ikaros/imunologia , Receptores Imunológicos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Artrite Reumatoide/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/patologia
15.
Int J Mol Sci ; 20(8)2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027208

RESUMO

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation of the synovial membrane, with thickening of the synovial layer, cellular hyperplasia, and infiltration of immune cells. Mast cells (MCs) are cells of the innate immunity present in healthy synovia and part of the cellular hyperplasia characterizing RA synovitis. Although their presence in synovia has been well described, the exact functions and the correlation of MCs with disease development and progression have been debated, particularly because of contradictory data obtained in animal models and from patients with longstanding disease. Here, we present a revision of the literature on MCs in RA, including the most recent observations obtained from patients with early RA, indicating MCs as relevant markers of disease severity in early RA.


Assuntos
Artrite Reumatoide/patologia , Mastócitos/patologia , Animais , Artrite Reumatoide/imunologia , Humanos , Imunomodulação , Inflamação/patologia , Ativação Linfocitária/imunologia , Membrana Sinovial/imunologia , Membrana Sinovial/patologia
16.
J Immunol Res ; 2019: 2641098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30937315

RESUMO

The inflammatory and autoimmune events preceding clinical symptoms in rheumatoid arthritis (RA) and other autoimmune diseases are difficult to study in human patients. Therefore, animal models that share immunologic and clinical features with human RA, such as pristane-induced arthritis (PIA), are valuable tools for assessing the primordial events related to arthritis susceptibility. PIA-resistant HIII and susceptible LIII mice were injected i.p. with pristane, and peritoneal lavage fluid was harvested in the early (7 days) and late (35 days) preclinical phases of PIA. Chemokine and cytokine levels were measured in lavage supernatant with ELISA, peritoneal inflammatory leukocytes were immunophenotyped by flow cytometry, and gene expression was determined by qRT-PCR. Leukocyte recruitment was quantitatively and qualitatively divergent in the peritoneum of HIII and LIII mice, with an early increase of CC chemokines (CCL2/CCL3/CCL5/CCL12/CCL22) in the susceptible LIII strain. Also, cytokines such as IL-12p40, IL-23, and IL-18 were elevated in LIII mice while IL-6 was increased in HIII animals. The results show that an early peritoneal CC chemokine response is an important feature of arthritis susceptibility and defines potential biomarkers in this model.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Quimiocinas CC/imunologia , Inflamação , Peritônio/imunologia , Animais , Artrite Experimental/induzido quimicamente , Biomarcadores , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Interleucina-6/imunologia , Masculino , Camundongos , Fenótipo , Terpenos/administração & dosagem
17.
Med Sci Monit ; 25: 3032-3040, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31019190

RESUMO

BACKGROUND T follicular helper (Tfh) cells are a subgroup of activated CD4+ T cells in the germinal centers of secondary lymphoid organs, they play critical roles in the development of many chronic autoimmune inflammatory diseases. The aim of this study was to investigate whether circulating Tfh cells contribute to the development of rheumatoid arthritis (RA). MATERIAL AND METHODS Thirty patients fulfilled the diagnosis criteria that was established by the American College of Rheumatology and 30 healthy controls were recruited. The frequency of Tfh cells in patients and collagen-induced arthritis (CIA) in DBA/1J mice were analyzed by flow cytometry. The serum IL-21 level was examined by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of Blimp-1 and Bcl-6 were detected by qRT-PCR. RESULTS RA patients had more CD4⁺PD-1⁺CXCR5⁺ Tfh cells in peripheral blood compared with healthy controls, and CIA in DBA/1J mice showed similar results. Higher mRNA expression of Bcl-6 and lower Blimp-1 mRNA expression were observed in patients with RA compared to healthy controls, and the expression level of IL-21 was higher in RA patients, which was also seen in CIA mice. Furthermore, the spleen CD4⁺ICOS⁺CXCR5⁺ Tfh cells in CIA mice show significantly higher frequency than that in the control mice. The percentage of CD4⁺PD-1⁺CXCR5⁺ Tfh cells was correlated positively with the values of erythrocyte sedimentation rate (ESR) (r=0.968, P<0.001), rheumatoid factor (RF) (r=0.962, P<0.001), C-reactive protein (CRP) (r=0.953, P<0.001), and anti-cyclic citrullinated peptide antibodies (ACPA) (r=0.966, P<0.001), and the level of serum interleukin (IL)-21 in RA patients showed positive correlation with ESR (r=0.982, P<0.001), RF (r=0.959, P<0.001), CRP (r=0.951, P<0.001), and ACPA (r=0.971, P<0.001) as well. CONCLUSIONS The activated Tfh cells in the peripheral blood may be responsible for the development of RA.


Assuntos
Artrite Reumatoide/imunologia , Receptor de Morte Celular Programada 1/imunologia , Receptores CXCR5/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Animais , Artrite Reumatoide/sangue , Autoanticorpos/imunologia , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Linfócitos T CD4-Positivos/imunologia , Feminino , Citometria de Fluxo , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucinas/sangue , Interleucinas/imunologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Pessoa de Meia-Idade , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CXCR5/sangue , Fator Reumatoide/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
18.
Reumatismo ; 71(1): 1-12, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30932437

RESUMO

Rheumatoid factor and antibodies against cyclic citrullinated peptides represent a diagnostic hallmark in rheumatoid arthritis (RA). However, over the last decades many other autoantibodies have been identified. Several proteins can trigger an aberrant autoimmune response in their native form while others acquire this feature after post-translational modifications such as citrullination, carbamylation or acetylation. It is of interest that also the enzymes catalyzing such post-translational modifications (e.g. the protein arginine deiminases) can transform themselves into autoantibodies in RA. The purpose of this review article is to provide an overview of relevant literature published over the last years regarding novel autoantibodies and their possible diagnostic and prognostic significance in RA.


Assuntos
Autoanticorpos/metabolismo , Citrulinação , Peptídeos Cíclicos/imunologia , Vimentina/imunologia , Anticorpos Antinucleares/imunologia , Anticorpos Antinucleares/metabolismo , Especificidade de Anticorpos , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/imunologia , Antígenos Nucleares do Vírus Epstein-Barr/metabolismo , Humanos , Hidrolases/imunologia , Hidrolases/metabolismo , Queratinas/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Carbamilação de Proteínas , Fator Reumatoide , Vimentina/metabolismo , Proteínas Virais/imunologia , Proteínas Virais/metabolismo
19.
Clin Exp Rheumatol ; 37(5): 872-878, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943138

RESUMO

Rheumatoid arthritis is a chronic autoimmune disease characterised by unbearable joint pain as well as bone and cartilage destruction. Although RA development is greatly controlled, the pain and bone damage failed to be relieved and managed. Leukotriene B4 (LTB4) has been proved to play an essential role in the induction of pain and bone damage. The nerve injury of RA can promote the production of LTB4, which act on their receptors, leading to the increased release of pro-inflammatory cytokines and ROS to reduce neuron viability and pain threshold. Moreover, LTB4-BLT1 activation can also increase intracellular calcium concentration and neuron excitability as well as NF-κB pathway activation, which further promote the production of MMP-9 and CXC3R-1. The mutual promotion between LTB4 and neutrophil accumulation accelerates the release of TNF-α and IL-ß, which enhance both peripheral and central nerve system sensitisation. LTB4 also involve in TrpV1 channel activation and modulation of P2X3 receptor activation. All above mechanisms contribute to the development of RA pain. IL-23, cPLA2 and PI3K increase the production of CD11b+Gr1high myeloid subtype and calcium concentration, which promote the production of LTB4 and further accelerate IL-17 and TNF activation as well as calcium influx to conduce to osteoclastogenesis, resulting in aggregated bone damage. Our review is the first to conclude the signalling pathways and associated molecules in LTB4-induced pain and bone damage.


Assuntos
Artrite Reumatoide , Osso e Ossos/metabolismo , Leucotrieno B4 , Dor/metabolismo , Receptores do Leucotrieno B4/metabolismo , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/terapia , Humanos , Leucotrieno B4/metabolismo , Leucotrieno B4/fisiologia , Terapia de Alvo Molecular , Transdução de Sinais
20.
Clin Exp Rheumatol ; 37(5): 756-761, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30943139

RESUMO

OBJECTIVES: To compare different methods of antidrug antibody (ADA) against adalimumab detection in ankylosing spondylitis (AS) patients and the impact of ADA on adalimumab drug levels and mean ASDAS-CRP. METHODS: We used the acid-dissociation-radioimmunoassay (ARIA), antidrug-binding-test (ABT) and a bridging Enzyme-linked Immunosorbent Assay (ELISA) to detect ADA at 4, 12 and 24 weeks of treatment. Patients were divided into groups; all assays negative (All-neg), only ARIA positive (ARIA-only-pos), ARIA and ABT positive, bridging ELISA negative (ARIA/ABT-double-pos) and all assays positive (All-pos). RESULTS: Eighty-three consecutive AS patient were included. At week 4, 18% compared to 11% and 0% of the patients tested positive for ADA in the ARIA, ABT and bridging ELISA, respectively. At week 12 and 24, cumulative 52% and 69% patients tested positive in the ARIA, compared to 27% and 30% patients in the ABT and 2% patients in the bridging ELISA. Adalimumab levels between All-neg and ARIA-only-pos were 9.1 (5.5-12.5) and 8.5 (5.7-12.3). Drug levels differed between ARIA/ABT-double-pos (2.7 (1.3-4.4)) and All-neg (9.1 (5.5-12.5)). All-pos patients had undetectable drug levels. Mean ASDAS-CRP at week 24 differs between All-neg (1.9 (±1.2)), and All-pos (3.8 (±1.9)) and ARIA/ABT-double-pos (2.0 (±1.1)) and All-pos. CONCLUSIONS: The majority of AS patients had detectable ADA against adalimumab in the ARIA. The ARIA detects more ADA compared to the less drug tolerant ABT and bridging ELISA. The clinical relevance depends on the impact on the bio-availability of the drug. A drug level measurement therefore helps to interpret ADA data regardless of type of assay used.


Assuntos
Adalimumab/imunologia , Anticorpos Monoclonais Humanizados/imunologia , Artrite Reumatoide , Espondilite Anquilosante , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Tolerância a Medicamentos , Ensaio de Imunoadsorção Enzimática , Humanos , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/imunologia
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