RESUMO
BACKGROUND: Viral infections may trigger autoimmunity in genetically predisposed individuals. Immunizations mimic viral infections immunologically, but only in rare instances vaccinations coincide with the onset of autoimmunity. Inadvertent vaccine injection into periarticular shoulder tissue can cause inflammatory tissue damage ('shoulder injury related to vaccine administration, SIRVA). Thus, this accident provides a model to study if vaccine-induced pathogen-specific immunity accompanied by a robust inflammatory insult may trigger autoimmunity in specific genetic backgrounds. METHODS: We studied 16 otherwise healthy adults with suspected SIRVA occurring following a single work-related influenza immunization campaign in 2017. We performed ultrasound, immunophenotypic analyses, HLA typing, and influenza- and self-reactivity functional immunoassays. Vaccine-related bone toxicity and T cell/osteoclast interactions were assessed in vitro. FINDINGS: Twelve of the 16 subjects had evidence of inflammatory tissue damage on imaging, including bone erosions in six. Tissue damage was associated with a robust peripheral blood T and B cell activation signature and extracellular matrix-reactive autoantibodies. All subjects with erosions were HLA-DRB1*04 positive and showed extracellular matrix-reactive HLA-DRB1*04 restricted T cell responses targeting heparan sulfate proteoglycan (HSPG). Antigen-specific T cells potently activated osteoclasts via RANK/RANK-L, and the osteoclast activation marker Trap5b was high in sera of patients with an erosive shoulder injury. In vitro, the vaccine component alpha-tocopheryl succinate recapitulated bone toxicity and stimulated osteoclasts. Auto-reactivity was transient, with no evidence of progression to rheumatoid arthritis or overt autoimmune disease. CONCLUSION: Vaccine misapplication, potentially a genetic predisposition, and vaccine components contribute to SIRVA. The association with autoimmunity risk allele HLA-DRB1*04 needs to be further investigated. Despite transient autoimmunity, SIRVA was not associated with progression to autoimmune disease during two years of follow-up.
Assuntos
Inflamação/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/imunologia , Cápsula Articular/imunologia , Orthomyxoviridae/fisiologia , Osteoclastos/imunologia , Linfócitos T/imunologia , Adulto , Autoimunidade , Doença Crônica , Matriz Extracelular/metabolismo , Feminino , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Proteoglicanas de Heparan Sulfato/imunologia , Teste de Histocompatibilidade , Humanos , Masculino , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Fosfatase Ácida Resistente a Tartarato/sangue , Vacinação/efeitos adversos , Adulto JovemRESUMO
Rheumatoid arthritis (RA) is a debilitating autoimmune disease of unknown cause, characterized by infiltration and accumulation of activated immune cells in the synovial joints where cartilage and bone destructions occur. Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) was shown to be involved in the regulation of MDSC differentiation. The purpose of the present study was to investigate the effect of inhibition of SHIP1 on the expansion of MDSCs in RA using a collagen-induced inflammatory arthritis (CIA) mouse model. In DBA/1 mice, treatment with a small molecule-specific SHIP1 inhibitor 3α-aminocholestane (3AC) induced a marked expansion of MDSCs in vivo. Both pretreatment with 3AC of DBA/1 mice prior to CIA induction and intervention with 3AC during CIA progression significantly reduced disease incidence and severity. Adoptive transfer of MDSCs isolated from 3AC-treated mice, but not naïve MDSCs from normal mice, into CIA mice significantly reduced disease incidence and severity, indicating that the 3AC-induced MDSCs were the cellular mediators of the observed amelioration of the disease. In conclusion, inhibition of SHIP1 expands MDSCs in vivo and attenuates development of CIA in mice. Small molecule-specific inhibition of SHIP1 may therefore offer therapeutic benefit to patients with RA and other autoimmune diseases.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Experimental/tratamento farmacológico , Colestanos/farmacologia , Células Supressoras Mieloides/imunologia , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/genética , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Comunicação Celular , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Expressão Gênica , Humanos , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Cápsula Articular/patologia , Camundongos , Camundongos Endogâmicos DBA , Camundongos Knockout , Células Supressoras Mieloides/citologia , Células Supressoras Mieloides/transplante , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/antagonistas & inibidores , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/imunologia , Índice de Gravidade de Doença , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/patologiaRESUMO
Effective treatment of osteoarthritis (OA) remains a huge clinical challenge despite major research efforts. Different tissues and cell-types within the joint contribute to disease pathogenesis, and there is great heterogeneity between patients in terms of clinical features, genetic characteristics and responses to treatment. Inflammation and the most abundant immune cell type within the joint, macrophages, have now been recognised as possible players in disease development and progression. Here we discuss recent findings on the involvement of synovial inflammation and particularly the role of synovial macrophages in OA pathogenesis. Understanding macrophage involvement may hold the key for improved OA treatments.
Assuntos
Suscetibilidade a Doenças , Cápsula Articular/imunologia , Cápsula Articular/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Osteoartrite/etiologia , Osteoartrite/metabolismo , Animais , Biomarcadores , Cartilagem/imunologia , Cartilagem/metabolismo , Cartilagem/patologia , Plasticidade Celular/imunologia , Humanos , Cápsula Articular/patologia , Ativação de Macrófagos/imunologia , Macrófagos/patologia , Osteoartrite/patologiaRESUMO
The human immune system has evolved to recognize and eradicate pathogens, a process that is known as "host defense". If, however, the immune system does not work properly, it can mistakenly attack the body's own tissues and induce autoimmune diseases. Rheumatoid arthritis (RA) is such an autoimmune disease in which the synovial joints are predominately attacked by the immune system. Moreover, RA is associated with bone destruction and joint deformity. Although biologic agents have propelled RA treatment forward dramatically over the past 30 years, a considerable number of patients with RA still experience progressive bone damage and joint disability. That is to be expected since current RA therapies are all intended to halt inflammation but not to alleviate bone destruction. A better understanding of bone erosions is crucial to developing a novel strategy to treat RA-associated erosions. This review provides insights into RA-associated bone destruction and perspectives for future clinical interventions.
Assuntos
Artrite Reumatoide/complicações , Fatores Biológicos/farmacologia , Conservadores da Densidade Óssea/farmacologia , Osteoporose/imunologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Fatores Biológicos/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Caderinas/farmacologia , Caderinas/uso terapêutico , Humanos , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Cápsula Articular/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/imunologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Osteogênese/efeitos dos fármacos , Osteogênese/imunologia , Osteoporose/tratamento farmacológico , Osteoporose/patologia , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Ligante RANK/antagonistas & inibidores , Ligante RANK/imunologia , Ligante RANK/metabolismo , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Líquido Sinovial/efeitos dos fármacos , Líquido Sinovial/imunologiaRESUMO
OBJECTIVE: Activin A is known to be highly expressed in rheumatoid synovium. In the present study, we investigated the effect of inflammatory cytokines on activin A production and its role in rheumatoid inflammation using freshly prepared rheumatoid synovial cells (fresh-RSC). METHODS: Fresh-RSC from patients with rheumatoid arthritis were obtained and stimulated with multiple cytokines for activin A production. Gene expression levels of activin A and inflammatory cytokines were determined by quantitative PCR (qPCR) analysis. An enzyme-linked immunosorbent assay (ELISA) was used to measure activin A and CXCL10 in culture supernatants. The osteoclasts generated from human peripheral monocytes by RANKL stimulation were identified by tartrate-resistant acid phosphatase staining and bone resorption assay using Osteo plate. The expression levels of NFATc1 and cathepsin K, critical intracellular proteins for osteoclastogenesis, were determined by Western blotting. RESULTS: Activin A production in fresh-RSC was markedly enhanced by the synergistic effect of TGF-ß1 with inflammatory cytokines, including TNFα, IL-1ß, and IL-6. Activin A inhibited TNFα-induced CXCL10, an important chemoattractant for pathogen-activated T cells and monocytes of osteoclast precursors, but it did not affect the expression of inflammatory cytokines and chemokines. In addition, activin A directly inhibited the expression of NFATc1 and cathepsin K, as well as osteoclast formation in human samples. CONCLUSION: Our data indicated that TGF-ß1 is involved in the expression of activin A at inflamed joints. Activin A mainly exerts an anti-inflammatory action, which prevents joint damage via the regulation of CXCL10 and osteoclastogenesis.
Assuntos
Ativinas/genética , Quimiocina CXCL10/genética , Cápsula Articular/citologia , Osteogênese , Fator de Necrose Tumoral alfa/genética , Diferenciação Celular , Células Cultivadas , Citocinas/imunologia , Regulação para Baixo , Humanos , Cápsula Articular/imunologia , Leucócitos Mononucleares/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Mononuclear phagocytes, including monocytes and macrophages, are a central component of the host's innate immune system designated to protect against invading pathogens. However, these cells do not only interact with various parts of the innate and adaptive immune system, but also fulfill indispensable duties during the control of tissue homeostasis and organ function. Moreover, macrophages are crucially involved in tissue remodeling and repair in response to damage. Simultaneously, mononuclear phagocytes might also contribute to the pathogenesis of various inflammatory and autoimmune diseases. In particular, their potential role in inflammatory joint diseases such as rheumatoid arthritis (RA) has drawn increasing attention and substantially shaped our general understanding of the role of monocytes and macrophages during health and disease. This review summarizes our current knowledge about the origin and function of mononuclear phagocytes within the joint and addresses their involvement in joint inflammation.
Assuntos
Artrite Reumatoide/imunologia , Cápsula Articular/citologia , Macrófagos/imunologia , Monócitos/imunologia , Líquido Sinovial/citologia , Animais , Doenças Autoimunes/metabolismo , Microambiente Celular/imunologia , Citocinas/metabolismo , Humanos , Imunidade Inata , Cápsula Articular/imunologia , Macrófagos/citologia , Macrófagos/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Líquido Sinovial/imunologiaRESUMO
BACKGROUND: The onset of seropositive rheumatoid arthritis (RA) is preceded by the presence of specific autoantibodies in the absence of synovial inflammation. Only a subset of these at-risk individuals will develop clinical disease. This impedes efforts to implement early interventions that may prevent onset of clinically manifest disease. Here we analyse whether clonal changes in the B cell receptor (BCR) repertoire can reliably predict onset of signs and symptoms. METHODS: In a prospective cohort study in 21 individuals at risk for RA based on the presence of autoantibodies, the BCR repertoire of paired peripheral blood and synovial tissue samples was analysed using next-generation BCR sequencing. BCR clones that were expanded beyond 0.5% of the total repertoire were labelled dominant. The relative risk (RR) for onset of arthritis was assessed using the presence of ≥5 dominant BCR clones as cut-off. Findings in peripheral blood were validated in an independent prospective cohort of 50 at-risk individuals. Based on the test cohort, individuals in the validation cohort were considered positive if peripheral blood at study entry showed ≥5 dominant BCR clones. FINDINGS: Both in the test and validation cohort, the presence of ≥5 dominant BCR clones in peripheral blood was significantly associated with arthritis development after follow-up (validation cohort RR 6.3, 95% CI 2.7 to 15, p<1×10-4). Even when adjusted for a recently described clinical prediction rule the association remained intact (RR 5.0, 95% CI 1.2 to 20, p=0.024). When individuals developed arthritis, dominant BCR clones disappeared from peripheral blood and appeared in synovial tissue, suggesting a direct role of these clones in disease pathogenesis. INTERPRETATION: Dominant BCR clones in peripheral blood predict onset of clinical signs and symptoms of RA in at-risk individuals with high accuracy. Our data suggest that during onset of RA these clones shift from peripheral blood to the target tissue.
Assuntos
Artrite Reumatoide/imunologia , Receptores de Antígenos de Linfócitos B/sangue , Adulto , Autoanticorpos/análise , Autoanticorpos/imunologia , Células Clonais , Feminino , Seguimentos , Humanos , Cápsula Articular/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Receptores de Antígenos de Linfócitos B/genética , Risco , Fatores de RiscoRESUMO
Structural damage of cartilage and bone tissue is a hallmark of rheumatoid arthritis (RA). The resulting joint destruction constitutes one of the major disease consequences for patients and creates a significant burden for the society. The main cells executing bone and cartilage degradation are osteoclasts and fibroblast-like synoviocytes, respectively. The function of both cell types is heavily influenced by the immune system. In the last decades, research has identified several mediators of structural damage, ranging from infiltrating immune cells and inflammatory cytokines to autoantibodies. These factors result in an inflammatory milieu in the affected joints which leads to an increased development and function of osteoclasts and the transformation of fibroblast-like synoviocytes towards a highly migratory and destructive phenotype. In addition, repair mechanisms mediated by osteoblasts and chondrocytes are strongly impaired by the presence of pro-inflammatory cytokines. This article will review the current knowledge on the mechanisms of joint inflammation and the destruction of bone and cartilage.
Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Animais , Artrite Reumatoide/patologia , Autoanticorpos/imunologia , Osso e Ossos/imunologia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Cartilagem/imunologia , Cartilagem/metabolismo , Cartilagem/patologia , Condrócitos/metabolismo , Citocinas/metabolismo , Fibroblastos/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Cápsula Articular/imunologia , Cápsula Articular/metabolismo , Cápsula Articular/patologia , Osteoclastos/imunologia , Osteoclastos/metabolismoRESUMO
The profound alterations in the structure, cellular composition, and function of synovial tissue in rheumatoid arthritis (RA) are the basis for the persistent inflammation and cumulative joint destruction that are hallmarks of this disease. In RA, the synovium develops characteristics of a tertiary lymphoid organ, with extensive infiltration of lymphocytes and myeloid cells. Concurrently, the fibroblast-like synoviocytes undergo massive hyperplasia and acquire a tissue-invasive phenotype. In this review, we summarize key components of these processes, focusing on recently-described roles of selected molecular markers of these cellular components of RA synovitis.
Assuntos
Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Biomarcadores , Cápsula Articular/imunologia , Cápsula Articular/metabolismo , Animais , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/genética , Comunicação Celular/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/patologia , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/citologia , Membrana Sinovial/imunologia , Membrana Sinovial/metabolismo , Membrana Sinovial/patologiaRESUMO
This study tested the hypothesis that subsets of human T helper cells can orchestrate leukocyte adhesion to synovial fibroblasts (SFbs), thus regulating the retention of leukocytes in the joints of juvenile idiopathic arthritis (JIA) patients. Several cell types, such as monocytes/macrophages, granulocytes, T and B lymphocytes, SFbs and osteoclasts participate in joint tissue damage JIA. Among T cells, an enrichment of classic and non-classic Th1 subsets, has been found in JIA synovial fluid (SF), compared to peripheral blood (PB). Moreover, it has been shown that IL-12 in the SF of inflamed joints mediates the shift of Th17 lymphocytes towards the non-classic Th1 subset. Culture supernatants of Th17, classic and non-classic Th1 clones, have been tested for their ability to stimulate proliferation, and to induce expression of adhesion molecules on SFbs, obtained from healthy donors. Culture supernatants of both classic and non-classic Th1, but not of Th17, clones, were able to induce CD106 (VCAM-1) up-regulation on SFbs. This effect, mediated by tumor necrosis factor (TNF)-α, was crucial for the adhesion of circulating leukocytes on SFbs. Finally, we found that SFbs derived from SF of JIA patients expressed higher levels of CD106 than those from healthy donors, resembling the phenotype of SFbs activated in vitro with Th1-clones supernatants. On the basis of these findings, we conclude that classic and non-classic Th1 cells induce CD106 expression on SFbs through TNF-α, an effect that could play a role in leukocytes retention in inflamed joints.
Assuntos
Artrite Juvenil/imunologia , Meios de Cultivo Condicionados/farmacologia , Cápsula Articular/imunologia , Células Th1/imunologia , Molécula 1 de Adesão de Célula Vascular/imunologia , Adolescente , Adulto , Artrite Juvenil/genética , Artrite Juvenil/patologia , Estudos de Casos e Controles , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Criança , Pré-Escolar , Técnicas de Cocultura , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Fibroblastos/patologia , Expressão Gênica , Humanos , Cápsula Articular/patologia , Masculino , Cultura Primária de Células , Líquido Sinovial/citologia , Células Th1/citologia , Células Th1/metabolismo , Células Th17/citologia , Células Th17/imunologia , Células Th17/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Molécula 1 de Adesão de Célula Vascular/genéticaRESUMO
OBJECTIVE: Lumbar facet joint degeneration (FJD) may be an important cause of low back pain (LBP) and sciatica. The goal of this study was to characterize cellular alterations of inflammatory factor expression and neovascularization in human degenerative facet joint capsular (FJC) tissue. These alterations in FJC tissues in pain stimulation were also assessed. DESIGN: FJs were obtained from consented patients undergoing spinal reconstruction surgery and cadaveric donors with no history of back pain. Histological analyses of the FJs were performed. Cytokine antibody array and quantitative real-time polymerase chain reaction (qPCR) were used to determine the production of inflammatory cytokines, and western blotting analyses (WB) were used to assay for cartilage-degrading enzymes and pain mediators. Ex vivo rat dorsal root ganglion (DRG) co-culture with human FJC tissues was also performed. RESULTS: Increased neovascularization, inflammatory cell infiltration, and pain-related axonal-promoting factors were observed in degenerative FJCs surgically obtained from symptomatic subjects. Increased VEGF, (NGF/TrkA), and sensory neuronal distribution were also detected in degenerative FJC tissues from subjects with LBP. qPCR and WB results demonstrated highly upregulated inflammatory cytokines, pain mediators, and cartilage-degrading enzymes in degenerative FJCs. Results from ex vivo co-culture of the DRG and FJC tissue demonstrated that degenerative FJCs increased the expression of inflammatory pain molecules in the sensory neurons. CONCLUSION: Degenerative FJCs possess greatly increased inflammatory and angiogenic features, suggesting that these factors play an important role in the progression of FJD and serve as a link between joint degeneration and neurological stimulation of afferent pain fibers.
Assuntos
Degeneração do Disco Intervertebral/genética , Cápsula Articular/metabolismo , Dor Lombar/genética , Vértebras Lombares , Osteoartrite da Coluna Vertebral/genética , RNA Mensageiro/metabolismo , Escoliose/genética , Espondilolistese/genética , Articulação Zigapofisária/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Western Blotting , Cadáver , Técnicas de Cocultura , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Feminino , Gânglios Espinais , Humanos , Imuno-Histoquímica , Degeneração do Disco Intervertebral/imunologia , Degeneração do Disco Intervertebral/metabolismo , Cápsula Articular/imunologia , Dor Lombar/imunologia , Dor Lombar/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Neural/metabolismo , Osteoartrite da Coluna Vertebral/imunologia , Osteoartrite da Coluna Vertebral/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptor trkA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Escoliose/imunologia , Escoliose/metabolismo , Espondilolistese/imunologia , Espondilolistese/metabolismo , Regulação para Cima , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem , Articulação Zigapofisária/imunologiaRESUMO
Using rheumatoid arthritis (RA) and periodontitis mouse models, we demonstrate that RA and periodontitis share many pathological features, such as deregulated cytokine production, increased immune-cell infiltration, increased expression of Toll-like receptors (TLRs), and enhanced osteoclast activity and bone erosion. We reveal that genetic deletion of cathepsin K (Ctsk) caused a radical reduction in inflammation and bone erosion within RA joint capsules and periodontal lesions, a drastic decrease in immune-cell infiltration, and a significant reduction in osteoclasts, macrophages, dendritic and T-cells. Deficiency of Ctsk greatly decreased the expression of TLR-4, 5, and 9 and their downstream cytokines in periodontal gingival epithelial lesions and synovial RA lesions. Hence, Ctsk may be targeted to treat RA and periodontitis simultaneously due to its shared osteoimmune role.
Assuntos
Artrite Reumatoide/metabolismo , Reabsorção Óssea/etiologia , Catepsina K/metabolismo , Imunidade Inata , Osteocondrite/etiologia , Osteoclastos/imunologia , Periodontite/metabolismo , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Artrite Reumatoide/fisiopatologia , Bacteroidetes/crescimento & desenvolvimento , Bacteroidetes/imunologia , Catepsina K/genética , Cruzamentos Genéticos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Cápsula Articular/imunologia , Cápsula Articular/metabolismo , Cápsula Articular/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Periodontite/imunologia , Periodontite/microbiologia , Periodontite/fisiopatologia , Periodonto/imunologia , Periodonto/metabolismo , Periodonto/microbiologia , Periodonto/patologia , Porphyromonas gingivalis/crescimento & desenvolvimento , Porphyromonas gingivalis/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/patologia , Treponema denticola/crescimento & desenvolvimento , Treponema denticola/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The aim of this study is to explore the effects of icariin on cytokine induced ankylosing spondylitis fibroblast osteogenesis type expression and its molecular mechanism. The normal fibroblasts were collected as normal control group, and the fibroblasts of hip joint capsule of AS patients were collected, which were respectively added in fetal bovine serum (group AS), fetal bovine serum and cytokines (BMP-2+TGF-beta 1) (group AS), and cell factor solution (icariin group), and observed of the osteogenic expression of fibroblast, to evaluate the impact of Icariin on it. The ALP activity, the content of collagen, osteocalcin content and cbfa1mRNA and OCmRNA of fibroblast of AS group increased compared to the normal control group and AS control group (P < 0.01), indicating that icariin can significantly inhibit the above changes (P < 0.01). Icariin can inhibit fibroblast further osteogenic differentiation through inhibiting the effect of cytokines on the fibroblast osteogenesis type markers and osteogenic gene expression and osteogenic differentiation.
Assuntos
Proteína Morfogenética Óssea 2/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Fibroblastos/efeitos dos fármacos , Flavonoides/farmacologia , Articulação do Quadril/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Espondilite Anquilosante/patologia , Fator de Crescimento Transformador beta1/farmacologia , Adulto , Fosfatase Alcalina/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Colágeno/metabolismo , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Articulação do Quadril/imunologia , Articulação do Quadril/metabolismo , Articulação do Quadril/patologia , Humanos , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Cápsula Articular/metabolismo , Cápsula Articular/patologia , Masculino , Osteocalcina/genética , Osteocalcina/metabolismo , RNA Mensageiro/metabolismo , Espondilite Anquilosante/genética , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/metabolismo , Adulto JovemRESUMO
Since their discovery in 1948, glucocorticoids have been widely used clinically to treat inflammatory disorders like rheumatoid arthritis. However, their usefulness, especially in rheumatoid arthritis therapy, is hampered by severe side effects on bone leading to glucocorticoid-induced osteoporosis. The molecular and cellular mechanisms mediating the beneficial and adverse effects remain poorly understood. Nevertheless, advanced molecular biological analyses and in vivo approaches using conditional mutant mice have helped to unravel in part the underlying mechanisms of immunosuppression and side effects of glucocorticoid therapy in arthritis, thereby contributing to an improved understanding of these therapeutically important hormones.
Assuntos
Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Glucocorticoides/farmacologia , Animais , Anti-Inflamatórios/uso terapêutico , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Fenômenos Fisiológicos Celulares/efeitos dos fármacos , Glucocorticoides/uso terapêutico , Humanos , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Cápsula Articular/patologia , Células Mieloides/efeitos dos fármacos , Células Mieloides/imunologia , Receptores de Glucocorticoides/fisiologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
OBJECTIVE: Evidence is accumulating that synovial tissue plays an active role in osteoarthritis (OA), however, exact understanding of its contribution is lacking. In order to further elucidate its role in the OA process, we aimed to identify the secretion pattern of soluble mediators by synovial tissue and to assess its ability to initiate cartilage degeneration. METHODS: Synovial tissue explants (STEs) obtained from donors without history of OA (n = 8) or from end stage OA patients (n = 16) were cultured alone or together with bovine cartilage explants in the absence or presence of IL-1α. The secretion of 48 soluble mediators was measured and the effect on glycosaminoglycan (GAG) release and matrix metalloproteinase (MMP) activity was determined. RESULTS: Normal and OA STEs secreted comparable levels of almost all measured soluble mediators. However, in the presence of IL-1α these mediators were less secreted by OA than by normal STEs of which 15 differed significantly (p<0.01). No effect of normal or OA STEs on GAG release from the cartilage explants was observed, and no differences in MMP activity between OA and normal STEs were detected. CONCLUSIONS: Unexpectedly, a comparable secretion profile of soluble mediators was found for OA and normal STEs while the reduced responsiveness of OA STEs to an inflammatory trigger indicates a different state of this tissue in OA patients. The effects could be the result of prolonged exposure to an inflammatory environment in OA development. Further understanding of the pro-inflammatory and inflammation resolving mechanisms during disease progression in synovial tissue may provide valuable targets for therapy in the future.
Assuntos
Cartilagem Articular/metabolismo , Mediadores da Inflamação/metabolismo , Cápsula Articular/metabolismo , Osteoartrite/metabolismo , Adolescente , Idoso , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/imunologia , Bovinos , Glicosaminoglicanos/biossíntese , Glicosaminoglicanos/imunologia , Humanos , Inflamação , Mediadores da Inflamação/análise , Mediadores da Inflamação/imunologia , Interleucina-1alfa/farmacologia , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Masculino , Metaloproteinases da Matriz/imunologia , Metaloproteinases da Matriz/metabolismo , Pessoa de Meia-Idade , Osteoartrite/imunologia , Técnicas de Cultura de TecidosRESUMO
We previously reported that photodynamic therapy (PDT) using intra-articular methylene blue (MB) could be used to treat arthritis in mice caused by bioluminescent methicillin-resistant Staphylococcus aureus (MRSA) either in a therapeutic or in a preventative mode. PDT accumulated neutrophils into the mouse knee via activation of chemoattractants such as inflammatory cytokines or chemokines. In this study, we asked whether PDT combined with antibiotics used for MRSA could provide added benefit in controlling the infection. We compared MB-PDT alone, systemic administration of either linezolid (LZD) alone or vancomycin (VCM) alone or the combination of PDT with either LZD or VCM. Real-time noninvasive imaging was used to serially follow the progress of the infection. PDT alone was the most effective, whereas LZD alone was ineffective and VCM alone showed some benefit. Surprisingly the addition of LZD or VCM reduced the therapeutic effect of PDT alone (P < 0.05). Considering that PDT in this mouse model stimulates neutrophils to be antibacterial rather than actively killing the bacteria, we propose that LZD and VCM might inhibit the activation of inflammatory cytokines without eradicating the bacteria, and thereby reduce the therapeutic effect of PDT.
Assuntos
Acetamidas/farmacologia , Antibacterianos/farmacologia , Artrite Infecciosa/tratamento farmacológico , Staphylococcus aureus Resistente à Meticilina , Azul de Metileno/farmacologia , Oxazolidinonas/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Infecções Estafilocócicas/tratamento farmacológico , Vancomicina/farmacologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/patologia , Artrite Infecciosa/imunologia , Artrite Infecciosa/patologia , Citocinas/biossíntese , Citocinas/imunologia , Antagonismo de Drogas , Quimioterapia Combinada , Injeções Intra-Articulares , Cápsula Articular/efeitos dos fármacos , Cápsula Articular/imunologia , Cápsula Articular/patologia , Luz , Linezolida , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/patologia , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/patologiaRESUMO
Tendon, ligament, and capsular insertions are parts of "enthesis organs" whereby the enthesis itself has an elaborate functional integration with the adjacent soft tissues and the synovium in particular. The purpose of this article is to review the sophisticated degree of integration between insertions and adjacent synovium in what has been dubbed "synovio-entheseal complexes" (SEC). SEC arise at multiple sites in the immediate vicinity of insertions and may also arise within the joint capsule at sites well away from enthesis insertions. Not only does this relationship between the enthesis and synovium hold in synovial joints, but it is also crucial for understanding the microanatomical basis for joint disease localization to tendons in the seronegative spondyloarthropathies as well as in other conditions including osteoarthritis. The fibrocartilages at insertions are prone to microdamage whereas this tissue is completely devoid of immune cells. In healthy conditions, the synovium lubricates and nourishes the entheseal associated fibrocartilages, but damage or aberrant tissue repair responses at the insertion may manifest as an immediately adjacent synovitis or tenosynovitis, given that the synovium has resident immune cell populations and the ability to undergo substantial hyperplasia. Therefore SEC are likely to represent key orchestrators that contribute to joint inflammation by mechanisms that have been hitherto poorly appreciated.
Assuntos
Cápsula Articular/patologia , Ligamentos/patologia , Espondiloartropatias/patologia , Membrana Sinovial/patologia , Sinovite/patologia , Tendinopatia/patologia , Tendões/patologia , Animais , Modelos Animais de Doenças , Fibrocartilagem/imunologia , Fibrocartilagem/patologia , Humanos , Hiperplasia , Cápsula Articular/imunologia , Ligamentos/imunologia , Espondiloartropatias/imunologia , Membrana Sinovial/imunologia , Sinovite/imunologia , Tendinopatia/imunologia , Tendões/imunologiaRESUMO
Increasing evidence suggests that regulatory T cell (Treg) function is impaired in chronic inflammatory diseases such as rheumatoid arthritis (RA). Here we demonstrate that Tregs are unable to modulate the spontaneous production of TNF-α from RA synovial cells cultured from the diseased synovium site. Cytokine (IL-2, IL-6, TNF-α) activated T cells (Tck), cells we previously demonstrated to mimic the effector function of pathogenic RA synovial T cells, contained Tregs that survived and divided in this cytokine environment; however, the up-regulation of key molecules associated with Treg function (CTLA-4 and LFA-1) was impaired. Furthermore, Tregs were unable to suppress the function of Tcks, including contact-dependent induction of TNF-α from macrophages, supporting the concept that impaired Treg function/responsiveness contributes to chronicity of RA. However, ectopic foxp3 expression in both Tcks and pathogenic RA synovial T cells attenuated their cytokine production and function, including contact-dependent activation of macrophages. This diminished response to cytokine activation after ectopic foxp3 expression involved inhibited NF-κB activity and differed mechanistically from that displayed endogenously in conventional Tregs. These results suggest that diseases such as RA may perpetuate owing to the inability of Tregs to control cytokine-activated T-cell function. Understanding the mechanism whereby foxp3 attenuates the pathogenic function of synovial T cells may provide insight into the mechanisms of chronicity in inflammatory disease and potentially reveal new therapeutic candidates.
Assuntos
Artrite Reumatoide/imunologia , Fatores de Transcrição Forkhead/imunologia , Cápsula Articular/imunologia , Linfócitos T Reguladores/imunologia , Citometria de Fluxo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Cápsula Articular/citologia , Cápsula Articular/metabolismo , Lentivirus , Luciferases , NF-kappa B/imunologia , NF-kappa B/metabolismo , Transdução Genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: To compare the inflammatory changes of antigen-induced temporomandibular joint (TMJ) arthritis in rabbits by different histological methods and to evaluate the immunomodulatory effect of intra-articular corticosteroid injections histologically. METHODS: 35 rabbits (10 weeks old) pre-sensibilized with ovalbumin were divided into three groups: a placebo group of five (saline), an arthritis group of 15 (ovalbumin) and a steroid-treated group of 15 (ovalbumin + corticosteroid). Additionally, a group of seven rabbits receiving no sensibilization with ovalbumin and no intra-articular injections served as controls. Histomorphometry of the inflammatory changes in the subsynovial connective tissue (SSCT) of the TMJ included: (i) semi-quantitative (S-Q) scoring of inflammation and synovial proliferation, (ii) thickness measurements and fractional surface and (iii) stereological quantitative assessment of volume and plasma cells in thick sections of the SSCT by an optical fractionator. RESULTS: The histomorphometry showed synovial proliferation in both the arthritis and the steroid groups. The plasma cell count obtained by the optical fractionator was significantly reduced when treating the TMJ with corticosteroids. However, the thickness of the synovial lining and volume of the SSCT as well as S-Q scoring of inflammation showed no difference between the arthritis and the steroid-treated groups. The optical fractionator proved a superior tool compared to S-Q assessments. CONCLUSION: Counting of plasma cells in the SSCT showed that corticosteroids reduced the inflammation, but did not eliminate it. Semiquantitative scoring of synovial proliferation and inflammation demonstrated low sensitivity regarding changes in immunomodulation in antigen-induced arthritis compared to stereological quantitative estimations using an optical fractionator.
Assuntos
Anti-Inflamatórios/uso terapêutico , Artrite Juvenil/prevenção & controle , Membrana Sinovial/patologia , Transtornos da Articulação Temporomandibular/prevenção & controle , Articulação Temporomandibular/patologia , Triancinolona Acetonida/análogos & derivados , Corticosteroides/uso terapêutico , Animais , Artrite Experimental/imunologia , Artrite Experimental/prevenção & controle , Artrite Juvenil/imunologia , Contagem de Células , Modelos Animais de Doenças , Feminino , Cápsula Articular/imunologia , Cápsula Articular/patologia , Plasmócitos/citologia , Plasmócitos/imunologia , Coelhos , Estatísticas não Paramétricas , Membrana Sinovial/imunologia , Articulação Temporomandibular/imunologia , Transtornos da Articulação Temporomandibular/imunologia , Triancinolona Acetonida/uso terapêuticoRESUMO
Power Doppler and spectral Doppler ultrasonography were used to scan 127 knee joints of 72 patients with rheumatoid arthritis (RA). Synovial effusion thickness and synovial proliferation (pannus) thickness, as well as the flow signal diameter, were measured on ultrasonogram prints of the power Doppler using digital calipers. In addition, color-flow signal grades on power Doppler and the resistance index (RI) values on spectral Doppler were evaluated. The values of these five variables were compared among 58 joints with superficial pattern flow signals and 69 joints with deep pattern flow signals. Compared with the joints with deep pattern signals, the joints with superficial pattern signals had significantly higher mean values of effusion thickness (P < 0.0001) and flow signal grades (P < 0.0001), and significantly lower mean RI (P < 0.0001). On the other hand, the joints with deep pattern signals had a significantly higher value of signal diameter (P = 0.0125) and had a trend to higher value of pannus thickness (P = 0.079) as well. Significant correlations were observed between effusion thickness and signal grades (P < 0.0001); effusion thickness and RI (P < 0.0001); signal diameter and pannus thickness (P = 0.0102); signal diameter and RI (P < 0.0001); and signal grades and RI (P < 0.0001). The ultrasonographic measurements of synovitis in RA patients provide valuable information on synovial inflammation.