38,366 research outputs found
Chemokines in arthritis: key molecules in pathogenesis and potential therapeutic targets
No full textAn increasing wealth of evidence suggests an important role for chemokines and their receptors in the pathogenesis of inflammation. In this review, the authors explore the role of chemokines in inflammatory joint diseases, with particular emphasis on rheumatoid arthritis. Recent progress aimed at modulating the chemokine and chemokine receptor system for therapy will also be discussed
The synovial membrane as a prognostic tool in rheumatoid arthritis
No full textThe ability to effectively treat patients with rheumatoid arthritis (RA) has become increasingly feasible with the use of powerful treatment regimens early on in the disease. The use of such regimens has, however, created a pressing requirement for better prognostic markers to allow the targeting of these treatments to those most at need, hence minimizing expense and toxicity. As the synovial membrane has been ever more recognised as the primary pathogenetic site in RA its role as a prognostic indicator has been explored. As yet no reliable single prognostic marker has been identified. This article discusses the range of pathological variables already examined and those markers holding most potential
Secondary and ectopic lymphoid tissue responses in rheumatoid arthritis: from inflammation to autoimmunity and tissue damage/remodeling
No full textRheumatoid arthritis is a chronic systemic inflammatory disease primarily affecting the synovium of diarthrodial joints. Despite the currently unknown etiology, overwhelming evidence indicates that both innate and adaptive immunity play a central role in disease pathogenesis. In this review, we consider recent evidence examining the mechanisms of lymphoid tissue reactivity in rheumatoid arthritis with a focus on the dynamics controlling secondary and ectopic lymphoid tissue response. We then examine the cellular and molecular mechanisms regulating the biopathology of these processes with specific emphasis on cell trafficking, contribution to autoimmunity, and joint damage-repair. We finally provide a brief overview of the most recent studies addressing the clinical relevance of synovial lymphoid tissue analysis as a diagnostic and prognostic tool as well as its response to current biological therapies
Can Synovial Pathobiology Integrate with Current Clinical and Imaging Prediction Models to Achieve Personalized Health Care in Rheumatoid Arthritis?
Get PDFAlthough great progress has been made in the past decade toward understanding the pathogenesis of rheumatoid arthritis (RA), clinicians remain some distance from a goal of personalized health care. The capacity to diagnose RA early, predict prognosis, and moreover predict response to biologic therapies has been a research focus for many years. How currently available clinical prediction models can facilitate such goals is reviewed in this article. In addition, the role of current imaging techniques in this regard is also discussed. Finally, the authors review the current literature regarding synovial biomarkers and consider whether integration of synovial pathobiology into clinical prediction algorithms may enhance their predictive value
ANTI-VCA AND EBNA1 ANTIBODIES ARE PRODUCED IN THE RHEUMATOID SYNOVIUM IN THE PRESENCE OF ECTOPIC LYMPHOID STRUCTURES AND CORRELATE WITH ACPA PRODUCTION
No full textNo abstract availabl
Erratum to: Effect of moderate red wine intake on cardiac prognosis after recent acute myocardial infarction of subjects with Type 2 diabetes mellitus (Diabetic Medicine, (2006), 23, 9, (974-981), 10.1111/j.1464-5491.2006.01886.x)
No full textIn an article by Marfella et al, the author name C. Saron is incorrect and should be listed as C. Sardu. Therefore the correct author list is: R. Marfella, F. Cacciapuoti, M. Siniscalchi, F. C. Sasso, F. Marchese, F. Cinone, E. Musacchio, M. A. Marfella, L. Ruggiero, G. Chiorazzo, D. Liberti, G. Chiorazzo, G. F. Nicoletti, C. Sardu, F. D'Andrea, C. Ammendola, M. Verza and L. Coppola.In an article by Marfella et al, the author name C. Saron is incorrect and should be listed as C. Sardu. Therefore the correct author list is: R. Marfella, F. Cacciapuoti, M. Siniscalchi, F. C. Sasso, F. Marchese, F. Cinone, E. Musacchio, M. A. Marfella, L. Ruggiero, G. Chiorazzo, D. Liberti, G. Chiorazzo, G. F. Nicoletti, C. Sardu, F. D'Andrea, C. Ammendola, M. Verza and L. Coppola
Ectopic Lymphoid Structures Support Ongoing Production of Class-Switched Autoantibodies in Rheumatoid Synovium
No full textBackgroundFollicular structures resembling germinal centres (GCs) that are characterized by follicular dendritic cell (FDC) networks have long been recognized in chronically inflamed tissues in autoimmune diseases, including the synovium of rheumatoid arthritis (RA). However, it is debated whether these ectopic structures promote autoimmunity and chronic inflammation driving the production of pathogenic autoantibodies. Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific markers of RA, predict a poor prognosis, and have been suggested to be pathogenic. Therefore, the main study objectives were to determine whether ectopic lymphoid structures in RA synovium: (i) express activation-induced cytidine deaminase (AID), the enzyme required for somatic hypermutation and class-switch recombination (CSR) of Ig genes; (ii) support ongoing CSR and ACPA production; and (iii) remain functional in a RA/severe combined immunodeficiency (SCID) chimera model devoid of new immune cell influx into the synovium.Methods and findingsUsing immunohistochemistry (IHC) and quantitative Taqman real-time PCR (QT-PCR) in synovial tissue from 55 patients with RA, we demonstrated that FDC+ structures invariably expressed AID with a distribution resembling secondary lymphoid organs. Further, AID+/CD21+ follicular structures were surrounded by ACPA+/CD138+ plasma cells, as demonstrated by immune reactivity to citrullinated fibrinogen. Moreover, we identified a novel subset of synovial AID+/CD20+ B cells outside GCs resembling interfollicular large B cells. In order to gain direct functional evidence that AID+ structures support CSR and in situ manufacturing of class-switched ACPA, 34 SCID mice were transplanted with RA synovium and humanely killed at 4 wk for harvesting of transplants and sera. Persistent expression of AID and Igamma-Cmu circular transcripts (identifying ongoing IgM-IgG class-switching) was observed in synovial grafts expressing FDCs/CD21L. Furthermore, synovial mRNA levels of AID were closely associated with circulating human IgG ACPA in mouse sera. Finally, the survival and proliferation of functional B cell niches was associated with persistent overexpression of genes regulating ectopic lymphoneogenesis.ConclusionsOur demonstration that FDC+ follicular units invariably express AID and are surrounded by ACPA-producing plasma cells provides strong evidence that ectopic lymphoid structures in the RA synovium are functional and support autoantibody production. This concept is further confirmed by evidence of sustained AID expression, B cell proliferation, ongoing CSR, and production of human IgG ACPA from GC+ synovial tissue transplanted into SCID mice, independently of new B cell influx from the systemic circulation. These data identify AID as a potential therapeutic target in RA and suggest that survival of functional synovial B cell niches may profoundly influence chronic inflammation, autoimmunity, and response to B cell-depleting therapies
High expression levels of the B cell chemoattractant CXCL13 in rheumatoid synovium are a marker of severe disease
Get PDFOBJECTIVE:
The B cell chemoattractant chemokine ligand 13 (CXCL13) is emerging as a new biochemical marker in RA. This study was undertaken to dissect the relationship between CXCL13 expression levels in the synovium and clinico-pathological variables relevant to RA pathogenesis and outcome.
METHODS:
Synovial tissues from 71 RA patients were evaluated by immunohistochemistry. Thirty paired samples were used for comparative gene expression analysis by quantitative real-time PCR. CXCL13 levels were analysed in relation to cellular, molecular and clinical features of inflammation, lymphocyte activation and joint damage.
RESULTS:
In patients with early disease (<12 months duration), CXCL13 expression correlated significantly with synovial markers of local disease activity and systemic inflammation. Such correlation was less evident in established RA. Notably, the association with lymphocyte infiltration and with expression of B/T cell-related activation and proliferation genes, such as activation-induced cytidine deaminase, IFN-γ and IL-2, remained highly significant independent of disease duration and local disease activity. Patients featuring the highest levels of CXCL13 were more frequently ACPA positive and IgG ACPA titres were increased in the high CXCL13 expression group. Furthermore, the frequency of erosive disease on radiographs was significantly higher in the upper tertile of CXCL13 expression (P = 0.01 with adjustment for disease duration and ACPA). Accordingly, synovial CXCL13 and the local receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin (OPG) ratio significantly co-varied (ρ = 0.52, P < 0.01), independent of the level of local inflammation.
CONCLUSION:
Synovial CXCL13 appears to be a marker of a more severe pattern of RA disease, characterized by increased lymphocyte activation and bone remodelling beyond the level of conventional markers of inflammation
Mature antigen-experienced T helper cells synthesize and secrete the B cell chemoattractant CXCL13 in the inflammatory environment of the rheumatoid joint
No full textOBJECTIVE: Synovial B cells play a critical role in rheumatoid arthritis (RA), being involved in autoantibody synthesis, T cell activation, and cytokine production. CXCL13 is a B cell chemoattractant that is instrumental in synovial B cell organization; the regulatory determinants of CXCL13 in inflammation are poorly characterized. This study was undertaken to investigate the functional involvement of synovial T cells in the ectopic expression of CXCL13 in RA. METHODS: CXCL13 production and regulation were addressed using immunohistochemistry, in situ hybridization, quantitative polymerase chain reaction, multicolor flow cytometry, and enzyme-linked immunosorbent assay, by in situ-ex vivo analysis and in vitro functional assays with rheumatoid synovial tissue and primary cells. RESULTS: CXCL13 messenger RNA and protein expression and spontaneous CXCL13 secretion were detected in RA synovial fluid T cells but were not detected (or were detected only occasionally) in peripheral blood T cells. Analysis of tissue expression confirmed cytoplasm localization of CXCL13 in T lymphocytes infiltrating B cell follicles and small perivascular aggregates. Multicolor characterizations in synovial fluid demonstrated CXCL13 expression in antigen-experienced T helper cells, frequently characterized by terminal differentiation and the lack of the follicular helper T cell markers CXCR5 and BCL6 protein. In vitro functional assays revealed the enhancing effect of T cell receptor-CD28 engagement on CXCL13 production and secretion in primary cells. CONCLUSION: Our findings define a new functional property of synovial T cells, demonstrating their active involvement in the local production of B cell chemoattractants, and support a direct contribution of the adaptive immune system and antigen-dependent signals in the mechanisms of B cell localization in RA
Synovial tissue heterogeneity and peripheral blood biomarkers
No full textRheumatoid arthritis is characterized by multiple pathobiological processes and heterogeneous clinical phenotypes. Not surprisingly, the inflamed synovium harbors an equally complex pathology. This includes variability in infiltrating and resident cell populations, spatial arrangements, and cell-cell interactions, as well as gene expression profiles. Remarkable progress in our understanding of the many facets of tissue heterogeneity has been facilitated by the increasing availability of patients' material and the development of advanced research technologies. The next challenge is to capitalize on the large amount of data generated to elucidate the specific pathogenic pathways disparately activated in different patients and/or different phases of the disease. When tissue pathology can be reliably explored through noninvasive circulating biomarkers, then the circle will be closed. We attempt to highlight key advances in the understanding of synovial tissue heterogeneity in rheumatoid arthritis and summarize novel perspectives in synovial biomarker discovery in relation to peripheral blood
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