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1.  Synovial biology and T cells in rheumatoid arthritis 
Events that occur in rheumatoid arthritis synovial tissues are responsible for the signs and symptoms of joint inflammation and for the eventual destruction of articular and periarticular structures that lead to joint dysfunction and disability. The three most abundant cell populations in RA synovium are synovial macrophages (type A synoviocytes), synovial fibroblasts (type B synoviocytes) and infiltrating T lymphocytes. Other important cell populations include B lymphocytes, dendritic cells, plasma cells, mast cells and osteoclasts. Our current understanding of rheumatoid arthritis is moving beyond previous concepts that view this disease as the consequence of a specific and focused humoral or cellular autoimmune response to a single autoantigen. Rather, a new view of rheumatoid arthritis is emerging, which seeks to understand this disease as the product of pathologic cell–cell interactions occurring within a unique and defined environment, the synovium. T lymphocytes in rheumatoid arthritis synovium interact closely with dendritic cells, the most potent antigen-presenting cell population in the immune system. T cells also interact with monocytes and macrophages and cytokine-activated T cells may be, especially, suited to trigger production of the important cytokine TNFα by synovial macrophages. Recent evidence also suggests a potent bidirectional interaction between synovial T cells and synovial fibroblasts, which can lead to activation of both cell types. An important role for synovial B lymphocytes has been emphasized recently, both by experimental data and by results of clinical interventions. B cells in synovium can interact with fibroblasts as well as with other cells of the immune system and their potential role as antigen-presenting cells in the joint is as yet underexplored. Rheumatoid arthritis synovium may be one of the most striking examples of pathologic, organ-specific interactions between immune system cells and resident tissue cell populations. This view of rheumatoid arthritis also leads to the prediction that novel approaches to treatment will more logically target the intercellular communication systems that maintain such interactions, rather than attempt to ablate a single cell population.
doi:10.1016/j.pathophys.2005.07.005
PMCID: PMC3533491  PMID: 16112560
T cells; B cells; Fibroblasts; Dendritic cells; Monocytes
2.  Detailed analysis of the cell infiltrate and the expression of mediators of synovial inflammation and joint destruction in the synovium of patients with psoriatic arthritis: implications for treatment 
Annals of the Rheumatic Diseases  2006;65(12):1551-1557.
Background
The synovial tissue is a primary target of many inflammatory arthropathies, including psoriatic arthritis (PsA). Identification of proinflammatory molecules in the synovium may help to identify potentially therapeutic targets.
Objective
To investigate extensively the features of cell infiltration and expression of mediators of inflammation and joint destruction in the synovium of patients with PsA compared with patients with rheumatoid arthritis matched for disease duration and use of drugs.
Methods
Multiple synovial tissue biopsy specimens were obtained by arthroscopy from an inflamed joint in 19 patients with PsA (eight oligoarthritis, 11 polyarthritis) and 24 patients with rheumatoid arthritis. Biopsy specimens were analysed by immunohistochemistry to detect T cells, plasma cells, fibroblast‐like synoviocytes, macrophages, proinflammatory cytokines, matrix metalloproteinases and tissue inhibitor metalloproteinase‐1, adhesion molecules and vascular markers. Stained sections were evaluated by digital image analysis.
Results
The synovial infiltrate of patients with PsA and rheumatoid arthritis was comparable with regard to numbers of fibroblast‐like synoviocytes and macrophages. T cell numbers were considerably lower in the synovium of patients with PsA. The number of plasma cells also tended to be lower in PsA. The expression of tumour necrosis factor alpha (TNFα), interleukin (IL) 1β, IL6 and IL18 was as high in PsA as in rheumatoid arthritis. The expression of matrix metalloproteinases, adhesion molecules and vascular markers was comparable for PsA and rheumatoid arthritis.
Conclusion
These data show increased proinflammatory cytokine expression in PsA synovium, comparable to results obtained for rheumatoid arthritis, and support the notion that, in addition to TNFα blockade, there may be a rationale for treatments directed at IL1β, IL6 and IL18.
doi:10.1136/ard.2005.050963
PMCID: PMC1798447  PMID: 16728461
3.  Developments in the synovial biology field 2006 
Synovial pathophysiology is a complex and synergistic interplay of different cell populations with tissue components, mediated by a variety of signaling mechanisms. All of these mechanisms drive the affected joint into inflammation and drive the subsequent destruction of cartilage and bone. Each cell type contributes significantly to the initiation and perpetuation of this deleterious concert, especially in rheumatoid arthritis. Rheumatoid arthritis synovial fibroblasts and macrophages, both cell types with pivotal roles in inflammation and destruction, but also T cells and B cells are crucial for complex network in the inflamed synovium. An even more complex cellular crosstalk between these key players maintains a process of chronic inflammation. As outlined in the present review, in the past year substantial progress has been made to elucidate further details of the rich pathophysiology of rheumatoid arthritis, which may also facilitate the identification of novel targets for future therapeutic strategies.
doi:10.1186/ar2140
PMCID: PMC1906804  PMID: 17442097
4.  Macrophages in Synovial Inflammation 
Synovial macrophages are one of the resident cell types in synovial tissue and while they remain relatively quiescent in the healthy joint, they become activated in the inflamed joint and, along with infiltrating monocytes/macrophages, regulate secretion of pro-inflammatory cytokines and enzymes involved in driving the inflammatory response and joint destruction. Synovial macrophages are positioned throughout the sub-lining layer and lining layer at the cartilage–pannus junction and mediate articular destruction. Sub-lining macrophages are now also considered as the most reliable biomarker for disease severity and response to therapy in rheumatoid arthritis (RA). There is a growing understanding of the molecular drivers of inflammation and an appreciation that the resolution of inflammation is an active process rather than a passive return to homeostasis, and this has implications for our understanding of the role of macrophages in inflammation. Macrophage phenotype determines the cytokine secretion profile and tissue destruction capabilities of these cells. Whereas inflammatory synovial macrophages have not yet been classified into one phenotype or another it is widely known that TNFα and IL-l, characteristically released by M1 macrophages, are abundant in RA while IL-10 activity, characteristic of M2 macrophages, is somewhat diminished. Here we will briefly review our current understanding of macrophages and macrophage polarization in RA as well as the elements implicated in controlling polarization, such as cytokines and transcription factors like NFκB, IRFs and NR4A, and pro-resolving factors, such as LXA4 and other lipid mediators which may promote a non-inflammatory, pro-resolving phenotype, and may represent a novel therapeutic paradigm.
doi:10.3389/fimmu.2011.00052
PMCID: PMC3342259  PMID: 22566842
macrophage; arthritis; inflammation
5.  Macrophages in rheumatoid arthritis 
Arthritis Research  2000;2(3):189-202.
The abundance and activation of macrophages in the inflamed synovial membrane/pannus significantly correlates with the severity of rheumatoid arthritis (RA). Although unlikely to be the 'initiators' of RA (if not as antigen-presenting cells in early disease), macrophages possess widespread pro-inflammatory, destructive, and remodeling capabilities that can critically contribute to acute and chronic disease. Also, activation of the monocytic lineage is not locally restricted, but extends to systemic parts of the mononuclear phagocyte system. Thus, selective counteraction of macrophage activation remains an efficacious approach to diminish local and systemic inflammation, as well as to prevent irreversible joint damage.
doi:10.1186/ar86
PMCID: PMC130001  PMID: 11094428
cytokine; fibroblast; macrophage; monocyte; nitric oxide; peripheral blood; reactive oxygen species; rheumatoid arthritis; synovial membrane; T-cell
6.  Immunolocalization of matrix metalloproteinase 3 (stromelysin) in rheumatoid synovioblasts (B cells): correlation with rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1989;48(8):645-653.
Metalloproteinases produced by connective tissue cells may play a key part in the destruction of joints in rheumatoid arthritis. Matrix metalloproteinase 3 (MMP-3; stromelysin) capable of degrading cartilage proteoglycans and type IX collagen and of activating procollagenase was immunolocalised in hyperplastic synovial lining cells in rheumatoid synovium, but not in the cells of normal synovium. Cells responsible for synthesis of MMP-3 have the phenotype of synovioblasts (B cells) by immunoelectron microscopy, but not of phagocytic synovial macrophages (A cells). Cultured monolayer of rheumatoid synovial cells synthesises MMP-3 only under treatment with macrophage conditioned medium. Immunolocalisation of MMP-3 in rheumatoid synovium and cultured synovial cells was possible when the specimens were treated with a monovalent ionophore, monensin. These results suggest that MMP-3 is synthesised and secreted continuously without storage from hyperplastic synovioblasts stimulated by factor(s) derived from activated macrophages present in the synovium.
Images
PMCID: PMC1003840  PMID: 2675782
7.  Upregulation of tumor necrosis factor receptor-associated factor 6 correlated with synovitis severity in rheumatoid arthritis 
Arthritis Research & Therapy  2012;14(3):R133.
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease leading to joint destruction and disability. Focal bone erosion is due to excess bone resorption of osteoclasts. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is one of the critical mediators both in inflammatory signal pathway and differentiation and resorption activity of osteoclasts. Here we aimed to investigate TRAF6 expression in RA synovium and its correlation with histological synovitis severity and radiological joint destruction in RA.
Methods
Synovitis score was determined in needle biopsied synovium from 44 patients with active RA. Synovium from nine patients with osteoarthritis (OA) and seven with orthopedic arthropathies (Orth.A) were enrolled as "less inflamed" disease controls. Serial sections were stained immunohistochemically for TRAF6 as well as CD68 (macrophage), CD3 (T cell), CD20 (B cell), CD38 (plasmocyte), CD79a (B lineage cells from pre-B cell to plasmocyte stage), and CD34 (endothelial cell). Double immunofluorescence staining of TRAF6 and CD68 were tested. Densities of positive staining cells were determined and correlated with histological disease activity (synovitis score) and radiographic joint destruction (Sharp score).
Results
TRAF6 expression was found in the intimal and subintimal area of RA synovium, with intense staining found in the endochylema and nucleus of intimal synoviocytes and subintimal inflammatory cells. Double immunofluorescence staining showed TRAF6 was expressed in most of the intimal cells and obviously expressed in CD68+ cells and some other CD68- cells in subintimal area. Synovial TRAF6 was significantly over-expressed in the RA group compared with the OA and Orth.A group (2.53 ± 0.94 vs. 0.72 ± 0.44 and 0.71 ± 0.49, P < 0.0001). Synovial TRAF6 expression in RA correlated significantly with synovitis score (r = 0.412, P = 0.006), as well as the inflammatory cell infiltration (r = 0.367, P = 0.014). Significant correlation was detected between synovial TRAF6 expression and intimal CD68+ cells, as well as the cell density of subintimal CD68+ cells, CD3+ cells, CD20+ cells, CD38+ cells, and CD79a+ cells (all P < 0.05).
Conclusions
Elevated synovial TRAF6 expression correlated with synovitis severity and CD68+ cell density in RA. It is, therefore, hypothesized that synovial TRAF6 is involved in the pathogenesis of synovial inflammation and osteoclast differentiation in RA.
doi:10.1186/ar3866
PMCID: PMC3446516  PMID: 22656185
8.  Microsatellite analysis in rheumatoid arthritis synovial fibroblasts 
Annals of the Rheumatic Diseases  2000;59(5):386-389.
OBJECTIVES—Rheumatoid arthritis (RA) is a chronic disease characterised by irreversible destruction of the affected joints. As aggressive transformed-appearing synovial fibroblasts are commonly found at the site of invasion of the rheumatoid synovium into the adjacent cartilage and bone, the presence of microsatellite instability (MSI) and expression of mismatch repair enzymes as a possible mechanism in the alteration of these cells was examined.
METHODS—DNA was extracted from the synovial fibroblasts and blood of 20 patients with long term RA undergoing joint replacement, and the presence of MSI was studied at 10 microsatellite loci. In addition, immunohistochemistry was performed to evaluate the expression of the two major mismatch repair enzymes (hMLH1 and hMSH2) in rheumatoid synovium.
RESULTS—MSI could not be detected in any of the fibroblast cell populations derived from the 20 different rheumatoid synovial samples. In addition, strong expression of mismatch repair enzymes could be seen in numerous cells, including fibroblasts, throughout the synovium.
CONCLUSIONS—Applying the currently used and established markers for MSI, the data show for the first time that MSI does not appear to have an important role in alteration of rheumatoid synovial fibroblasts into an aggressive phenotype. On the other hand, strong mismatch repair enzyme synthesis in rheumatoid synovium supports the hypothesis of continuing DNA repair, presumably due to long term, inflammation induced DNA damage.


doi:10.1136/ard.59.5.386
PMCID: PMC1753134  PMID: 10784522
9.  Tyrosine kinases as targets for the treatment of rheumatoid arthritis 
Nature Reviews. Rheumatology  2009;5(6):317-324.
As critical regulators of numerous cell signaling pathways, tyrosine kinases are implicated in the pathogenesis of several diseases, including rheumatoid arthritis (RA). In the absence of disease, synoviocytes produce factors that provide nutrition and lubrication for the surrounding cartilage tissue; few cellular infiltrates are seen in the synovium. In RA, however, macrophages, neutrophils, T cells and B cells infiltrate the synovium and produce cytokines, chemokines and degradative enzymes that promote inflammation and joint destruction. In addition, the synovial lining expands owing to the proliferation of synoviocytes and infiltration of inflammatory cells to form a pannus, which invades the surrounding bone and cartilage. Many of these cell responses are regulated by tyrosine kinases that operate in specific signaling pathways, and inhibition of a number of these kinases might be expected to provide benefit in RA.
doi:10.1038/nrrheum.2009.82
PMCID: PMC3401602  PMID: 19491913
10.  Bone resorption by cells isolated from rheumatoid synovium. 
Annals of the Rheumatic Diseases  1992;51(11):1223-1229.
Cellular mechanisms accounting for the osteolysis of rheumatoid erosions are poorly understood. Cells were isolated and characterised from the synovium of 16 patients with rheumatoid arthritis (RA) and four patients with osteoarthritis and their ability to resorb bone was assessed using a scanning electron microscope bone resorption assay. Macrophages were the major cell type isolated from the synovium of patients with RA. These produced extensive roughening of the bone surface without resorption pit formation. This low grade type of bone resorption was not affected by systemic (calcitonin, parathyroid hormone, 1,25-dihydroxyvitamin D3) or local (interleukin 1, prostaglandin E2) factors influencing bone resorption. Macrophage mediated bone resorption differs qualitatively and quantitatively from that of osteoclasts but is likely to play an important part in the development of marginal erosions in RA.
Images
PMCID: PMC1012460  PMID: 1334644
11.  Co-Opting Endogenous Immunoglobulin for the Regulation of Inflammation and Osteoclastogenesis in Humans and Mice 
Arthritis and rheumatism  2011;63(12):3897-3907.
Objective
Cells of the monocytic lineage play fundamental roles in the regulation of health, ranging from the initiation and resolution of inflammation to bone homeostasis. In rheumatoid arthritis (RA), the inflamed synovium exhibits characteristic infiltration of macrophages along with local osteoclast maturation, which, together, drive chronic inflammation and downstream articular destruction. The aim of this study was to explore an entirely novel route of immunoglobulin-mediated regulation, involving simultaneous suppression of the inflammatory and erosive processes in the synovium.
Methods
Using in vivo and in vitro studies of human cells and a murine model of RA, the ability of staphylococcal protein A (SPA) to interact with and modulate cells of the monocytic lineage was tested. In addition, the efficacy of SPA as a therapeutic agent was evaluated in murine collagen-induced arthritis (CIA).
Results
SPA showed a capacity to appropriate circulating IgG, by generating small immunoglobulin complexes that interacted with monocytes, macrophages, and preosteoclasts. Formation of these complexes resulted in Fcγ receptor type I–dependent polarization of macrophages to a regulatory phenotype, rendering them unresponsive to activators such as interferon-γ. The antiinflammatory complexes also had the capacity to directly inhibit differentiation of preosteoclasts into osteoclasts in humans. Moreover, administration of SPA in the early stages of disease substantially alleviated the clinical and histologic erosive features of CIA in mice.
Conclusion
These findings demonstrate the overarching utility of immunoglobulin complexes for the prevention and treatment of inflammatory diseases. The results shed light on the interface between immunoglobulin complex–mediated pathways, osteoclastogenesis, and associated pathologic processes. Thus, therapeutic agents designed to harness all of these properties may be an effective treatment for arthritis, by targeting both the innate inflammatory response and prodestructive pathways.
doi:10.1002/art.30629
PMCID: PMC3598489  PMID: 22127707
12.  Managing Macrophages in Rheumatoid Arthritis by Reform or Removal 
Current rheumatology reports  2012;14(5):445-454.
Macrophages play a central role in the pathogenesis of rheumatoid arthritis (RA). There is an imbalance of inflammatory and antiinflammatory macrophages in RA synovium. Although the polarization and heterogeneity of macrophages in RA have not been fully uncovered, the identity of macrophages in RA can potentially be defined by their products, including the co-stimulatory molecules, scavenger receptors, different cytokines/chemokines and receptors, and transcription factors. In the last decade, efforts to understand the polarization, apoptosis regulation, and novel signaling pathways in macrophages, as well as how distinct activated macrophages influence disease progression, have led to strategies that target macrophages with varied specificity and selectivity. Major targets that are related to macrophage development and apoptosis include TNF-α, IL-1, IL-6, GM-CSF, M-CSF, death receptor 5 (DR5), Fas, and others, as listed in Table 1. Combined data from clinical, preclinical, and animal studies of inhibitors of these targets have provided valuable insights into their roles in the disease progression and, subsequently, have led to the evolving therapeutic paradigms in RA. In this review, we propose that reestablishment of macrophage equilibrium by inhibiting the development of, and/or eliminating, the proinflammatory macrophages will be an effective therapeutic approach for RA and other autoimmune diseases.
doi:10.1007/s11926-012-0272-4
PMCID: PMC3638732  PMID: 22855296
Macrophage; Polarization; Rheumatoid arthritis; Therapy; Management; Reform; Removal; Joint recruitment; Inflammation; Depletion; TRAIL
13.  Prostaglandins and Rheumatoid Arthritis 
Arthritis  2012;2012:239310.
Rheumatoid arthritis (RA) is a chronic, autoimmune, and complex inflammatory disease leading to bone and cartilage destruction, whose cause remains obscure. Accumulation of genetic susceptibility, environmental factors, and dysregulated immune responses are necessary for mounting this self-reacting disease. Inflamed joints are infiltrated by a heterogeneous population of cellular and soluble mediators of the immune system, such as T cells, B cells, macrophages, cytokines, and prostaglandins (PGs). Prostaglandins are lipid inflammatory mediators derived from the arachidonic acid by multienzymatic reactions. They both sustain homeostatic mechanisms and mediate pathogenic processes, including the inflammatory reaction. They play both beneficial and harmful roles during inflammation, according to their site of action and the etiology of the inflammatory response. With respect to the role of PGs in inflammation, they can be effective mediators in the pathophysiology of RA. Thus the use of agonists or antagonists of PG receptors may be considered as a new therapeutic protocol in RA. In this paper, we try to elucidate the role of PGs in the immunopathology of RA.
doi:10.1155/2012/239310
PMCID: PMC3502782  PMID: 23193470
14.  Cellular targets of interleukin‐18 in rheumatoid arthritis 
Annals of the Rheumatic Diseases  2007;66(11):1411-1418.
Recent data are presented which indicate a critical role for interleukin (IL)‐18 in rheumatoid arthritis (RA). The T cells and macrophages invading the synovium or in the synovial fluid are the chief cellular targets of IL‐18 in RA. Neutrophils, dendritic cells and endothelial cells may also be cellular mediators of IL‐18. The direct effect of IL‐18 on fibroblast‐like synoviocytes or chondrocytes may not be essential or important. In RA, IL‐18, which is mainly produced by macrophages, activates T cells and macrophages to produce proinflammatory cytokines, chemokines, adhesion molecules and RANKL which, in turn, perpetuate chronic inflammation and induce bone and cartilage destruction.
doi:10.1136/ard.2006.067793
PMCID: PMC2111635  PMID: 17502360
15.  Synovial stromal cells from rheumatoid arthritis patients attract monocytes by producing MCP-1 and IL-8 
Arthritis Research  2001;3(2):118-126.
Macrophages that accumulate in the synovium of rheumatoid arthritis patients play an important role in the pathogenesis of this inflammatory disease. However, the mechanism by which macrophages are attracted into the inflamed synovium and accumulate there has not been completely delineated. The results of this study show that rheumatoid arthritis synovial stromal cells produce the chemokines monocyte chemotactic protein-1 and IL-8, and these have the capacity to attract peripheral monocytes. These results suggest that one of the mechanisms by which macrophages accumulate in the inflamed synovium is by responding to the chemokines produced locally.
PMCID: PMC17828  PMID: 11178119
chemokine; monocyte; rheumatoid arthritis
16.  Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus? 
Acetylcholine, the principal vagus neurotransmitter, inhibits inflammation by suppressing the production of pro-inflammatory cytokines through a mechanism dependent on the α7 nicotinic acetylcholine receptor subunit (alpha7nAChR) that explains why vagus nerve stimulation is anti-inflammatory in nature. Strong expression of alpha7nAChR in the synovium of rheumatoid arthritis and psoriatic arthritis patients was detected. Peripheral macrophages and synovial fibroblasts respond in vitro to specific alpha7nAChR cholinergic stimulation with potent inhibition of proinflammatory cytokines. Fibroblasts balance inflammatory mechanisms and arthritis development through feedback cholinergic stimulation by nearby immune cells. Collagen induced arthritis in alpha7nAChR(-/-) mice was significantly severe and showed increased synovial inflammation and joint destruction compared to the wild-type mice. Similar to vagal nerve stimulation and alpha7nAChR agonists, polyunsaturated fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also suppress inflammation. In view of their similar anti-inflammatory actions, it is proposed that vagal nerve stimulation, alpha7nAChR agonists and EPA and DHA may augment the formation of anti-inflammatory lipid molecules: lipoxins, resolvins, protectins and maresins. This implies that therapies directed at regulation of the cholinergic and alpha7nAChR mediated mechanisms and enhancing the formation of lipoxins, resolvins, protectins and maresins may halt and/or ameliorate rheumatoid arthritis, lupus and other rheumatological conditions.
doi:10.1186/1476-511X-10-19
PMCID: PMC3037330  PMID: 21261967
17.  Hypoxia-Inducible Factor-2α Is an Essential Catabolic Regulator of Inflammatory Rheumatoid Arthritis 
PLoS Biology  2014;12(6):e1001881.
Hypoxia-inducible factor-2α (HIF-2α) is sufficient to cause experimental rheumatoid arthritis and acts to regulate the functions of fibroblast-like cells from tissue surrounding joints, independent of HIF-1α.
Rheumatoid arthritis (RA) is a systemic autoimmune disorder that manifests as chronic inflammation and joint tissue destruction. However, the etiology and pathogenesis of RA have not been fully elucidated. Here, we explored the role of the hypoxia-inducible factors (HIFs), HIF-1α (encoded by HIF1A) and HIF-2α (encoded by EPAS1). HIF-2α was markedly up-regulated in the intimal lining of RA synovium, whereas HIF-1α was detected in a few cells in the sublining and deep layer of RA synovium. Overexpression of HIF-2α in joint tissues caused an RA-like phenotype, whereas HIF-1α did not affect joint architecture. Moreover, a HIF-2α deficiency in mice blunted the development of experimental RA. HIF-2α was expressed mainly in fibroblast-like synoviocytes (FLS) of RA synovium and regulated their proliferation, expression of RANKL (receptor activator of nuclear factor–κB ligand) and various catabolic factors, and osteoclastogenic potential. Moreover, HIF-2α–dependent up-regulation of interleukin (IL)-6 in FLS stimulated differentiation of TH17 cells—crucial effectors of RA pathogenesis. Additionally, in the absence of IL-6 (Il6−/− mice), overexpression of HIF-2α in joint tissues did not cause an RA phenotype. Thus, our results collectively suggest that HIF-2α plays a pivotal role in the pathogenesis of RA by regulating FLS functions, independent of HIF-1α.
Author Summary
Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation in joint tissues leading to destruction of cartilage and bone. Despite some therapeutic advances, the etiology of RA pathogenesis is not yet clear, and effective treatment of RA remains a significant, unmet medical need. Hypoxia is a prominent feature of inflamed tissue within RA-affected joints, and earlier work has implicated limited involvement of hypoxia-inducible factor (HIF)-1 α. We explored the role of a second HIF family member, HIF-2α, in RA pathogenesis. We showed that HIF-2α is markedly increased in the tissue lining the RA-affected joints. Notably and in contrast to HIF-1α, when overexpressed in normal mouse joint tissues, HIF-2α is sufficient to cause RA-like symptoms. Conversely, an HIF-2α deficiency blocks the development of experimental arthritis in mice. We discovered further that HIF-2α regulates RA pathogenesis by modulating various RA-associated functions of joint-specific fibroblast-like cells, including proliferation, expression of cytokines, chemokines, and matrix-degrading enzymes, and bone-remodeling potential. HIF-2α also increases the ability of these cells to promote interleukin-6–dependent differentiation of TH17 cells, a known effector of RA pathogenesis. We thus show that HIF-1α and HIF-2α have distinct roles and act via different mechanisms in RA pathogenesis.
doi:10.1371/journal.pbio.1001881
PMCID: PMC4051611  PMID: 24914685
18.  Orphan receptor GPR15/BOB is up-regulated in rheumatoid arthritis 
Cytokine  2014;67(2):53-59.
Highlights
•Expression of orphan receptor GPR15/BOB was examined in RA and non-RA subjects.•GPR15/BOB protein was observed on macrophages in synovia and increased in RA.•GPR15/BOB messenger RNA was detected in all RA and a minority of non-RA synovia.•GPR15/BOB protein increased on blood monocytes and neutrophils in RA.•The orphan receptor is up-regulated in a chronic inflammatory disease.
Chemokine receptors on leukocytes mediate the recruitment and accumulation of these cells within affected joints in chronic inflammatory diseases such as rheumatoid arthritis (RA). Identification of involved receptors offers potential for development of therapeutic interventions. The objective of this study was to investigate the expression of orphan receptor GPR15/BOB in the synovium of RA and non-RA patients and in peripheral blood of RA patients and healthy donors.
GPR15/BOB protein and messenger RNA expression were examined in RA and non-RA synovium by immunofluorescence and reverse-transcription polymerase chain reaction (RT-PCR) respectively. GPR15/BOB expression on peripheral blood leukocytes was analysed by flow cytometry and GPR15/BOB messenger RNA was examined in peripheral blood monocytes by RT-PCR.
GPR15/BOB protein was observed in CD68+ and CD14+ macrophages in synovia, with greater expression in RA synovia. GPR15/BOB protein was expressed in all patient synovia whereas in non-RA synovia expression was low or absent. Similarly GPR15/BOB messenger RNA was detected in all RA and a minority of non-RA synovia. GPR15/BOB protein was expressed on peripheral blood leukocytes from RA and healthy individuals with increased expression by monocytes and neutrophils in RA. GPR15/BOB messenger RNA expression was confirmed in peripheral blood monocytes.
In conclusion GPR15/BOB is expressed by macrophages in synovial tissue and on monocytes and neutrophils in peripheral blood, and expression is up-regulated in RA patients compared to non-RA controls. This orphan receptor on monocytes/macrophages and neutrophils may play a role in RA pathophysiology.
doi:10.1016/j.cyto.2014.02.015
PMCID: PMC3996549  PMID: 24725539
Orphan receptor GPR15/BOB; Rheumatoid arthritis; Monocyte/macrophage; Neutrophils; Inflammation
19.  Immune regulation of bone loss by Th17 cells 
A significant macrophage and T-cell infiltrate commonly occurs in inflammatory joint conditions such as rheumatoid arthritis that have significant bone destruction. Cytokines produced by activated macrophages and T cells are implicated in arthritis pathogenesis and are involved in osteoclast-mediated bone resorption. The scope of the present review is to analyze current knowledge and to provide a better understanding of how macrophage-derived factors promote the differentiation of a novel T-helper subset (Th17) that promotes osteoclast formation and activation.
doi:10.1186/ar2502
PMCID: PMC2592787  PMID: 18983698
20.  The role of human T-lymphocyte-monocyte contact in inflammation and tissue destruction 
Arthritis Research  2002;4(Suppl 3):S169-S176.
Chapter summary
Contact-mediated signaling of monocytes by human stimulated T lymphocytes (TL) is a potent proinflammatory mechanism that triggers massive upregulation of the proinflammatory cytokines IL-1 and tumor necrosis factor-α. These two cytokines play an important part in chronic destructive diseases, including rheumatoid arthritis. To date this cell–cell contact appears to be a major endogenous mechanism to display such an activity in monocyte-macrophages. Since TL and monocyte-macrophages play a pivotal part in the pathogenesis of chronic inflammatory diseases, we investigated the possible ligands and counter-ligands involved in this cell–cell interaction. We also characterized an inhibitory molecule interfering in this process, apolipoprotein A-I. This review aims to summarize the state of the art and importance of contact-mediated monocyte activation by stimulated TL in cytokine production in rheumatoid arthritis and mechanisms that might control it.
doi:10.1186/ar558
PMCID: PMC3240134  PMID: 12110136
cytokines; inflammation; monocytes; rheumatoid arthritis; T lymphocytes
21.  Mast cells are the main interleukin 17-positive cells in anticitrullinated protein antibody-positive and -negative rheumatoid arthritis and osteoarthritis synovium 
Arthritis Research & Therapy  2011;13(5):R150.
Introduction
Mast cells have been implicated to play a functional role in arthritis, especially in autoantibody-positive disease. Among the cytokines involved in rheumatoid arthritis (RA), IL-17 is an important inflammatory mediator. Recent data suggest that the synovial mast cell is a main producer of IL-17, although T cells have also been implicated as prominent IL-17 producers as well. We aimed to identify IL-17 expression by mast cells and T cells in synovium of arthritis patients.
Methods
Synovial samples of anticitrullinated protein antibody-positive (ACPA+) and ACPA-negative (ACPA-) RA and osteoarthritis (OA) patients were stained for IL-17 in combination with CD117 (mast cells), CD3 (T cells) and CD68 (macrophages). Concentrations of IL-17 in synovial fluid were determined by ELISA.
Results
The number of IL-17+ cells in synovium was comparable in all groups. Although the vast majority of IL-17+ cells are mast cells, no difference in the percentage of IL-17+ mast cells was observed. Nonetheless, levels of IL-17 in synovial fluid were increased in ACPA+ RA patients compared to ACPA- RA and OA patients.
Conclusions
The synovial mast cell is the main IL-17+ cell in all three arthritis groups analyzed. These data are relevant for studies aimed at blocking IL-17 in the treatment of arthritis.
doi:10.1186/ar3466
PMCID: PMC3308080  PMID: 21933391
22.  Essential Role for the C5a Receptor in Regulating the Effector Phase of Synovial Infiltration and Joint Destruction in Experimental Arthritis 
The Journal of Experimental Medicine  2002;196(11):1461-1471.
A characteristic feature of rheumatoid arthritis is the abundance of inflammatory cells in the diseased joint. Two major components of this infiltrate are neutrophils in the synovial fluid and macrophages in the synovial tissue. These cells produce cytokines including tumor necrosis factor α and other proinflammatory mediators that likely drive the disease through its effector phases. To investigate what mechanisms underlie the recruitment of these cells into the synovial fluid and tissue, we performed expression analyses of chemoattractant receptors in a related family that includes the anaphylatoxin receptors and the formyl-MetLeuPhe receptor. We then examined the effect of targeted disruption of two abundantly expressed chemoattractant receptors, the receptors for C3a and C5a, on arthritogenesis in a mouse model of disease. We report that genetic ablation of C5a receptor expression completely protects mice from arthritis.
doi:10.1084/jem.20020205
PMCID: PMC2194257  PMID: 12461081
arthritis; C5a receptors; granulocytes; chemoattractants; monocytes
23.  Anti-Sa antibodies: prognostic and pathogenetic significance to rheumatoid arthritis 
Arthritis Research & Therapy  2004;6(2):86-89.
Anti-Sa antibodies are detected in the serum of 20–47% of patients with rheumatoid arthritis. These antibodies have a high degree of specificity for the disease, and appear to identify a subset of early rheumatoid arthritis patients destined to have aggressive and destructive disease. It has recently been confirmed that anti-Sa antibodies are directed to citrullinated vimentin, thus placing them in the anti-citrulline family of autoantibodies. The Sa antigen has previously been shown to be present in synovium. This, along with the demonstration of citrullinated proteins in rheumatoid synovium, suggests that anti-Sa antibodies may play a pathogenetic role in the initiation and/or persistence of rheumatoid synovitis.
doi:10.1186/ar1171
PMCID: PMC400444  PMID: 15059270
anti-citrulline antibodies; anti-Sa; autoantibodies; prognosis; rheumatoid arthritis; synovium
24.  Analysis of the cell infiltrate and expression of matrix metalloproteinases and granzyme B in paired synovial biopsy specimens from the cartilage-pannus junction in patients with RA 
Annals of the Rheumatic Diseases  2001;60(6):561-565.
OBJECTIVES—Examination of synovial tissue (ST) obtained at surgery because of end stage destructive rheumatoid arthritis (RA) showed that macrophages and fibroblasts are the major cell types at the cartilage-pannus junction (CPJ). This study aimed at defining the cell infiltrate and mediators of joint destruction in ST selected at arthroscopy from the CPJ in patients with RA who did not require joint surgery.
METHODS—Paired synovial biopsy specimens were obtained at arthroscopy from ST adjacent to the CPJ and the suprapatellar pouch from the knee joints of 17 patients with RA. Immunohistological analysis was performed using monoclonal antibodies to detect T cells, B cells, plasma cells, macrophages, fibroblast-like synoviocytes, mast cells, and granzyme B+ cytotoxic cells as well as the expression of metalloproteinase (MMP)-1, MMP-3, and MMP-13. The sections were evaluated by computer assisted image analysis and semiquantitative analysis.
RESULTS—The cell infiltrate comprised mainly T cells, macrophages, and plasma cells. The ST was also infiltrated by the other cell types, but at lower numbers. Expression of MMPs was abundant, especially MMP-3. The features of ST at the CPJ were generally similar to those at the suprapatellar pouch.
CONCLUSIONS—The synovium at the CPJ in patients with RA who did not require joint surgery exhibits, in general, the same type of cell infiltrate and expression of MMPs and granzymes as ST from the suprapatellar pouch. The pathological changes that have been described at the CPJ in patients with RA with end stage, destructive disease may well reflect the transition to a process in which macrophages, fibroblast-like synoviocytes, and other cell types become increasingly important.


doi:10.1136/ard.60.6.561
PMCID: PMC1753677  PMID: 11350843
25.  Increased Lymphocyte Infiltration in Rheumatoid Arthritis Is Correlated with an Increase in LTi-like Cells in Synovial Fluid 
Immune Network  2013;13(6):240-248.
In this study, we compared the immune cell populations in rheumatoid arthritis (RA) synovial fluid, which shows lymphoid tissue-like structure, with those in tonsils, which are normal secondary lymphoid tissues. Firstly, we found that CD4-CD11b+ macrophages were the major population in RA synovial fluid and that B cells were the major population in tonsils. In addition, synovial fluid from patients with osteoarthritis, which is a degenerative joint disease, contained CD4+CD11b+ monocytes as the major immune cell population. Secondly, we categorized three groups based on the proportion of macrophages found in RA synovial fluid: (1) the macrophage-high group, which contained more than 80% macrophages; (2) the macrophage-intermediate group, which contained between 40% and 80% macrophages; and (3) the macrophage-low group, which contained less than 40% macrophages. In the macrophage-low group, more lymphoid tissue inducer (LTi)-like cells were detected, and the expression of OX40L and TRANCE in these cells was higher than that in the other groups. In addition, in this group, the suppressive function of regulatory T cells was downregulated. Finally, CXCL13 expression was higher in RA synovial fluid than in tonsils, but CCL21 expression was comparable in synovial fluid from all groups and in tonsils. These data demonstrate that increased lymphocyte infiltration in RA synovial fluid is correlated with an increase in LTi-like cells and the elevation of the chemokine expression.
doi:10.4110/in.2013.13.6.240
PMCID: PMC3875782  PMID: 24385942
Lymphoid tissue inducer; Rheumatoid arthritis; Tonsil

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