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26.  Cytokine regulation in RA synovial tissue: role of T cell/macrophage contact-dependent interactions 
Arthritis Research  2002;4(Suppl 3):S177-S182.
Chapter summary
Several groups have documented the expression of cytokines in rheumatoid arthritis synovial tissue over the past 15 years or so. These studies have indicated that most cytokines examined are expressed at the mRNA levels at least, and many other cytokines are found in abundance as proteins. Our attention has recently focused on the mechanisms that induce and regulate tumour necrosis factor and IL-10. Other workers and ourselves have found that cell–cell contact is an important signal for the induction of cytokines, and our work has demonstrated that tumour necrosis factor and IL-10 production in rheumatoid arthritis synovial joint cells cultures is dependent on T cell/macrophage interaction. In this chapter, we review recent advances in this area and also highlight areas where new therapeutic intervention opportunities arise.
doi:10.1186/ar556
PMCID: PMC3240132  PMID: 12110137
cognate; differentiation; macrophage; signalling; T cells
27.  Studies of T-cell activation in chronic inflammation 
Arthritis Research  2002;4(Suppl 3):S197-S211.
Chapter summary
The strong association between specific alleles encoded within the MHC class II region and the development of rheumatoid arthritis (RA) has provided the best evidence to date that CD4+ T cells play a role in the pathogenesis of this chronic inflammatory disease. However, the unusual phenotype of synovial T cells, including their profound proliferative hyporesponsiveness to TCR ligation, has challenged the notion that T-cell effector responses are driven by cognate cartilage antigens in inflamed synovial joints. The hierarchy of T-cell dysfunction from peripheral blood to inflamed joint suggests that these defects are acquired through prolonged exposure to proinflammatory cytokines such as tumour necrosis factor (TNF)-α. Indeed, there are now compelling data to suggest that chronic cytokine activation may contribute substantially to the phenotype and effector function of synovial T cells. Studies reveal that chronic exposure of T cells to TNF uncouples TCR signal transduction pathways by impairing the assembly and stability of the TCR/CD3 complex at the cell surface. Despite this membrane-proximal effect, TNF selectively uncouples downstream signalling pathways, as is shown by the dramatic suppression of calcium signalling responses, while Ras/ERK activation is spared. On the basis of these data, it is proposed that T-cell survival and effector responses are driven by antigen-independent, cytokine-dependent mechanisms, and that therapeutic strategies that seek to restore T-cell homeostasis rather than further depress T-cell function should be explored in the future.
doi:10.1186/ar557
PMCID: PMC3240133  PMID: 12110140
inflammation; rheumatoid arthritis; signal transduction; T cells; TNF
28.  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
29.  The immunological synapse 
Arthritis Research  2002;4(Suppl 3):S119-S125.
Chapter summary
T-cell activation requires interaction of T-cell antigen receptors with proteins of the major histocompatibility complex (antigen). This interaction takes place in a specialized cell–cell junction referred to as an immunological synapse. The immunological synapse contains at least two functional domains: a central cluster of engaged antigen receptors and a surrounding ring of adhesion molecules. The segregation of the T-cell antigen receptor (TCR) and adhesion molecules is based on size, with the TCR interaction spanning 15 nm and the lymphocyte-function-associated antigen-1 (LFA-1) interaction spanning 30–40 nm between the two cells. Therefore, the synapse is not an empty gap, but a space populated by both adhesion and signaling molecules. This chapter considers four aspects of the immunological synapse: the role of migration and stop signals, the role of the cytoskeleton, the role of self-antigenic complexes, and the role of second signals.
doi:10.1186/ar559
PMCID: PMC3240135  PMID: 12110130
activation; adhesion; immunological synapse; inhibition; signaling
30.  High-efficiency gene transfer into nontransformed cells: utility for studying gene regulation and analysis of potential therapeutic targets 
Arthritis Research  2002;4(Suppl 3):S215-S225.
Chapter summary
The elucidation of the signalling pathways involved in inflammatory diseases, such as rheumatoid arthritis, could provide long sought after targets for therapeutic intervention. Gene regulation is complex and varies depending on the cell type, as well as the signal eliciting gene activation. However, cells from certain lineages, such as macrophages, are specialised to degrade exogenous material and consequently do not easily transfect. Methods for high-efficiency gene transfer into primary cells of various lineages and disease states are desirable, as they remove the uncertainties associated with using transformed cell lines. Significant research has been undertaken into the development of nonviral and viral vectors for basic research, and as vehicles for gene therapy. We briefly review the current methods of gene delivery and the difficulties associated with each system. Adenoviruses have been used extensively to examine the role of various cytokines and signal transduction molecules in the pathogenesis of rheumatoid arthritis. This review will focus on the involvement of different signalling molecules in the production of tumour necrosis factor alpha by macrophages and in rheumatoid synovium. While the NF-κB pathway has proven to be a major mediator of tumour necrosis factor alpha production, it is not exclusive and work evaluating the involvement of other pathways is ongoing.
doi:10.1186/ar560
PMCID: PMC3240136  PMID: 12110141
adenovirus; gene transfer; macrophage; NF-κB; rheumatoid arthritis
31.  Tissue engineering: chondrocytes and cartilage 
Arthritis Research  2002;4(Suppl 3):S63-S68.
Chapter summary
Tissue engineering offers new strategies for developing treatments for the repair and regeneration of damaged and diseased tissues. These treatments, using living cells, will exploit new developments in understanding the principles in cell biology that control and direct cell function. Arthritic diseases that affect so many people and have a major impact on the quality of life provide an important target for tissue engineering. Initial approaches are in cartilage repair; in our own programme we are elucidating the signals required by chondrocytes to promote new matrix assembly. These principles will extend to other tissues of the musculoskeletal system, including the repair of bone, ligament and tendon.
doi:10.1186/ar561
PMCID: PMC3240137  PMID: 12110124
extracellular matrix; joint disease; osteoarthritis; regenerative medicine
32.  Interactions between leukocytes and endothelial cells in gout: lessons from a self-limiting inflammatory response 
Arthritis Research  2002;4(Suppl 3):S91-S97.
Chapter summary
Interactions with endothelium are necessary for leukocytes to pass from the blood into extravascular tissues, and such interactions are facilitated in inflammation by the coordinated expression of endothelial adhesion molecules and chemoattractants. Although the general mechanisms and intracellular pathways of endothelial activation are now fairly well characterised in vitro, relatively little detailed information exists on how endothelial activation changes during the course of inflammatory responses and how such change influences the amount of leukocyte recruitment and the types of leukocytes recruited. Having developed a radiolabelled-antibody-uptake technique for quantifying the expression of endothelial adhesion molecules in relation to leukocyte trafficking, we have analysed the acute, self-limiting inflammatory response to injection of monosodium urate (MSU) crystals. Our studies have supported the view that endothelial activation is closely paralleled by leukocyte recruitment at the onset of the response and have highlighted separate vascular and extravascular stages of downregulation. More recent studies addressing the extravascular contribution to downregulation point to an important role for monocyte–macrophage differentiation in limiting further endothelial activation as a consequence of phagocytosis of MSU crystals.
doi:10.1186/ar562
PMCID: PMC3240138  PMID: 12110127
endothelium; gout; leukocyte trafficking; macrophage; monocyte
33.  Insights into integrin-ligand binding and activation from the first crystal structure 
Arthritis Research  2002;4(Suppl 3):S69-S78.
Chapter summary
Integrin receptors transduce bidirectional signals between extracellular adhesion molecules and intracellular cytoskeletal and signalling molecules. The structural basis of integrin signalling is unknown, but the recent publication of the first crystal structure of the extracellular domain of integrin αVβ3 has provided a number of insights. In this review, previous structure–function analyses of integrins that have employed biochemical and molecular biological approaches are placed in the context of the crystal structure, and novel routes to the development of integrin antagonists are discussed.
doi:10.1186/ar563
PMCID: PMC3240139  PMID: 12110125
adhesion; cations; extracellular matrix; integrin; structure
34.  Perspectives for TNF-α-targeting therapies 
Arthritis Research  2002;4(Suppl 3):S17-S24.
Chapter summary
Rheumatoid arthritis (RA) is the most common chronic autoimmunopathy, clinically leading to joint destruction as a consequence of the chronic inflammatory processes. The pathogenesis of this disabling disease is not well understood, but molecular events leading to tissue inflammation with cartilage and bone destruction are now better defined. Therapy with slow-acting, disease-modifying antirheumatic drugs (DMARDs), such as low-dose methotrexate, which is generally accepted as a standard, leads to a significant amelioration of symptoms but does not stop joint destruction. Due to these disappointing treatment options and the identification of certain inflammatory mediators as therapeutic targets, novel therapeutic agents such as monoclonal antibodies, cytokine-receptor/human-immunoglobulin constructs or recombinant human proteins have been tested in RA with some success. Clinical trials testing anti-TNF-α agents, alone or in combination with methotrexate, have convincingly shown the feasibility and efficacy of these novel approaches to the therapy of RA. A clinical trial testing combination therapy with chimeric (mouse/human) anti-TNF-α monoclonal antibody infliximab and methotrexate showed, for the first time in any RA trial, that there was no median radiological progression in the groups given infliximab plus methotrexate over a 12-month observation period. Similar encouraging results might arise from trials employing other TNF-α-directed agents, such as the fully human monoclonal antibody D2E7, the p75 TNF-α-receptor/Ig construct, etanercept, or others, as discussed in this review. Combination partners other than methotrexate will be established as suitable cotreatment along with anti-TNF-α biologicals. Forthcoming new indications for TNF-α-targeted therapies are discussed.
doi:10.1186/ar564
PMCID: PMC3240140  PMID: 12110119
D2E7; etanercept; infliximab; TNF-α; therapy
35.  The paradigm of IL-6: from basic science to medicine 
Arthritis Research  2002;4(Suppl 3):S233-S242.
Chapter summary
IL-6 is a pleiotropic cytokine with a wide range of biological activities in immune regulation, hematopoiesis, inflammation, and oncogenesis. Its activities are shared by IL-6-related cytokines such as leukemia inhibitory factor and oncostatin M. The pleiotropy and redundancy of IL-6 functions have been identified by using a unique receptor system comprising two functional proteins: an IL-6 receptor (IL-6R) and gp130, the common signal transducer of cytokines related to IL-6. Signal transduction through gp130 is mediated by two pathways: the JAK–STAT (Janus family tyrosine kinase–signal transducer and activator of transcription) pathway and the Ras mitogen-activated protein kinase pathway. The negative regulators of IL-6 signaling have also been identified, although the physiological roles of the molecules are not yet fully understood. The pathological roles of IL-6 have also been clarified in various disease conditions, such as inflammatory, autoimmune, and malignant diseases. On the basis of the findings, a new therapeutic approach to block the IL-6 signal using humanized anti-IL-6R antibody for rheumatoid arthritis, Castleman's disease, and multiple myeloma has been attempted.
doi:10.1186/ar565
PMCID: PMC3240141  PMID: 12110143
cytokines; gp130; interleukin-6; SOCS; rheumatoid arthritis
36.  Genes and environment in arthritis: can RA be prevented? 
Arthritis Research  2002;4(Suppl 3):S31-S36.
Chapter summary
Understanding of how interactions between genes and environment contribute to the development of arthritis is a central issue in understanding the etiology of rheumatoid arthritis (RA), as well as for eventual subsequent efforts to prevent the disease. In this paper, we review current published data on genes and environment in RA as well as in certain induced animal models of disease, mainly those in which adjuvants only or adjuvants plus organ-specific autoantigens are used to induce arthritis. We refer to some new data on environmental and genetic factors of importance for RA generated from a large case–control study in Sweden (1200 patients, 1200 matched controls). We found an increased risk of seropositive but not of seronegative RA in smokers, and there are indications that this effect may be due to a gene–environment interaction involving MHC class II genes. We also found an increased risk of RA in individuals heavily exposed to mineral oils. This was of particular interest because mineral oils are strong inducers of arthritis in certain rodent strains and because polymorphisms in human genetic regions syntenic with genes predisposing for oil-induced arthritis in rats have now been shown to associate with RA in humans. Taken together, our data support the notion that concepts and data on gene-environment interactions in arthritis can now be taken from induced animal models of arthritis to generate new etiological hypotheses for RA.
doi:10.1186/ar566
PMCID: PMC3240142  PMID: 12110121
animal model; environmental factors; genetics; major histocompatibiity complex; rheumatoid arthritis
37.  The instructive role of dendritic cells on T-cell responses 
Arthritis Research  2002;4(Suppl 3):S127-S132.
Chapter summary
Immune responses are initiated in the T-cell areas of secondary lymphoid organs where naïve T lymphocytes encounter dendritic cells (DCs) that present antigens taken up in peripheral tissues. DCs represent the interface between the universe of foreign and tissue-specific antigens and T lymphocytes, and they are the key players in the regulation of cell-mediated immunity. We discuss how the nature of the DC maturation stimuli and the density and quality of DCs present in the T-cell areas of secondary lymphoid organs determine the magnitude and class of the T-cell response.
doi:10.1186/ar567
PMCID: PMC3240143  PMID: 12110131
dendritic cells; effector and memory T cells; T-cell activation; T-cell tolerance
38.  Why do we not have a cure for rheumatoid arthritis? 
Arthritis Research  2002;4(Suppl 3):S297-S301.
Chapter summary
There are currently unprecedented opportunities to treat rheumatoid arthritis using well-designed, highly effective, targeted therapies. This will result in a substantial improvement in the outcome of this disorder for most affected individuals, if they can afford these therapies. Yet our lack of understanding of the basic mechanisms that initiate and sustain this disease remains a major obstacle in the search for a definitive cure. It is possible, if not likely, that our best approach will be to identify individuals at risk and devise reliable, safe methods of preventing the disease before it occurs. The means to do this are currently unknown but should serve as a major focus of research.
doi:10.1186/ar568
PMCID: PMC3240144  PMID: 12110149
etiology; prevention; rheumatoid arthritis; therapy
39.  Signaling for survival and apoptosis in the immune system 
Arthritis Research  2002;4(Suppl 3):S243-S252.
Chapter summary
Signal transduction induced by tumor necrosis factor (TNF) family members and their receptors has been an intensive area of research for several years. The major impact of these studies has been the delineation of apoptotic and cell survival signaling pathways. These discoveries, coupled with major advances in the study of mammalian apoptotic machinery, constitute a promising blueprint of the molecular network governing the fate of all living cells. In this review, we concentrate on the fate of cells in the immune system, where regulation of cell death and cell survival is a frequent and important exercise. A small imbalance in favor of either fate can result in disastrous pathological outcomes, such as cancer, autoimmunity or immune deficiency. It is an insurmountable task to discuss all molecules reported in the literature that are implicated in lymphocyte death or survival. We have therefore focused on discoveries made by mouse gene targeting, as these studies provide the most physiologically relevant information on each molecule. We begin with a description of signaling channels initiated by TNF receptor type 1 engagement, which can lead to either cell survival or to cell death. The point of bifurcation of this pathway and the decision-making molecules FADD, TRAF2 and RIP are discussed. We then follow apoptotic and survival pathways from upstream to downstream, describing many important players involved in signal transduction. Molecules important for NF-κB and JNK/stress-activated protein kinase activation such as IKKβ, NEMO, MAP3K and TRAF6 are discussed, as is the impact of BAFF and its receptors on B-cell survival. Mouse mutants that have helped to define the mammalian apoptosis execution machinery, including animals lacking Apaf-1, caspase-3 and caspase-9, are also described. We conclude with a brief analysis of the potential therapeutic options arising from this body of work.
doi:10.1186/ar569
PMCID: PMC3240145  PMID: 12110144
apoptosis; inflammation; mutant mice; signal transduction
40.  Multiple roles for tumor necrosis factor-α and lymphotoxin α/β in immunity and autoimmunity 
Arthritis Research  2002;4(Suppl 3):S141-S152.
Chapter summary
Tumor necrosis factor (TNF)-α and lymphotoxin (LT) α/β play multiple roles in the development and function of the immune system. This article focuses on three important aspects of the effects of these cytokines on the immune response and on autoimmunity. In several experimental systems (Jurkat T cells, murine T-cell hybridomas), TNF-α appears to cause a downregulation of signaling through the TCR, revealed by changes in calcium flux, activation of p21, p23 and ZAP70, and a decrease in nuclear activation of NF-κB. Previous and present results suggest that TNF-α interferes in some manner with signaling through the TCR, at a locus yet to be delineated. Transgenic expression of LTβR-Fc in nonobese diabetic (NOD) transgenic mice results in prevention of type 1 diabetes in NOD mice as long as the level of expression of the fusion protein (under the control of the cytomegalovirus promoter) remains above a level of 2–3 μg/ml. Once the expression levels of the fusion protein have dropped below this critical level, the diabetic process resumes and the animals become diabetic at 40–50 weeks of age, whereas nontransgenic littermates develop diabetes by 25–30 weeks of age. The paradoxical effects of neonatal TNF-α administration in NOD mice in increasing incidence of and hastening onset of type 1 diabetes, while neonatal anti-TNF administration completely prevents all signs of islet cell autoimmunity, are due partly to the low levels of CD4+CD25+ T cells in NOD mice. These low levels are reduced by a further 50% on neonatal administration of nontoxic levels of TNF-α. In contrast, neonatal administration of anti-TNF-α results in a dramatic increase in the levels of CD4+CD25+ regulatory T cells, to levels beyond those seen in wild-type untreated NOD mice. TNF-α and LTα/β thus have pleomorphic regulatory effects on the development and expression of autoimmunity.
doi:10.1186/ar570
PMCID: PMC3240146  PMID: 12110133
autoimmunity; immunity; lymphotoxin α/β; tumor necrosis factor alpha
41.  HLA-B27: natural function and pathogenic role in spondyloarthritis 
Arthritis Research  2002;4(Suppl 3):S153-S158.
Chapter summary
The human leukocyte antigen HLA-B27 is strongly associated with development of a group of inflammatory arthritides collectively known as the spondyloarthritides. We have set out to define the natural immunological function of HLA-B27, and then to apply this knowledge to understand its pathogenic role. Human leukocyte antigen class 1 molecules bind antigenic peptides for cell surface presentation to cytotoxic T lymphocytes. HLA-B27 binds and presents peptides from influenza, HIV, Epstein-Barr virus, and other viruses. This leads to vigorous and specific cytotoxic T lymphocyte responses, which play an important role in the body's immune response to these viruses. HLA-B27 thus carries out its natural function highly effectively. Although many theories have been proposed to explain the role of HLA-B27 in the pathogenesis of spondyloarthropathy, we favour those postulating that the pathogenic role of HLA-B27 stems from its natural function. For example, the 'arthritogenic' peptide hypothesis suggests that disease results from the ability of HLA-B27 to bind a unique peptide or a set of antigenic peptides. Additionally, a number of lines of evidence from our laboratory and other laboratories have suggested that HLA-B27 has unusual cell biology. We have recently demonstrated that HLA-B27 is capable of forming disulfide-bonded homodimers. These homodimers are expressed on the cell surface and are ligands for a number of natural killer and related immunoreceptors, expressed on a variety of cell types including natural killer cells, T lymphocytes and B lymphocytes, and members of the monocyte/macrophage lineage. We are currently investigating the possibility that such interactions could be involved in disease pathogenesis.
doi:10.1186/ar571
PMCID: PMC3240147  PMID: 12110134
cytotoxic C cell; HLA-B27; peptide; spondyloarthritis
42.  Matrix metalloproteinases in arthritic disease 
Arthritis Research  2002;4(Suppl 3):S39-S49.
Chapter summary
The role of matrix metalloproteinases in the degradative events invoked in the cartilage and bone of arthritic joints has long been appreciated and attempts at the development of proteinase inhibitors as potential therapeutic agents have been made. However, the spectrum of these enzymes orchestrating connective tissue turnover and general biology is much larger than anticipated. Biochemical studies of the individual members of the matrix metalloproteinase family are now underway, ultimately leading to a more detailed understanding of the function of their domain structures and to defining their specific role in cellular systems and the way that they are regulated. Coupled with a more comprehensive and detailed study of proteinase expression in different cells of joint tissues during the progress of arthritic diseases, it will be possible for the future development and application of highly specific proteinase inhibitors to be directed at specific key cellular events.
doi:10.1186/ar572
PMCID: PMC3240148  PMID: 12110122
matrix metalloproteinases; osteoarthritis; proteinase inhibitors; rheumatoid arthritis
43.  Engineering of tissue inhibitor of metalloproteinases mutants as potential therapeutics 
Arthritis Research  2002;4(Suppl 3):S51-S61.
Chapter summary
Matrix metalloproteinases (MMPs) play a central role in many biological processes such as development, morphogenesis and wound healing, but their unbalanced activities are implicated in numerous disease processes such as arthritis, cancer metastasis, atherosclerosis, nephritis and fibrosis. One of the key mechanisms to control MMP activities is inhibition by endogenous inhibitors called tissue inhibitors of metalloproteinases (TIMPs). This review highlights the structures and inhibition mechanism of TIMPs, the biological activities of TIMPs, the unique properties of TIMP-3, and the altered specificity towards MMPs achieved by mutagenesis. A potential therapeutic use of TIMP variants is discussed.
doi:10.1186/ar573
PMCID: PMC3240149  PMID: 12110123
aggrecanase; collagenase; extracellular matrix; matrix metalloproteinases; proteinase inhibitor
44.  Chemokine receptors on dendritic cells promote autoimmune reactions 
Arthritis Research  2002;4(Suppl 3):S183-S188.
Chapter summary
This paper presents a brief review of several lines of evidence suggesting that chemokine receptors on dendritic cells play an important role in breaking tolerance to self and in inducing autoimmunity. First, we have shown that an idiotypic self-antigen obtained from malignant murine lymphomas, when covalently linked to selected chemokines or defensins that interact with receptors on immature dendritic cells (iDCs), has the capacity to break tolerance to self and induce humoral or cell-mediated anti-tumor responses. Since unlinked antigens mixed with the same chemokines or defensins or antigens fused with a mutant ligand deficient in receptor-binding capacity were not immunogenic, we propose that delivery of an antigen coupled to a ligand for receptors on iDCs promotes the processing and subsequent presentation of the antigen, resulting in immunoadjuvant effects. In a second study, we observed that two of five aminoacyl tRNA synthetases (aaRSs) – which act as autoantigens to which some patients with myositis have autoantibodies – were chemotactic for activated monocytes, T cells, and iDCs. These aaRSs interacted with either CC chemokine receptor (CCR)5 or CCR3, as was shown by desensitization with chemokines and the response of cell lines transfected with the chemokine receptor. Presumably, these autoantigens therefore have the capacity to attract inflammatory cells, including iDCs, to infiltrate affected muscle cells. These observations suggest the hypothesis that antigens delivered to receptors on iDCs are potent immunogens capable of breaking self-tolerance to tumor antigens to induce autoimmune diseases.
doi:10.1186/ar574
PMCID: PMC3240150  PMID: 12110138
aminoacyl + RNA synthetase; autoimmune myositis; chemokine receptors; dendritic cells; idiotypic lymphoma antigen
45.  Angiogenesis in rheumatoid arthritis 
Arthritis Research  2002;4(Suppl 3):S81-S90.
Chapter Summary
The expansion of the synovial lining of joints in rheumatoid arthritis (RA) and the subsequent invasion by the pannus of underlying cartilage and bone necessitate an increase in the vascular supply to the synovium, to cope with the increased requirement for oxygen and nutrients. The formation of new blood vessels – termed 'angiogenesis' – is now recognised as a key event in the formation and maintenance of the pannus in RA. This pannus is highly vascularised, suggesting that targeting blood vessels in RA may be an effective future therapeutic strategy. Disruption of the formation of new blood vessels would not only prevent delivery of nutrients to the inflammatory site, but could also lead to vessel regression and possibly reversal of disease. Although many proangiogenic factors are expressed in the synovium in RA, the potent proangiogenic cytokine vascular endothelial growth factor (VEGF) has been shown to a have a central involvement in the angiogenic process in RA. The additional activity of VEGF as a vascular permeability factor may also increase oedema and hence joint swelling in RA. Several studies have shown that targeting angiogenesis in animal models of arthritis ameliorates disease. Our own study showed that inhibition of VEGF activity in murine collagen-induced arthritis, using a soluble VEGF receptor, reduced disease severity, paw swelling, and joint destruction. Although no clinical trials of anti-angiogenic therapy in RA have been reported to date, the blockade of angiogenesis – and especially of VEGF – appears to be a promising avenue for the future treatment of RA.
doi:10.1186/ar575
PMCID: PMC3240151  PMID: 12110126
angiogenesis; therapy; VEGF
46.  Endothelial activation: intracellular signaling pathways 
Arthritis Research  2002;4(Suppl 3):S109-S116.
Chapter summary
Tumor necrosis factor (TNF) is the prototypic proinflammatory cytokine and endothelial cells are the principal cellular targets of its actions. Here I review the responses of endothelial cells to TNF, with emphasis on the induction of endothelial leukocyte adhesion molecules. I focus on the biochemistry and cell biology of signal transduction in TNF-treated endothelial cells that lead to the expression of adhesion molecules.
doi:10.1186/ar576
PMCID: PMC3240152  PMID: 12110129
adhesion molecules; cytokines; inflammation; leukocytes; tumor necrosis factor
47.  Epidemiology and genetics of rheumatoid arthritis 
Arthritis Research  2002;4(Suppl 3):S265-S272.
Chapter summary
The prevalence of rheumatoid arthritis (RA) is relatively constant in many populations, at 0.5–1.0%. However, a high prevalence of RA has been reported in the Pima Indians (5.3%) and in the Chippewa Indians (6.8%). In contrast, low occurrences have been reported in populations from China and Japan. These data support a genetic role in disease risk. Studies have so far shown that the familial recurrence risk in RA is small compared with other autoimmune diseases. The main genetic risk factor of RA is the HLA DRB1 alleles, and this has consistently been shown in many populations throughout the world. The strongest susceptibility factor so far has been the HLA DRB1*0404 allele. Tumour necrosis factor alleles have also been linked with RA. However, it is estimated that these genes can explain only 50% of the genetic effect. A number of other non-MHC genes have thus been investigated and linked with RA (e.g. corticotrophin releasing hormone, oestrogen synthase, IFN-γ and other cytokines). Environmental factors have also been studied in relation to RA. Female sex hormones may play a protective role in RA; for example, the use of the oral contraceptive pill and pregnancy are both associated with a decreased risk. However, the postpartum period has been highlighted as a risk period for the development of RA. Furthermore, breastfeeding after a first pregnancy poses the greatest risk. Exposure to infection may act as a trigger for RA, and a number of agents have been implicated (e.g. Epstein–Barr virus, parvovirus and some bacteria such as Proteus and Mycoplasma). However, the epidemiological data so far are inconclusive. There has recently been renewed interest in the link between cigarette smoking and RA, and the data presented so far are consistent with and suggestive of an increased risk.
doi:10.1186/ar578
PMCID: PMC3240153  PMID: 12110146
environment; family studies; HLA; occurrence; rheumatoid arthritis
48.  Therapy of systemic lupus erythematosus: a look into the future 
Arthritis Research  2002;4(Suppl 3):S25-S30.
This manuscript is dedicated to Professor Tiny Maini in admiration of his grand mind and great work, in thankful appreciation of the numerous hours of our scientific debates, discussions on the future of rheumatology, and great personal enjoyment over the past 15 years, and with sincere gratitude for his support, guidance, and friendship over so many years.
Chapter Summary
The prognosis for patients with systemic lupus erythematosus has greatly improved over the past two decades. However, therapies that are more effective and that have fewer sequelae are needed to rescue patients from organ failure and further reduce mortality. Research under way, including that into induction of tolerance to self-antigens, prevention of the consequences of pathogenic autoantibody production, interference with the cytokine network and signal transduction, the identification and treatment of any infectious triggers, and stem cell therapy, offers hope of improved remedies or even of cure. Given the fact that a number of biological therapies for rheumatologic disease are already in use or are in the development stage, such progress may come soon.
doi:10.1186/ar579
PMCID: PMC3240154  PMID: 12110120
systemic lupus erythematosus; therapy
49.  Humanized mice as a model for rheumatoid arthritis 
Arthritis Research  2002;4(Suppl 3):S133-S140.
Chapter Summary
Genetic susceptibility to rheumatoid arthritis (RA), a common autoimmune disease, is associated with certain HLA-DR4 alleles. Treatments are rarely curative and are often tied to major side effects. We describe the development of a humanized mouse model wherein new, less toxic, vaccine-like treatments for RA might be pretested. This model includes four separate transgenes: HLA-DR*0401 and human CD4 molecules, a RA-related human autoantigenic protein (HCgp-39), and a T-cell receptor (TCRαβ) transgene specific for an important HCgp-39 epitope, eliciting strong Th1 responses in the context of HLA-DR*0401.
doi:10.1186/ar580
PMCID: PMC3240155  PMID: 12110132
autoimmunity; HCgp-39; HLA-DR4 transgenic mice; rheumatoid arthritis; T-cell receptor transgenic mice
50.  Signaling crosstalk between RANKL and interferons in osteoclast differentiation 
Arthritis Research  2002;4(Suppl 3):S227-S232.
Chapter summary
Regulation of osteoclast differentiation is an aspect central to the understanding of the pathogenesis and the treatment of bone diseases such as autoimmune arthritis and osteoporosis. In fact, excessive signaling by RANKL (receptor activator of nuclear factor κB ligand), a member of the tumor necrosis factor (TNF) family essential for osteoclastogenesis, may contribute to such pathological conditions. Here we summarize our current work on the negative regulation of osteoclastogenesis by unique signaling crosstalk between RANKL and interferons (IFNs). First, activated T cells maintain bone homeostasis by counterbalancing the action of RANKL through production of IFN-γ. This cytokine induces rapid degradation of the RANK (receptor activator of nuclear factor κB) adapter protein TRAF6 (TNF-receptor-associated factor 6), resulting in strong inhibition of the RANKL-induced activation of NF-κB and JNK (c-Jun N-terminal kinase). Second, RANKL induces the IFN-β gene but not IFN-α genes, in osteoclast precursor cells, and that IFN-β strongly inhibits the osteoclast differentiation by interfering with the RANKL-induced expression of c-Fos. The series of in vivo experiments revealed that these two distinct IFN-mediated regulatory mechanisms are both important to maintain homeostasis of bone resorption. Collectively, these studies revealed novel aspects of the two types of IFN, beyond their original roles in the immune response, and may offer a molecular basis for the treatment of bone diseases.
doi:10.1186/ar581
PMCID: PMC3240156  PMID: 12110142
arthritis; interferon; osteoclast; osteoporosis; RANKL

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