The role of the T cell in autoimmune inflammation

T cells, in particular CD4+ T cells, have been implicated in mediating many aspects of autoimmune inflammation. However, current evidence suggests that the role played by CD4+ T cells in the development of rheumatoid inflammation exceeds that of activated proinflammatory T-helper (Th)1 effector cells that drive the chronic autoimmune response. Subsets of CD4+ T cells with regulatory capacity, such as CD25+ regulatory T (Treg) cells and Th2 cells, have been identified, and recent observations suggest that in rheumatoid arthritis the function of these regulatory T cells is severely impaired. Thus, in rheumatoid arthritis, defective regulatory mechanisms might allow the breakdown of peripheral tolerance, after which the detrimental Th1-driven immune response evolves and proceeds to chronic inflammation. Here, we review the functional abnormalities and the contribution of different T cell subsets to rheumatoid inflammation.     

Endothelial cell phenotypes in the rheumatoid synovium: activated,angiogenic, apoptotic and leaky

Endothelial cells are active participants in chronic inflammatory diseases. These cells undergo phenotypic changes that can be characterised as activated, angiogenic, apoptotic and leaky. In the present review, these phenotypes are described in the context of human rheumatoid arthritis as the disease example. Endothelial cells become activated in rheumatoid arthritis pathophysiology, expressing adhesion molecules and presenting chemokines, leading to leukocyte migration from the blood into the tissue. Endothelial cell permeability increases, leading to oedema formation and swelling of the joints. These cells proliferate as part of the angiogenic response and there is also a net increase in the turnover of endothelial cells since the number of apoptotic endothelial cells increases. The endothelium expresses various cytokines, cytokine receptors and proteases that are involved in angiogenesis, proliferation and tissue degradation. Associated with these mechanisms is a change in the spectrum of genes expressed, some of which are relatively endothelial specific and others are widely expressed by other cells in the synovium. Better knowledge of molecular and functional changes occurring in endothelial cells during chronic inflammation may lead to the development of endothelium-targeted therapies for rheumatoid arthritis and other chronic inflammatory diseases.     

Apigenin-induced apoptosis is mediated by reactive oxygen species and activation of ERK1/2 in rheumatoid fibroblast-like synoviocytes

Fibroblast-like synovial cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA), as these cells are involved in inflammation and joint destruction. Apigenin, a dietary plant-flavonoid, is known to have many functions in animal cells including anti-proliferative and anticancer activities, but its role in human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) has not been reported. In this study, we investigated the roles of apigenin in RA-FLSs. The survival rate decreased, and apoptotic cell death was induced by apigenin treatment in RA-FLSs. Apigenin treatment resulted in activation of the mitogen-activated protein kinase (MAPK) ERK1/2, and pretreatment with an ERK inhibitor PD98059 dramatically reduced apigenin-induced apoptosis. We found that apigenin-mediated production of a large amount of intracellular reactive oxygen species (ROS) caused activation of ERK1/2 and apoptosis; treatment with the antioxidant Tiron strongly inhibited the apigenin-induced generation of ROS, phosphorylation of ERK1/2, and apoptotic cell death. Apigenin-induced apoptotic cell death was mediated through activation of the effectors caspase-3 and caspase-7, and was blocked by pretreatment with Z-VAD-FMK (a pan-caspase inhibitor). These results showed that apigenin-induced ROS and oxidative stress-activated ERK1/2 caused apoptotic cell death in apigenin-treated RA-FLSs.     

IL-17 and Th17 cells in human inflammatory diseases

IL-17 was discovered in 1995/96 as a T cell derived cytokine with effects on inflammation and neutrophil activation. In 2006, the precise cell source of IL-17 was identified in the mouse, and these cells were named Th17 cells. They play a role in various human diseases associated with inflammation and destruction such as rheumatoid arthritis, psoriasis, Crohn's disease, multiple sclerosis, where IL-17 can be seen as a therapeutic target.     

Cells of the synovium in rheumatoid arthritis. Synovial fibroblasts

For some time synovial fibroblasts have been regarded simply as innocent synovial cells, mainly responsible for synovial homeostasis. During the past decade, however, a body of evidence has accumulated illustrating that rheumatoid arthritis synovial fibroblasts (RASFs) are active drivers of joint destruction in rheumatoid arthritis. Details regarding the intracellular signalling cascades that result in long-term activation and synthesis of proinflammatory molecules and matrix-degrading enzymes by RASFs have been analyzed. Molecular, cellular and animal studies have identified various interactions with other synovial and inflammatory cells. This expanded knowledge of the distinct role played by RASFs in the pathophysiology of rheumatoid arthritis has moved these fascinating cells to the fore, and work to identify targeted therapies to inhibit their joint destructive potential is underway.     

New insights into the role of mast cells in autoimmunity: Evidence for a common mechanism of action?

Mast cells are classically considered innate immune cells that act as first responders in many microbial infections and have long been appreciated as potent contributors to allergic reactions. However, recent advances in the realm of autoimmunity have made it clear that these cells are also involved in the pathogenic responses that exacerbate disease. In the murine models of multiple sclerosis, rheumatoid arthritis and bullous pemphigoid, both the pathogenic role of mast cells and some of their mechanisms of action are shared. Similar to their role in infection and a subset of allergic responses, mast cells are required for the efficient recruitment of neutrophils to sites of inflammation. Although this mast cell-dependent neutrophil response is protective in infection settings, it is postulated that neutrophils promote local vascular permeability and facilitate the entry of inflammatory cells that enhance tissue destruction at target sites. However, there is still much to learn. There is little information regarding mechanisms of mast cell activation in disease. Nor is it known how many mast cell-derived mediators are relevant and whether interactions with other cells are implicated in these diseases including T cells, B cells and astrocytes. Here we review the current state of knowledge about mast cells in autoimmune disease. We also discuss findings regarding newly discovered mast cell actions and factors that modulate mast cell function. We speculate that much of this new information will ultimately contribute to a greater understanding of the full range of mast cell actions in autoimmunity. This article is part of a Special Issue entitled: Mast cells in inflammation.     

Rheumatoid arthritis: regulation of synovial inflammation

Rheumatoid arthritis (RA) is a systemic, inflammatory autoimmune disorder that presents as a symmetric polyarthritis associated with swelling and pain in multiple joints, often initially occurring in the joints of the hands and feet. Articular inflammation causes activation and proliferation of the synovial lining, expression of inflammatory cytokines, chemokine-mediated recruitment of additional inflammatory cells, as well as B cell activation with autoantibody production. A vicious cycle of altered cytokine and signal transduction pathways and inhibition of programmed cell death contribute to synoviocyte and osteoclast mediated cartilage and bone destruction. A combination of targeted interventions at various stages in the pathogenesis of RA will likely be required to control symptoms in certain patients with this complex and potentially disabling disease. The regulation of rheumatoid synovial inflammation will be reviewed, followed by a brief summary of the therapeutic implications of these advances, including strategies targeting key cytokines, signal transduction molecules, co-stimulatory molecules, B cells, chemokines, and adhesion molecules.     

IL-23 induces human osteoclastogenesis via IL-17 <Emphasis Type="Italic">in vitro</Emphasis>, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.     

Vasculitis: mechanisms involved and clinical manifestations

Systemic vasculitis, an inflammatory necrotizing disease of the blood vessel walls, can occur secondary to autoimmune diseases, including connective tissue diseases. Various pathogenic mechanisms have been implicated in the induction of vasculitis, including cell-mediated inflammation, immune complex-mediated inflammation and autoantibody-mediated inflammation. This inflammatory activity is believed to contribute to accelerated atherosclerosis, and also leads to increased risk for cardiovascular events in patients with rheumatoid arthritis and systemic lupus erythematosus. Endothelial cell activation is a common pathogenic pathway in the systemic vasculitis associated with rheumatoid arthritis and systemic lupus erythematosus, with elevated levels of endothelin-1 potentially inducing vascular dysregulation.     

Sulfuretin, a major flavonoid isolated from Rhus verniciflua, ameliorates experimental arthritis in mice

AimSulfuretin, a major flavonoid isolated from Rhus verniciflua, is known to have anti-inflammatory effects. However, the mechanisms underlying the anti-inflammatory effect of sulfuretin on rheumatoid arthritis have not been elucidated. In this study we investigated whether sulfuretin treatment modulates the severity of arthritis in an experimental model.Main methodsWe evaluated the effects of sulfuretin on tumor necrosis factor-α (TNF-α)-treated human rheumatoid fibroblast-like synoviocytes (FLS) in vitro and on collagen-induced arthritis (CIA) mice in vivo.Key findingsIn vitro experiments demonstrated that sulfuretin suppressed the chemokine production, matrix metalloproteinase secretion, and cell proliferation induced by tumor necrosis factor-α in rheumatoid FLS. In addition, sulfuretin inhibited the osteoclast differentiation induced by macrophage colony-stimulating factor and receptor activator of NF-κB ligand in bone marrow macrophages. In mice with CIA, early intervention with sulfuretin prevented joint destruction, as evidenced by a lower cumulative disease incidence and an absence of diverse disease features based on hind paw thickness, radiologic and histopathologic findings, and inflammatory cytokine levels. In mice with established arthritis, sulfuretin treatment significantly reduced synovial inflammation and joint destruction. The in vitro and in vivo protective effects of sulfuretin were mediated by inhibition of the NF-κB signaling pathway.SignificanceThese results suggest that using sulfuretin to block the NF-κB pathway in rheumatoid joints reduces both inflammatory responses and joint destruction. Therefore, sulfuretin may have therapeutic value in preventing or delaying the progression of rheumatoid arthritis.     

Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis.

Synovial tissue affected by rheumatoid arthritis is characterized by proliferation, which leads to irreversible cartilage and bone destruction. Current and experimental treatments have been aimed mainly at correcting the underlying immune abnormalities, but these treatments often prove ineffective in preventing the invasive destruction. We studied the expression of cyclin-dependent kinase inhibitors in rheumatoid synovial cells as a means of suppressing synovial cell proliferation. Synovial cells derived from hypertrophic synovial tissue readily expressed p16INK4a when they were growth-inhibited. This was not seen in other fibroblasts, including those derived from normal and osteoarthritis-affected synovial tissues. In vivo adenoviral gene therapy with the p16INK4a gene efficiently inhibited the pathology in an animal model of rheumatoid arthritis. Thus, the induction of p16INK4a may provide a new approach to the effective treatment of rheumatoid arthritis.     

Recent developments in the immunobiology of rheumatoid arthritis

Progress into the understanding of immunopathology in rheumatoid arthritis is reviewed in the present article with regard to pro-inflammatory cytokine production, cell activation and recruitment, and osteoclastogenesis. Studies highlight the potential importance of T helper 17 cells and regulatory T cells in driving and suppressing inflammation in rheumatoid arthritis, respectively, and highlight other potential T-cell therapeutic targets. The genetic associations of the HLA shared epitope alleles with antibodies to citrullinated peptides in rheumatoid arthritis patients indicate that T cells are providing help to B cells to produce autoantibodies, and there is increasing evidence that these autoantibodies are pathogenic in rheumatoid arthritis.     

High avidity autoreactive T cells with a low signalling capacity through the T-cell receptor: central to rheumatoid arthritis pathogenesis?

Self-reactive T cells with low signalling capacity through the T-cell receptor were recently observed in the SKG mouse model of rheumatoid arthritis (RA) and have been linked to a spontaneous mutation in the ZAP-70 signal transduction molecule. Here we hypothesize that similar mechanisms also drive RA, associated with an abnormal innate and adaptive immune response driven by nuclear factor-kappaB activation and tumour necrosis factor secretion. Similar to the essential role played by pathogens in SKG mice, we propose that HLA-associated immunity to chronic viral infection is a key factor in the immune dysregulation and joint inflammation that characterize RA.     

Apoptosis as a target for gene therapy in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovial joints resulting from hyperplasia of synovial fibroblasts and infiltration of lymphocytes, macrophages and plasma cells, all of which manifest signs of activation. All these cells proliferate abnormally, invade bone and cartilage, produce an elevated amount of pro-inflammatory cytokines, metalloproteinases and trigger osteoclast formation and activation. Some of the pathophysiological consequences of the disease may be explained by the inadequate apoptosis, which may promote the survival of autoreactive T cells, macrophages or synovial fibroblasts. Although RA does not result from single genetic mutations, elucidation of the molecular mechanisms implicated in joint destruction has revealed novel targets for gene therapy. Gene transfer strategies include inhibition of pro-inflammatory cytokines, blockade of cartilage-degrading metalloproteinases, inhibition of synovial cell activation and manipulation of the Th1-Th2 cytokine balance. Recent findings have iluminated the idea that induction of apoptosis in the rheumatoid joint can be also used to gain therapeutic advantage in the disease. In the present review we will discuss different strategies used for gene transfer in RA and chronic inflammation. Particularly, we will high-light the importance of programmed cell death as a novel target for gene therapy using endogenous biological mediators, such as galectin-1, a beta-galactoside-binding protein that induces apoptosis of activated T cells and immature thymocytes.     

How does infliximab work in rheumatoid arthritis?

Since the initial characterization of tumor necrosis factor alpha (TNFalpha), it has become clear that TNFalpha has diverse biologic activity. The realization that TNFalpha plays a role in rheumatoid arthritis (RA) has led to the development of anti-TNF agents for the treatment of RA. Infliximab, a chimeric monoclonal antibody that specifically, and with high affinity, binds to TNFalpha and neutralizes the cytokine, is currently approved for the treatment of RA and Crohn's disease, another immune-inflammatory disorder. In addition to establishing the safety and efficacy of infliximab, clinical research has also provided insights into the complex cellular and cytokine-dependent pathways involved in the pathophysiology of RA, including evidence that supports TNFalpha involvement in cytokine regulation, cell recruitment, angiogenesis, and tissue destruction.     

Genetic epidemiology of rheumatoid arthritis: what to expect from Latin America?

Rheumatoid arthritis is a chronic and systemic autoimmune disease characterized by inflammation and destruction of the synovial joints. It affects approximately 0.5% of the Latin-American population and is three times more common in women than in men. Evidence of familial aggregation (lambdas=2-17) was the first indication of a genetic susceptibility to disease. As in other autoimmune diseases, it has a complex genetic basis. Results from whole-genome scans indicate that the HLA region contains a significant and consistent set of linked loci. However, HLA accounts for only one-third of the genetic susceptibility of disease, indicating that non-HLA genes are also involved in the disease susceptibility. In Latin-America, association with HLA-DRB1*0404 and TNF -308A alleles has been uniformly established; however, many other candidate genes remain to be studied. The identification of genetic factors conferring susceptibility to rheumatoid arthritis will contribute to the knowledge of the pathogenic mechanisms, ability to predict its occurrence, the development of diagnostic tools, prognosis, and treatment. The genetic epidemiology of rheumatoid arthritis is herein reviewed; a set of recommendations is provided for the design, analysis and interpretation of genetic association studies in the context of Latin-American populations.     

Toll-like receptor 4 is involved in inflammatory and joint destructive pathways in collagen-induced arthritis in DBA1J mice

In rheumatoid arthritis, a significant proportion of cytokine and chemokine synthesis is attributed to innate immune mechanisms. TLR4 is a prominent innate receptor since several endogenous ligands known to activate the innate immune system bind to it and may thereby promote joint inflammation. We generated TLR4 deficient DBA1J mice by backcrossing the TLR4 mutation present in C3H/HeJ strain onto the DBA1J strain and investigated the course of collagen-induced arthritis in TLR4 deficient mice in comparison to wild type littermates. The incidence of collagen- induced arthritis was significantly lower in TLR4 deficient compared to wild type mice (59 percent vs. 100 percent). The severity of arthritis was reduced in the TLR4 deficient mice compared to wild type littermates (mean maximum score 2,54 vs. 6,25). Mice deficient for TLR4 were virtually protected from cartilage destruction, and infiltration of inflammatory cells was reduced compared to wt mice. In parallel to the decreased clinical severity, lower anti-CCP antibody concentrations and lower IL-17 concentrations were found in the TLR4 deficient mice. The study further supports the role of TLR4 in the propagation of joint inflammation and destruction. Moreover, since deficiency in TLR4 led to decreased IL-17 and anti-CCP antibody production, the results indicate a link between TLR4 stimulation and the adaptive autoimmune response. This mechanism might be relevant in human rheumatoid arthritis, possibly in response to activating endogenous ligands in the affected joints.     

sTNFR-IgGFc融合基因在内皮细胞中的表达及其对小鼠关节炎模型的基因治疗研究

可溶性肿瘤坏死因子受体(sTNFR)可以拮抗肿瘤坏死因子的活性,因此已被用来治疗与TNF相关的炎性疾病。本研究将sTNFR与IgGFc片段的融合蛋白基因克隆到真核表达载体pStar上,转染到人的内皮细胞中,获得了表达。表达的sTNFR-IgGFc能够拮抗TNFα对L929细胞的细胞毒活性。将该质粒DNA与脂质体混合,经尾静脉注射到Ⅱ型胶原诱导的关节炎小鼠体内后,应用RT-PCR在鼠的肝脏检测到了sTNFR-IgGFc的表达,并显著地改善了治疗组小鼠关节炎症状和病理反应。这表明抗TNF基因治疗有可能作为治疗类风湿性关节炎的新的途径。     

Lack of reactive oxygen species breaks T cell tolerance to collagen type II and allows development of arthritis in mice

The view on reactive oxygen species (ROS) in inflammation is currently shifting from being considered damaging toward having a more complex role in regulating inflammatory reactions. We recently demonstrated a role of ROS in regulation of animal models for the autoimmune disease rheumatoid arthritis. Low levels of ROS production, due to a mutation in the Ncf1 gene coding for the Ncf1 (alias p47(phox)) subunit of the NADPH oxidase complex, was shown to be associated with increased autoimmunity and arthritis severity in both rats and mice. To further investigate the role of ROS in autoimmunity, we studied transgenic mice expressing collagen type II (CII) with a mutation (D266E) in the immunodominant epitope that mimics the rat and human CII (i.e., mutated mouse collagen or MMC). This mutation results in a stronger binding of the epitope to the MHC class II molecule and leads to more pronounced tolerance and resistance to arthritis induced with rat CII. When the Ncf1 mutation was bred into these mice, tolerance was broken, resulting in enhanced T cell autoreactivity, high titers of anti-CII Abs, and development of severe arthritis. These findings highlight the importance of a sufficient ROS production in maintenance of tolerance to self-Ags, a central mechanism in autoimmune diseases such as rheumatoid arthritis. This is important as we, for the first time, can follow the effect of ROS on molecular mechanisms where T cells are responsible for either protection or promotion of arthritis depending on the level of oxygen species produced.     

Long non‐coding RNAs in rheumatoid arthritis

Rheumatoid arthritis, a disabling autoimmune disease, is associated with altered gene expression in circulating immune cells and synovial tissues. Accumulating evidence has suggested that long non‐coding RNAs (lncRNAs), which modulate gene expression through multiple mechanisms, are important molecules involved in immune and inflammatory pathways. Importantly, many studies have reported that lncRNAs can be utilized as biomarkers for disease diagnosis and prognostication. Recently, dysregulation of lncRNAs in rheumatoid arthritis and other autoimmune diseases has been revealed. Experimental studies also confirmed their crosstalk with matrix metalloproteinases, nuclear factor‐κB signalling and T‐cell response pertinent to autoimmunity and inflammation. Circulating lncRNAs, such as HOTAIR, differentiated patients with rheumatoid arthritis from healthy subjects. Taken together, lncRNAs are good candidates as biomarkers and therapeutic targets in rheumatoid arthritis. Further investigation on in vivo delivery of these regulatory molecules and large‐cohort validation of their clinical applicability may be useful.