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REVIEW ARTICLE
Year : 2013  |  Volume : 138  |  Issue : 5  |  Page : 717-731

Temporal cytokine expression and the target organ attributes unravel novel aspects of autoimmune arthritis


Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD, USA

Date of Submission22-Nov-2012
Date of Web Publication9-Jan-2014

Correspondence Address:
Kamal D Moudgil
Professor, Department of Microbiology & Immunology, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF-1, Suite 380, Baltimore, MD 21201
USA
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Source of Support: None, Conflict of Interest: None


PMID: 24434324

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   Abstract 

Susceptibility to autoimmunity is determined by multiple factors. Defining the contribution of the quantitative versus qualitative aspects of antigen-directed immune responses as well as the factors influencing target organ susceptibility is vital to advancing the understanding of the pathogenesis of autoimmunity. In a series of studies, we have addressed these issues using the adjuvant-induced arthritis (AA) model of human rheumatoid arthritis (RA). Lewis rats are susceptible to AA following immunization with heat-killed Mycobacterium tuberculosis H37Ra, whereas Wistar-Kyoto (WKY) rats of the same MHC (major histocompatibility complex) haplotype are resistant. Comparative studies on these and other susceptible/resistant rodent strains have offered interesting insights into differential cytokine responses in the face of comparable T cell proliferative response to the disease relevant antigens. Study of the cytokine kinetics have also permitted validation of the disease-protective versus disease-aggravating effects of specific cytokines by treatment of rats/mice with those cytokines at different phases of the disease. In regard to the target organ attributes, the migration of arthritogenic leukocytes into the joints; the expression of mediators of inflammation, angiogenesis, and tissue damage; the role of vascular permeability; and the characteristics of vascular endothelial cells have been examined. Further, various inhibitors of angiogenesis are effective in suppressing arthritis. Taken together, the differential cytokine responses and unique attributes of the target organ have revealed novel aspects of disease susceptibility and joint damage in AA. The translation of this basic research in animal models to RA patients would not only advance our understanding of the disease process, but also offer novel avenues for immunomodulation of this disease.

Keywords: Adjuvant arthritis - angiogenesis - arthritis - autoimmunity - cytokines - inflammation - joints - matrix metalloproteinases - regulatory T cells - T helper cells


How to cite this article:
Astry B, Venkatesha SH, Moudgil KD. Temporal cytokine expression and the target organ attributes unravel novel aspects of autoimmune arthritis. Indian J Med Res 2013;138:717-31

How to cite this URL:
Astry B, Venkatesha SH, Moudgil KD. Temporal cytokine expression and the target organ attributes unravel novel aspects of autoimmune arthritis. Indian J Med Res [serial online] 2013 [cited 2021 May 8];138:717-31. Available from: https://www.ijmr.org.in/text.asp?2013/138/5/717/124674


   Introduction Top


The immune system is capable of effectively responding to and containing a wide variety of pathogens (foreign; non-self), while guarding against immune response to the host tissues (self) [1],[2],[3] . However, certain constellations of genetic and environmental factors may result in a breakdown of self tolerance resulting in anti-self immune response (autoreactivity), which if not regulated, can result in immune pathology and dysfunction (autoimmunity). At the cellular level, the induction of autoimmunity is a manifestation of an imbalance between pathogenic effector versus protective regulatory responses. The manifestations of autoimmunity may either be systemic or organ-specific. The traditional view of this dichotomy is based on the distribution of the antigen targeted by the autoimmune response, with widely-distributed autoantigens invoked in systemic diseases, while tissue-restricted self antigens implicated in organ-specific diseases. Although this scheme can explain the distribution of immune pathology in the body in many diseases, but it fails in other situations. The latter instances are those where the autoimmune response is directed against ubiquitously distributed antigens, yet the primary target of autoimmune damage may be limited to a particular tissue/organ [4],[5] .

It is increasingly being realized that the target antigen in organ-specific immunity may not necessarily be unique to that particular tissue/organ. Instead it may be distributed widely and yet the immune pathology may be predominantly focused on one or a few organs. This is illustrated in a couple of animal models of autoimmune arthritis. Adjuvant-induced arthritis (AA) in the rat is a well-studied model of human rheumatoid arthritis (RA) [6],[7] . It can be induced in the Lewis rat by immunization with heat-killed Mycobacterium tuberculosis H37Ra (Mtb). AA is a T cell-mediated disease. Interestingly, immune response against mycobacterial heat-shock protein 65 (Bhsp65) has been implicated in the immunopathogenesis of AA [5],[8],[9],[10],[11],[12],[13],[14] . Given the highly conserved nature of heat-shock proteins (Hsps), the T cells and antibodies directed against Bhsp65 are crossreactive with self hsp65 or other self ligands that mimic the foreign hsp65 epitopes. Further, Mtb also contains other heat-shock proteins besides Bhsp65. Hsp65 and other members of the Hsp60 family have been invoked not only in arthritis but also in multiple sclerosis (MS) and type I diabetes mellitus (T1D) [8],[15],[16],[17] . However, Mtb-immunized Lewis rats develop arthritis without any concurrent autoimmune damage to the central nervous system or the pancreatic β-islet cells. The latter two represent the target organs in MS and T1D, respectively and their corresponding animal models are experimental autoimmune encephalomyelitis and the non-obese diabetic mice.

Another example of the animal model of arthritis in which the autoimmune response is directed against a ubiquitously distributed antigen is the K/BxN model of arthritis [4],[18] . In this model, mice bearing a transgenic T cell receptor (TCR) specific for an epitope within ribonuclease, when crossed with non-obese diabetic (NOD) mice, develop spontaneous arthritis [18] . Interestingly, the above-mentioned TCR fortuitously crossreacts with a glycolytic enzyme, glucose 6-phosphate isomerase (GPI). Thus, spontaneous arthritis in these mice is the result of an autoimmune response against GPI, a widely distributed antigen.

The above examples relating to arthritis and similar ones involving other autoimmune diseases have given credence to the idea that the target organ attributes might play a vital role in their susceptibility to autoimmunity over and above the basic preconditions for the breakdown of self tolerance and the induction of autoreactivity. Broadly, the factors influencing the target organ susceptibility can be grouped into those that are extrinsic to that organ and others that are intrinsic. Extrinsic factors include, for example, the quantitative and qualitative aspects of the immune response generated in the peripheral lymphoid tissue draining the site of antigenic challenge or antigen encounter [12],[19],[20],[21] , and the kinetics of proinflammatory versus anti-inflammatory cytokines during the course of autoimmune arthritis [22],[23] . Intrinsic factors include the angiogenic process associated with arthritis [24],[25] , the local vasculature and its permeability [4] , the characteristics of the vascular endothelium of the joints [26] , and the local release of immunological and biochemical mediators of tissue damage [27],[28],[29],[30] . This article addresses specific examples of both extrinsic and intrinsic factors involved in the target organ damage in autoimmune arthritis. Most of the description is based on the rat AA model. However, at several places, examples from other animal models of arthritis have also been discussed. Further, some basic information has also been included on the subsets of T helper and regulatory T cells, the key pro-inflammatory cytokines, the inducers and regulators of angiogenesis, and the matrix metalloproteinases. All these cellular/soluble mediators play critical roles in the disease process in arthritis.


   Subsets of T helper cells and regulatory T cells involved in the pathogenesis of autoimmunity Top


T helper cells: The majority of animal models of RA are T cell-mediated diseases [29] similar to the human disease [31] . The CD4+ helper T cells play an important role in the initiation and progression of acute inflammation in situations involving immune response to self (autoimmunity) or foreign (e.g. infectious disease) antigens. The cytokines produced by these cells help to facilitate the activation and chemotactic migration of other cell types to the site of inflammation during the immune response. The most widely studied helper CD4+ T cell types are the

T helper 1 (Th1), Th2, and Th17. The cytokines produced by dendritic cells (DC) during an immune response are among the important factors that dictate the differentiation of T helper progenitor cells into specific subsets [32] [Figure 1]. For example, when activated DCs and macrophages produce interleukin (IL)-12, it activates the 'signal transducer and activator of transcription' (STAT) 4 pathway leading to the upregulation of the transcription factor 'T-box expressed in T cells' (T-bet). T-bet induces Th1 cell differentiation resulting in upregulation of interferon (IFN)γ and downregulation of 'GATA binding protein 3' (GATA3) and IL-4[32],[33]. The Th1 cell produces IFNγ and promotes cellular immune response. In contrast, IL-4 signaling through STAT6 leads to a Th2 differentiation, upregulation of GATA3, and downregulation of IFNγ[34] .

The Th2 cells produce IL-4, IL-5, and IL-13 and lead to B cell proliferation and antibody production. In this scheme of the two polar types of Th cells, Th1 and Th2, the immune responses and the diseases associated with them could be categorized as predominantly Th1- or Th2-mediated diseases. With the ability of Th1 to regulate Th2, and vice versa, the Th1-Th2 paradigm provided a fine conceptual framework to comprehend immune responses during health and disease. However, this Th1-Th2 paradigm had to be expanded and revised with the discovery of IL-23, which shares the p40 subunit with IL-12, and thereby was responsible for many of the immune effects that had previously been attributed to IL-12, or the lack of it [35] . In addition, newer cytokines (e.g. IL-17, IL-21, and IL-22) associated with inflammation were reported, which helped envision additional families of Th cells such as Th17 and Th22 [29] . It has now been shown that Th17 cells are involved in many autoimmune diseases once thought to be primarily Th1-driven, including RA [36] . The Th17 cells produce IL-17, IL-21, IL-22, and IL-23, and play a role in RA and mucosal immunity [37] . In mice, the Th17 cells differentiate from naïve T cells in the presence of transforming growth factor (TGF) β and IL-6. This process involves signaling through STAT3 and increased expression of the transcription factor 'retinoic acid receptor-related orphan receptor gamma t' (RORγt)[38]. Alternatively, Th17 cells can differentiate in the presence of IL-21 and TGFβ, as in the case of deficiency of IL-6. However, in the absence of IL-6, T cells preferentially differentiate into Forkhead box p 3 (Foxp3)-expressing CD4+CD25+ Foxp3+ T Reg cells, indicating that IL-6 is a regulator of the balance between Th17- T Reg [39] .

Regulatory T cells: There are several types of regulatory T cells. One of the recent additions to this group is the

T Reg cell. The phenotype of the T Reg is CD4+CD25+Foxp3+. These cells can either differentiate naturally in the thymus (nT Reg ) or be induced in the periphery (iT Reg ). The differentiation of T Reg requires TGFβ[40] . T Reg cells suppress effector cells by producing TGFβ and IL-10 and via cytotoxic T-lymphocyte antigen (CTLA)-4 expressed on their cell surface. A subset of CD8+CD25+ Foxp3+ TReg has also been described [41] . Other regulatory subsets are T r 1 and T h 3 [42] . The T r 1 cell is a CD4+CD25+Foxp3- T cell that requires IL-10 for its differentiation, and it secrets IL-10. The Th3 cell is a regulatory cell associated with the gut mucosa. It was shown to mediate the immunosuppressive effects of tolerance to the antigens administered via oral route (oral tolerance). Th3 cells mediate their suppressive action via secretion of TGFβ[42] . The balance between the effector T cells and the regulatory T cells determines whether or not autoreactive cells can induce an autoimmune response.


   The effector functions of the cytokines that play a key role in arthritis pathogenesis Top


In RA and animal models of arthritis, inflammatory cytokines play a pivotal role in driving the disease process [Table 1]. Accordingly, biologic medications targeting these cytokines are being used for the treatment of arthritis. The cytokines that have been studied extensively are TNFα, IL-1, and IL-6[43]. TNFα has been at the center of RA research for several years because of its vital role in joint destruction and the control over other proinflammatory cytokines. It has been shown that TNFα controls the production of IL-1β and IL-8 by synovial cells[46]. In addition to increasing the release of other cytokines, TNFα can increase cellular infiltration into the synovium by enhancing chemokine expression, endothelial cell activation, and angiogenesis [43]. Finally, TNFα and IL-1 cause bone damage, the hallmark of RA pathogenesis[47],[48]. In animal models of arthritis, IL-1β works in conjunction with IL-6 during the early phases of the disease, acting on endothelial cells to secrete chemokines like IL-8 and monocyte chemotactic protein (MCP)-1 to attract monocytes. IL-6 further upregulates chemokines that attract T cells, leading to enhanced cellular infiltration and beginning the transition from an acute inflammatory disease to a chronic immune disease [49] . These two phases are dominated by innate and adaptive immunity, respectively.
Table 1: Cytokines in autoimmune arthritis

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IL-17 is involved in the inflammatory response and it has been implicated in the pathogenesis of several autoimmune diseases including RA [50] and multiple sclerosis [51]. IL-17 is predominantly produced by the CD4+ Th17 cells. Other sources of IL-17 include CD8+ T cells, γδ T cells, natural killer T (NKT) cells, and lymphoid tissue inducer (LTi) cells [52],[53] . There are six isoforms of IL-17, with IL-17A most commonly referred to as IL-17. IL-17 is a proinflammatory cytokine that plays an important role in inflammation of the synovium during RA. IL-17 can help promote the production of inflammatory cytokines like IL-6 and leukemia inhibitory factor (LIF) [50] , and matrix degrading enzymes, matrix metalloproteinase (MMP) 1 and 3 by synovial fibroblasts [54] . IL-17 also induces osteoclastogenesis by upregulating receptor activator of NFκB (RANK) on osteoclast precursors and its ligand RANKL on the surface of activated T cells, resulting in bone erosion[55] . IL-17 also facilitates cellular infiltration either directly or by increasing the expression of chemokine (C-C motif) ligand (CCL) 20, CXC motif chemokine ligand (CXCL) 12, and CXCL5, and attracting B cells, T cells, neutrophils, and monocytes to the synovium [56],[57],[58] . The pannus formation (cellular infiltration into hyperplastic vascularized synovium) in an arthritic joint is enhanced further by the induction of IL-17-induced angiogenesis [59] .

IL-17 can be regulated by other cytokines. IL-1β, TNFα, and IL-23 increase IL-17 expression[29],[35],[36],[37], while IFNγ decreases IL-17 expression in autoimmune arthritis models[27]. IFNγ has for years been invoked as one of the major proinflammatory cytokines contributing to the pathogenesis of autoimmune diseases until the discovery of IL-17. However, recent studies have unraveled an opposite, anti-inflammatory role of IFNγ in arthritis models[27]. IFNγ-deficient mice showed an exacerbation of autoimmune arthritis and an increase in IL-17 [60]. Similarly, we observed in the adjuvant arthritis model that IFNγ was expressed at the highest levels in the recovery phase of the disease[22] . Further, the treatment of rats either during the incubation phase or after disease onset with exogenous IFNγ reduced disease severity[27]. In addition, pre-treatment of rats with a C-terminal epitope 465-479 of rat heat-shock protein 65 (Rhsp65) suppressed arthritis, increased IFNγ production, but reduced IL-17 expression[22] .

IFNγ functions as a regulatory cytokine, directly as well as indirectly, in autoimmune arthritis. One indirect effect that IFNγ has is the upregulation of IL-27, a cytokine that can reduce IL-17 production. IL-27 is an IL-12 superfamily cytokine, and it can prevent the differentiation of Th17 by reducing both the expression of RORγt and the phosphorylation of STAT3. Both of these transcription factors are integral to the differentiation of Th17[27] . IL-27 is comprised of two subunits, Epstein-Barr virus-induced gene 3 (EBI3) and p28. It is secreted by macrophages, dendritic cells, epithelial cells and a wide range of innate and adaptive immune cells, most notably the CD4+ T cells [61] . In addition to preventing pathogenic T cell differentiation, IL-27 can induce both the expression of program death-ligand 1 (PD-L1), a co-receptor that is a negative regulator of T cell function [56] , and the generation of IL-10-producing Tr1 cells [62] . IL-27 is also able to downregulate the expression of RANK on osteoclast precursors and RANKL on CD14+ cells, causing a decrease in osteoclastogenesis and thereby limiting bone loss [63] . Though the role of IL-27 in autoimmunity has not yet been fully defined, increasing evidence points to its anti-inflammatory and anti-arthritic activities.

Kinetics of cytokine expression during the course of arthritis and its correlation with disease susceptibility versus resistance

Animal models of human RA [29] permit comprehensive experimental studies on the pathogenesis of autoimmunity, including the role of T cells and cytokines in the disease process. Two of the commonly used models of RA are adjuvant arthritis (AA) in rats [7] and collagen-induced arthritis (CIA) in mice/rats [64] . The cytokines released during the course of autoimmune arthritis influence the severity of the pathological and clinical features of the disease [Figure 1] and [Figure 2]. The AA model system has extensively been used to examine the disease-related events at different time points in the course of the disease as well as for testing potential anti-arthritic agents for their therapeutic efficacy and side effects. However, not all rat strains are equally susceptible to autoimmune arthritis. The Lewis rat is highly susceptible to AA, whereas the Wistar-Kyoto (WKY) rat is resistant to arthritis despite having a similar major histocompatibility complex (MHC) haplotype as the Lewis rat [5],[11],[21] . WKY rats provide a good control for Lewis rats for studies on disease pathogenesis. In our studies, we have exploited this pair of rat strains for addressing important aspects of AA, for example, epitope mapping of the disease-related antigen Bhsp65 [5],[11] , cellular migration into the joints [67] , the dynamics and epitope reactivity of antibodies produced during AA [68] , and cytokine responses against Bhsp65 [22],[23],[27],[69] .

In different studies performed in the AA model, cytokine responses have been examined in the draining lymph nodes, spleen, synovial-infiltrating cells (SIC), or joint homogenates. Also, not all time points have been tested in each tissue. This makes it somewhat difficult to directly compare the profiles obtained using one tissue with that derived from another tissue. However, it is understandable that the peripheral lymphoid tissues and SIC might show similarities in certain cytokine responses, but differences in others. A set of representative profiles of pro-/anti-inflammatory cytokines in AA constructed from the results of different studies [22],[23],[27],[65],[66] is shown in [Figure 2]. In rats with AA, the expression of pro-inflammatory cytokines (TNFα, IL-1 and IL-6) showed a gradual increase from the incubation phase to the 'onset' phase. After that point, IL-1 and IL-6, but not TNFα levels decreased during the regression phase. Surprisingly, IL-17 expression was highest in the incubation phase of the disease, but thereafter its levels remained low throughout the disease. In contrast, the expression of IFNγ, IL-27, and IL-10 was low during the early incubation and onset phases of the disease, but it increased during the late stages correlating with disease regression. IL-10 is a well known anti-inflammatory cytokine. Our results point towards a disease-regulating role of IFNγ and IL-27 in AA. IFNγ is considered to be a prototypic pro-inflammatory cytokine. However, our studies have shown that this cytokine also possesses arthritis-suppressive activity [22] . In the case of IL-27, which is among the newer cytokines whose functional attributes have not yet been fully defined, our results [27] clearly demonstrate that it has anti-arthritic activity. For this reason, we have depicted IFNγ, IL-27, and IL-10 under anti-inflammatory cytokines [Figure 2].
Figure 1: CD4+ T cell differentiation and cellular phenotype. Naïve CD4+ T cells can differentiate into several different types of T helper (Th) or regulatory T (Treg or Tr) cells depending on the cytokine environment in which these are activated. The regulating transcription factors of these subsets and their characteristic effector cytokines are shown. (CD, cluster of differentiation; GATA3, GATA binding protein 3; T-bet, T-box expressed in T cells; RORγt, retinoic acid receptor-related orphan receptor gamma; Foxp3, Forkhead box p3; IL, interleukin; IFN, interferon; TGF, transforming growth factor.

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Figure 2: The dynamics of cytokine expression during the course of adjuvant arthritis. Adjuvant arthritis (AA) in the Lewis rat, induced following immunization with heat-killed M. tuberculosis H37Ra, displays distinct phases of the disease. These phases include incubation, onset, peak and regression. Proinflammatory cytokines play a vital role in the initiation and progression of arthritis, whereas anti-inflammatory cytokines facilitate regression of inflammatory arthritis. The levels of cytokines represented by the number of triangles are relative to each phase for that particular cytokine. (IL, interleukin; IFN, interferon; TNF, tumour necrosis factor).
Source: Refs 22, 23, 27, 65, 66


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In contrast to the AA-susceptible Lewis rats, the AA-resistant WKY rats had a different cytokine profile that helped us comprehend the lack of signs of disease following an arthritogenic challenge [27] . The pattern of expression of IL-17 in Wky0 rats was similar to that of Lewis rats. However, unlike Lewis rats, WKY rats also showed highest levels of expression of IL-27 and IFNγ at the same time as that of IL-17. We suggested that the concurrent expression of these two cytokines with IL-17 helped neutralize the pathological effects of IL-17 in WKY rats[27] . In contrast, IL-17 activity was unopposed in the incubation period in the case of Lewis rats, thereby explaining the development of arthritis.

Our results of modulation of AA by treatment of Lewis rats with exogenous cytokine yielded interesting results [27] . The treatment of Lewis rats with IL-17 in the incubation phase of the disease leads to disease aggravation as expected from the pathogenic role of IL-17 in AA. The most interesting finding was the effect of IL-27 treatment on the inhibition of AA. These results demonstrate that IL-27 plays an immunoregulatory role in AA [27]. Surprisingly, the treatment of rats with IFNγ or TNFα also offered protection against AA, showing that the timing of administration of certain cytokines that are typically considered to be proinflammatory (e.g. IFNγ and TNFα) may also lead to the suppression of arthritis [22],[23],[27] . This emphasizes the dual role of these proinflammatory cytokines [69] .

Taking together, studies on the temporal expression of cytokines in the AA-susceptible/-resistant rats have provided important and useful information regarding arthritis development and its deliberate control by cytokine treatment. For example, the cytokine profiles have provided insights into the relative contribution of different cytokines in the initiation and progression of AA, followed by the regression of inflammation [Figure 2]. Further, comparative studies in Lewis/WKY and other AA-susceptible/resistant rodent strains have offered interesting insights into differential cytokine responses in the face of comparable T cell proliferative response to the disease-related antigens. In addition, such studies have underscored the significance of the balance between the pro- and anti-inflammatory cytokines in determining (in part) whether arthritic inflammation would result or not following an arthritogenic stimulus, such as Mtb injection. Finally, the study of the cytokine kinetics has also permitted validation of the disease-protective versus disease-aggravating effects of specific cytokines as tested by the treatment of rats/mice at different phases of the disease.


   Cellular migration into the joints and characteristics of the synovial-infiltrating cells Top


Cellular infiltration into the synovium is a characteristic feature of RA. The resulting pannus invades the surrounding bone and cartilage and leads to tissue damage, pain and disability in the affected joints. There are various cell types that infiltrate the synovium of arthritic joints. The T cell migration into the synovium plays an important role in the activation and recruitment of other cell types. Most notably, Th17 cells that migrate into the synovium lead to neutrophil recruitment via IL-17-mediated induction of chemokines [70]. It has recently been shown that IL-17-induced neutrophil recruitment occurs indirectly through TNFα, which binds its receptor TNF receptor (TNFR)1[71] . T reg cells have also been isolated from inflamed synovium [71] , but at present the relative kinetics and frequencies of Th17 and Treg in the joints during the course of arthritis in animal models or RA patients are not yet defined.

Other cell types that are found in arthritic joints are macrophage- and fibroblast-synoviocytes, neutrophils, B cells, dendritic cells, and mast cells [72] . This cellular migration followed by accumulation of cells in the joints correlates with arthritis susceptibility as shown in our comparative study in the AA model using arthritis-susceptible Lewis rats and arthritis-resistant WKy0 rats [67] . Chemokines play an important role in cellular migration into the joints. Chemokines are upregulated by cytokines and can reciprocate, and lead to the increased cytokine expression causing persistent inflammation [73] . As a result, chemokines can be targeted directly or indirectly through the suppression of cytokines to treat RA. We have recently shown that a natural plant product (celastrol) can decrease inflammatory cytokine and chemokine production leading to the inhibition of cell migration and suppression of arthritis in the AA model [74] .


   Angiogenesis and its role in the pathogenesis of arthritis Top


Angiogenesis refers to the formation of new blood vessels from existing vessels, and it facilitates the nourishment and maintenance of growing tissue. Angiogenesis is considered to be one of the key mechanisms that promote chronic joint inflammation in RA [75] . During RA, hyperplastic synovium with immune cell infiltrates forms the pannus, which requires supply of oxygen and nutrients. Angiogenesis contributes to the formation and maintenance of the pannus in RA. The pannus is highly vascularized and it invades the articular cartilage and bone [76] . The actions of cytokines and other mediators of inflammation produced by the synovial-infiltrating cells result in cartilage damage and bone erosion in arthritic joints [76],[77] . Inhibition of angiogenesis by interfering with pathways driven by the vascular endothelial growth factor (VEGF) or other mediators results in delayed onset and reduced severity of arthritis in animal models, such as CIA in mice and AA in rats [78],[79],[80],[81],[82] . These observations provide additional support for the role of angiogenesis in the initiation and propagation of RA.

Angiogenesis involves multiple cell types and complex interplay of mediators and pathways [Table 2]. The formation of new vessels from a pre-existing vessel is a result of a series of events including selective degradation of vascular basement membrane and adjacent extracellular matrix, and migration of endothelial cells leading to tube formation and capillary growth [90],[91] . VEGF is a key factor mediating angiogenesis. The levels of VEGF in the serum and synovial fluid correlate with the severity of RA. High requirement of oxygen in the pannus, the growing tissue in arthritic joints, makes that tissue relatively hypoxic. Hypoxia induces gene expression of pro-angiogenic proteins such as VEGF via the activation of transcription factors known as hypoxia-inducible factors (HIFs) [91] . Activation of HIFs can also occur by proinflammatory cytokines. VEGF in turn recruits monocytes, which differentiate into macrophages and secrete matrix-degrading enzymes known as matrix metalloproteinases (MMPs). VEGF also induces the migration and proliferation of endothelial cells and smooth muscle cells, which lead to the formation of new capillaries [78],[83],[92] . Epidermal growth factor (EGF), fibroblast growth factor-2 (FGF-2), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), and platelet-derived growth factor (PDGF) serve as additional mediators of angiogenesis in RA [25],[92],[93] [Table 2].
Table 2: Mediators and inhibitors of angiogenesis

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Several cytokines such as TGF-β, TNF-α, IL-1, IL-6, IL-8, IL-13, IL-15, and IL-18 modulate the process of angiogenesis[84],[94],[95],[96],[97],[98],[99],[100],[101],[102] [Table 3]. For example, TGF-β and IL-1 stimulate the secretion of VEGF through the activation of HIF. These events are mediated via mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathway. The above-mentioned cytokines further enhance VEGF secretion induced by hypoxia. This cooperation between cytokines and hypoxia facilitates the secretion of large amounts of VEGF by synovial cells in the hypoxic environment in the arthritic joint resulting in increased angiogenesis.
Table 3: MMPs, ADAMTs and cathepsins, and their target molecules

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A variety of chemokines contribute to the angiogenic process in RA [Table 2]. The expression of CXCL12 [or, stromal cell-derived factor 1 (SDF-1)], is influenced by cytokines and hypoxia. SDF-1 in turn facilitates the recruitment of lymphocytes into the arthritic synovium [85] . The chemokine CX3 CL1 (or, fractalkine), also induces angiogenesis [103] . CCL21 (Exodus-2) induces endothelial cell migration and tube formation. These events involve PI3K [104] .

Other mediators that influence angiogenesis include angiogenin, platelet activating factor (PAF), angiopoietin, soluble adhesion molecules, and endothelial mediator endoglin. Further, macrophage migration inhibitory factor (MIF), junctional adhesion molecules (JAMs) and focal adhesion kinases (FAKs) are associated with inflammatory angiogenesis. Serum amyloid A (SAA) and sphingosine kinase have also been invoked in the angiogenic events [25] [Table 2].


   Matrix metalloproteinases (MMPs) and other cartilage-degrading enzymes Top


Articular cartilage, which is made of extracellular matrix (ECM) and chondrocytes, is the major tissue targeted in the joints in RA. In uncontrolled RA, there is a progressive damage to the joints leading to physical disabilities. Cartilage ECM contains primarily proteoglycans, aggrecan and collagen. Aggrecan associates with proteoglycans to form a network of collagen fibers, which are the main structural component of the matrix [105] . Articular cartilage is mainly composed of type II collagen, but it also contains collagen type IX XI and VI. The cartilage matrix also contains leucine-rich proteoglycans, including decorin, fibromodulin and biglycan [105] . Cartilage degradation can be mediated by a variety of proteases including MMPs, cathepsins (B, L, K) and "a disintegrin and metalloproteinase with thrombospondin motifs species" (ADAMTS) [96],[97],[98],[99],[100],[101],[102] [Table 3].

Cartilage degradation involves depletion of aggrecan and breakdown of collagen fibers [100] . Inflammatory immune cells in the joints release proinflammatory cytokines such as IL-1β, TNF-α and IL-17. These cytokines induce expression of MMPs (MMP-1, -2, -3, -7, -8, -9 and -13) and ADAMTS (ADAMTS 1, 4 and 5) in the synovial fibroblasts and chondrocytes[106],[107],[108],[109] . Proinflammatory cytokines are the main inducers of MMPs in these cells [101] . In addition, there is endogenous regulation of these enzymes in synovial fibroblasts. Members of both the MMP and ADAMTS families contribute to aggrecan degradation. Collagen type II resists degradation by most proteases owing to its triple-helical structure. Only MMP-1, -8, and -13 can degrade fibrillar collagens including types I, II and III collagen [110] . Following cleavage of the collagen molecules, the helices are disrupted and collagen is denatured into gelatin. Gelatin then forms the substrate for gelatinases, namely MMP-2 and -9 [96],[97],[110] . Type IX and XI collagens are degraded by MMP-3 and MMP-2 [102] . Other proteinases (cathepsins and ADAMTS) also play a role in the tissue damage in the joints [96],[97],[98],[99],[101],[111] . Inhibition of these enzymes is expected to offer protection against cartilage destruction in RA. Several therapeutic interventions to treat arthritis in animal models have shown to inhibit the activities of MMPs, particularly MMP-9. For example, the treatment of arthritic rats with IL-27 or celastrol has a significant inhibitory effect on MMP-9 activity [27],[28] . (Celastrol is a bioactive component of a Chinese herb, Celastrus and other related plants). In addition, selective MMP inhibitors have been tested for their cartilage-protective effects in experimental models of arthritis [112] . However, there is not much information available on the inhibition of ADAMTS in RA. The development of effective and safe inhibitors of MMPs and ADAMTS would offer new therapeutic agents to limit the joint destruction.

Tissue inhibitors of metalloproteinases (TIMPs) were originally identified as endogenous proteins that regulate MMPs. However, TIMPs also can regulate ADAMTS [113] . Four members of the TIMPs family, namely TIMP1, 2, 3 and 4 have been identified. The expression of TIMPs is tissue specific [113],[114] . At present, there is not much information on the role of TIMPs in RA. TIMPs are also known to influence cell growth and differentiation, cell migration, and angiogenesis, and these effects are independent of their inhibitory effect on MMPs [115] . Imbalance in the ratio of MMPs to TIMPs promotes abnormal degradation of ECM [116] . Therapeutic interventions to treat arthritis in animal models have been shown to maintain the balance between MMPs and TIMPs [117] . For example, Sinomenine, an alkaloid derived from the Chinese medicinal plant, Sinomenium acutum, has been shown to ameliorate CIA in rats by maintaining the balance between MMPs and TIMPs [117] . However, the protective role of TIMPs in RA has yet to be further explored.


   Influence of vascular permeability and vascular endothelial cell characteristics on target organ-directed autoimmunity Top


Recent studies have highlighted the role of vascular permeability of the blood vessels in the joints [4] and that of the fine characteristics of the vascular endothelial cells of the joint vasculature [26] in preferentially directing the systemic autoimmune responses to the joints. The K/BXN model of arthritis represents an autoimmune response against a systemic antigen, GPI. One of the mechanisms proposed for the preferential targeting of the distal joints of the paws invoked a vascular leak [4] . In our study on the AA model in which ubiquitously distributed Bhsp65 has been implicated in arthritis pathogenesis, we identified phage-encoded peptides that preferentially homed to the arthritic joints and showed binding to CD31+ vascular endothelial cells in the inflamed joints [26] . One of the two peptides also possessed anti-arthritic activity in addition to joint-homing attributes. Similarly, another study conducted in immunodeficient mice engrafted with human synovial tissue also reported isolation of synovial-binding peptides selected after the phage screening [118] . Taken together, these studies have opened up new avenues for further exploration of the characteristics of the joint vasculature in rendering the joints preferential targets of autoimmune attack. Additional studies are needed to determine the functional significance of unique attributes of the blood vessels as well as vascular endothelial cells in arthritis besides the much appreciated role of angiogenesis in this disease.


   Therapeutic approaches for the control of autoimmune arthritis Top


RA is an autoimmune disease driven by proinflammatory cytokines. Therefore, if the proinflammatory cytokines can be reduced, the inflammatory component of the disease can be suppressed and the destruction of bone and cartilage limited. Several disease-modifying antirheumatic drugs (DMARDs) are now available for the management of RA patients. These medications target inflammatory mediators and are less toxic compared to other drugs for RA. One of the newer groups of anti-arthritic drugs is biologics, which are based on inhibiting the actions of proinflammatory cytokines. The first group of these drugs targets TNFα- infliximab (a chimeric monoclonal antibody), etanercept (TNFR-Fc) and adalimumab (a human monoclonal antibody)[119],[120]. The anti-TNFα therapy has worked well, but approximately 40 per cent of RA patients fail to respond to this treatment [120],[121]. Accordingly, there are drugs targeting IL-1- Anakinra (recombinant IL-1 receptor antagonist) and AMG 108 (human monoclonal antibody against IL-1β), or IL-6 receptor - Tocilizumab (a human monoclonal antibody against IL-6 receptor). There was excitement with the targeting of IL-1 because IL-1 was shown to be solely responsible for cartilage damage but partially responsible for bone damage in mice transgenic for TNFα but deficient in IL-1 [122]. The IL-1-directed drugs have shown some efficacy in limiting inflammation, but IL-1 inhibition with Anakinra proved to have less bone damage protection than that observed with anti-TNFα treatment[123] .

As research on newer cytokines expands, there are increasing opportunities for new drugs to treat RA. IL-17 plays a critical role in the induction of arthritis [124] . Research on IL-17 has led to the development of a humanized anti-IL17 monoclonal antibody LY2439821, which has gone through phase-I clinical trials to determine patient tolerability and efficacy [125] . This anti-IL-17 antibody added to other DMARDs improved signs and symptoms of RA patients [125] . Since many cytokines signal through the Janus Kinase- Signal Transducer and Activator of Transcription (JAK-STAT) pathway, some new drugs targeting this pathway have been explored as therapeutics. For example, Tofacitinib (a JAK1 and JAK3 inhibitor), showed inhibition of the key cytokines relevant for arthritis, such as IL-17, IL-6 and IL-8 [126] .

Angiogenesis plays an important role in the disease pathogenesis in arthritis. Several endogenous factors that have angiostatic activity are produced by the synovium of arthritic joints [93] , but these factors may fail to effectively control angiogenesis and inflammation associated with arthritis. In this regard, several agents/approaches including some endogenous metabolites are being examined to control angiogenesis for eventual therapeutic use [24],[86],[87],[88],[89] [Table 2].

Finally, complementary and alternative medicine (CAM) products are increasingly being used by arthritis patients, who are seeking alternatives to expensive and toxic conventionally used drugs. Several studies have highlighted the anti-arthritic activity of various natural plant products in experimental models of arthritis [127],[128] . For example, in studies in the AA model, extracts of green tea [129] , celastrus [28],[30],[130] , and huo-luo-xiao-ling dan [131],[132] have been shown to offer protection against arthritis. We hope that a systematic validation of herbal products in RA patients might offer promising adjuncts to conventional drugs for the management of this debilitating disease.


   Acknowledgment Top


This work was supported by NIH grant R01AT004321. Authors thank Eugene Kim, Rajesh Rajaiah, Yinghua Yang, Hua Yu and Siddaraju Nanjundaiah for helpful discussions.

 
   References Top

1.Von Boehmer H. Selection of the T-cell repertoire: receptor-controlled checkpoints in T-cell development. Adv Immunol 2004; 84 : 201-38.  Back to cited text no. 1
    
2.Blackman MA, Kappler JW, Marrack P. T-cell specificity and repertoire. Immunol Rev 1988; 101 : 5-19.  Back to cited text no. 2
    
3.Moudgil KD, Sercarz EE. The self-directed T cell repertoire: its creation and activation. Rev Immunogenet 2000; 2 : 26-37.  Back to cited text no. 3
    
4.Binstadt BA, Patel PR, Alencar H, Nigrovic PA, Lee DM, Mahmood U, et al. Particularities of the vasculature can promote the organ specificity of autoimmune attack. Nat Immunol 2006; 7 : 284-92.  Back to cited text no. 4
    
5.Moudgil KD, Chang TT, Eradat H, Chen AM, Gupta RS, Brahn E, et al. Diversification of T cell responses to carboxy-terminal determinants within the 65-kD heat-shock protein is involved in regulation of autoimmune arthritis. J Exp Med 1997; 185 : 1307-16.  Back to cited text no. 5
    
6.Pearson C. Development of arthritis, periarthritis and periostitis in rats given adjuvants. Proc Soc Exp Biol (NY) 1956; 91 : 95-101.  Back to cited text no. 6
    
7.Taurog JD, Argentieri DC, McReynolds RA. Adjuvant arthritis. Methods Enzymol 1988; 162 : 339-55.  Back to cited text no. 7
    
8.Cohen IR. Autoimmunity to chaperonins in the pathogenesis of arthritis and diabetes. Annu Rev Immunol 1991; 9 : 567-89.  Back to cited text no. 8
    
9.van Eden W, Thole JE, van der Zee R, Noordzij A, van Embden JD, Hensen EJ, et al. Cloning of the mycobacterial epitope recognized by T lymphocytes in adjuvant arthritis. Nature 1988; 331 : 171-3.  Back to cited text no. 9
    
10.Anderton SM, van der Zee R, Prakken B, Noordzij A, van Eden W. Activation of T cells recognizing self 60-kD heat shock protein can protect against experimental arthritis. J Exp Med 1995; 181 : 943-52.  Back to cited text no. 10
    
11.Moudgil KD. Diversification of response to hsp65 during the course of autoimmune arthritis is regulatory rather than pathogenic. Immunol Rev 1998; 164 : 175-84.  Back to cited text no. 11
    
12.Durai M, Gupta RS, Moudgil KD. The T cells specific for the carboxyl-terminal determinants of self (rat) heat-shock protein 65 escape tolerance induction and are involved in regulation of autoimmune arthritis. J Immunol 2004; 172 : 2795-802.  Back to cited text no. 12
    
13.Yu H, Yang YH, Rajaiah R, Moudgil KD. Nicotine-induced differential modulation of autoimmune arthritis in the Lewis rat involves changes in interleukin-17 and anti-cyclic citrullinated peptide antibodies. Arthritis Rheum 2011; 63 : 981-91.  Back to cited text no. 13
    
14.Ulmansky R, Cohen CJ, Szafer F, Moallem E, Fridlender ZG, Kashi Y, et al. Resistance to adjuvant arthritis is due to protective antibodies against heat shock protein surface epitopes and the induction of IL-10 secretion. J Immunol 2002; 168 : 6463-9.  Back to cited text no. 14
    
15.Gao YL, Brosnan CF, Raine CS. Experimental autoimmune encephalomyelitis. Qualitative and semiquantitative differences in heat shock protein 60 expression in the central nervous system. J Immunol 1995; 154 : 3548-56.  Back to cited text no. 15
    
16.Cwiklinska H, Mycko MP, Luvsannorov O, Walkowiak B, Brosnan CF, Raine CS, et al. Heat shock protein 70 associations with myelin basic protein and proteolipid protein in multiple sclerosis brains. Int Immunol 2003; 15 : 241-9.  Back to cited text no. 16
    
17.Rajaiah R, Moudgil KD. Heat-shock proteins can promote as well as regulate autoimmunity. Autoimmun Rev 2009; 8 : 388-93.  Back to cited text no. 17
    
18.Monach P, Hattori K, Huang H, Hyatt E, Morse J, Nguyen L, et al. The K/BxN mouse model of inflammatory arthritis: theory and practice. Methods Mol Med 2007; 136 : 269-82.  Back to cited text no. 18
    
19.Durai M, Kim HR, Bala K, Moudgil KD. T cells against the pathogenic and protective epitopes of heat-shock protein 65 are crossreactive and display functional similarity: Novel aspect of regulation of autoimmune arthritis. J Rheumatol 2007; 34 : 2134-43.  Back to cited text no. 19
    
20.Durai M, Kim HR, Moudgil KD. The regulatory C-terminal determinants within mycobacterial heat shock protein 65 are cryptic and cross-reactive with the dominant self homologs: implications for the pathogenesis of autoimmune arthritis. J Immunol 2004; 173 : 181-8.  Back to cited text no. 20
    
21.Kim EY, Moudgil KD. The determinants of susceptibility/resistance to adjuvant arthritis in rats. Arthritis Res Ther 2009; 11 : 239.  Back to cited text no. 21
    
22.Kim EY, Chi HH, Bouziane M, Gaur A, Moudgil KD. Regulation of autoimmune arthritis by the pro-inflammatory cytokine interferon-gamma. Clin Immunol 2008; 127 : 98-106.  Back to cited text no. 22
    
23.Kim EY, Chi HH, Rajaiah R, Moudgil KD. Exogenous tumour necrosis factor alpha induces suppression of autoimmune arthritis. Arthritis Res Ther 2008; 10 : R38.  Back to cited text no. 23
    
24.Lainer-Carr D, Brahn E. Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis. Nat Clin Pract 2007; 3 : 434-42.  Back to cited text no. 24
    
25.Szekanecz Z, Besenyei T, Szentpetery A, Koch AE. Angiogenesis and vasculogenesis in rheumatoid arthritis. Curr Opin Rheumatol 2010; 22 : 299-306.  Back to cited text no. 25
    
26.Yang YH, Rajaiah R, Ruoslahti E, Moudgil KD. Peptides targeting inflamed synovial vasculature attenuate autoimmune arthritis. Proc Natl Acad Sci USA 2011; 108 : 12857-62.  Back to cited text no. 26
    
27.Rajaiah R, Puttabyatappa M, Polumuri SK, Moudgil KD. Interleukin-27 and interferon-gamma are involved in regulation of autoimmune arthritis. J Biol Chem 2011; 286 : 2817-25.  Back to cited text no. 27
    
28.Venkatesha SH, Yu H, Rajaiah R, Tong L, Moudgil KD. Celastrus-derived celastrol suppresses autoimmune arthritis by modulating antigen-induced cellular and humoral effector responses. J Biol Chem 2011; 286 : 15138-46.  Back to cited text no. 28
    
29.Astry B, Harberts E, Moudgil KD. A cytokine-centric view of the pathogenesis and treatment of autoimmune arthritis. J Interferon Cytokine Res 2011; 31 : 927-40.  Back to cited text no. 29
    
30.Nanjundaiah SM, Venkatesha SH, Yu H, Tong L, Stains JP, Moudgil KD. Celastrus and its bioactive celastrol protect against bone damage in autoimmune arthritis by modulating osteoimmune cross-talk. J Biol Chem 2012; 287 : 22216-26.  Back to cited text no. 30
    
31.Cope AP. T cells in rheumatoid arthritis. Arthritis Res Ther 2008; 10 (Suppl 1): S1.  Back to cited text no. 31
    
32.Liew FY. T(H)1 and T(H)2 cells: a historical perspective. Nat Rev Immunol 2002; 2 : 55-60.  Back to cited text no. 32
    
33.Seder RA, Gazzinelli R, Sher A, Paul WE. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci USA 1993; 90 : 10188-92.  Back to cited text no. 33
    
34.Hsieh CS, Heimberger AB, Gold JS, O′Garra A, Murphy KM. Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system. Proc Natl Acad Sci USA 1992; 89 : 6065-9.  Back to cited text no. 34
    
35.Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421 : 744-8.  Back to cited text no. 35
    
36.Peck A, Mellins ED. Breaking old paradigms: Th17 cells in autoimmune arthritis. Clin Immunol 2009; 132 : 295-304.  Back to cited text no. 36
    
37.Lubberts E. Th17 cytokines and arthritis. Semin Immunopathol 2010; 32 : 43-53.  Back to cited text no. 37
    
38.Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006; 441 : 235-8.  Back to cited text no. 38
    
39.Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007; 448 : 484-7.  Back to cited text no. 39
    
40.Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003; 198 : 1875-86.  Back to cited text no. 40
    
41.Singh RP, La Cava A, Wong M, Ebling F, Hahn BH. CD8+ T cell-mediated suppression of autoimmunity in a murine lupus model of peptide-induced immune tolerance depends on Foxp3 expression. J Immunol 2007; 178 : 7649-57.  Back to cited text no. 41
    
42.Weiner HL, da Cunha AP, Quintana F, Wu H. Oral tolerance. Immunol Rev 2011; 241 : 241-59.  Back to cited text no. 42
    
43.Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 2008; 118 : 3537-45.  Back to cited text no. 43
    
44.Zwerina J, Redlich K, Schett G, Smolen JS. Pathogenesis of rheumatoid arthritis: targeting cytokines. Ann NY Acad Sci 2005; 1051 : 716-29.  Back to cited text no. 44
    
45.Schurgers E, Billiau A, Matthys P. Collagen-induced arthritis as an animal model for rheumatoid arthritis: focus on interferon-gamma. J Interferon Cytokine Res 2011; 31 : 917-26.  Back to cited text no. 45
    
46.Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 1989; 2 : 244-7.  Back to cited text no. 46
    
47.Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 1986; 319 : 516-8.  Back to cited text no. 47
    
48.Joosten LA, Helsen MM, Saxne T, van De Loo FA, Heinegard D, van Den Berg WB. IL-1 alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol 1999; 163 : 5049-55.  Back to cited text no. 48
    
49.Ferraccioli G, Bracci-Laudiero L, Alivernini S, Gremese E, Tolusso B, De Benedetti F. Interleukin-1beta and interleukin-6 in arthritis animal models: roles in the early phase of transition from acute to chronic inflammation and relevance for human rheumatoid arthritis. Mol Med 2010; 16 : 552-7.  Back to cited text no. 49
    
50.Chabaud M, Fossiez F, Taupin JL, Miossec P. Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines. J Immunol 1998; 161 : 409-14.  Back to cited text no. 50
    
51.Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, et al. Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 2008; 172 : 146-55.  Back to cited text no. 51
    
52.Albanesi C, Scarponi C, Cavani A, Federici M, Nasorri F, Girolomoni G. Interleukin-17 is produced by both Th1 and Th2 lymphocytes, and modulates interferon-gamma- and interleukin-4-induced activation of human keratinocytes. J Invest Dermatol 2000; 115 : 81-7.  Back to cited text no. 52
    
53.Sawa S, Lochner M, Satoh-Takayama N, Dulauroy S, Berard M, Kleinschek M, et al. RORgammat+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nat Immunol 2011; 12 : 320-6.  Back to cited text no. 53
    
54.Agarwal S, Misra R, Aggarwal A. Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produce proinflammatory cytokines and matrix metalloproteinases. J Rheumatol 2008; 35 : 515-9.  Back to cited text no. 54
    
55.Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med 2006; 203 : 2673-82.  Back to cited text no. 55
    
56.Hirahara K, Ghoreschi K, Yang XP, Takahashi H, Laurence A, Vahedi G, et al. Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. Immunity 2012; 36 : 1017-30.  Back to cited text no. 56
    
57.Kim KW, Cho ML, Kim HR, Ju JH, Park MK, Oh HJ, et al. Up-regulation of stromal cell-derived factor 1 (CXCL12) production in rheumatoid synovial fibroblasts through interactions with T lymphocytes: role of interleukin-17 and CD40L-CD40 interaction. Arthritis Rheum 2007; 56 : 1076-86.  Back to cited text no. 57
    
58.Ruddy MJ, Shen F, Smith JB, Sharma A, Gaffen SL. Interleukin-17 regulates expression of the CXC chemokine LIX/CXCL5 in osteoblasts: implications for inflammation and neutrophil recruitment. J Leukoc Biol 2004; 76 : 135-44.  Back to cited text no. 58
    
59.Pickens SR, Volin MV, Mandelin AM, 2 nd , Kolls JK, Pope RM, Shahrara S. IL-17 contributes to angiogenesis in rheumatoid arthritis. J Immunol 2010; 184 : 3233-41.  Back to cited text no. 59
    
60.Irmler IM, Gajda M, Brauer R. Exacerbation of antigen-induced arthritis in IFN-gamma-deficient mice as a result of unrestricted IL-17 response. J Immunol 2007; 179 : 6228-36.  Back to cited text no. 60
    
61.Pflanz S, Hibbert L, Mattson J, Rosales R, Vaisberg E, Bazan JF, et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol 2004; 172 : 2225-31.  Back to cited text no. 61
    
62.Awasthi A, Carrier Y, Peron JP, Bettelli E, Kamanaka M, Flavell RA, et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat Immunol 2007; 8 : 1380-9.  Back to cited text no. 62
    
63.Kalliolias GD, Zhao B, Triantafyllopoulou A, Park-Min KH, Ivashkiv LB. Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling. Arthritis Rheum 2010; 62 : 402-13.  Back to cited text no. 63
    
64.Courtenay JS, Dallman MJ, Dayan AD, Martin A, Mosedale B. Immunisation against heterologous type II collagen induces arthritis in mice. Nature 1980; 283 : 666-8.  Back to cited text no. 64
    
65.Szekanecz Z, Halloran MM, Volin MV, Woods JM, Strieter RM, Kenneth Haines G, 3 rd , et al. Temporal expression of inflammatory cytokines and chemokines in rat adjuvant-induced arthritis. Arthritis Rheum 2000; 43 : 1266-77.  Back to cited text no. 65
    
66.Bush KA, Walker JS, Lee CS, Kirkham BW. Cytokine expression and synovial pathology in the initiation and spontaneous resolution phases of adjuvant arthritis: interleukin-17 expression is upregulated in early disease. Clin Exp Immunol 2001; 123 : 487-95.  Back to cited text no. 66
    
67.Mia MY, Kim EY, Satpute SR, Moudgil KD. The dynamics of articular leukocyte trafficking and the immune response to self heat-shock protein 65 influence arthritis susceptibility. J Clin Immunol 2008; 28 : 420-31.  Back to cited text no. 67
    
68.Kim HR, Kim EY, Cerny J, Moudgil KD. Antibody responses to mycobacterial and self heat shock protein 65 in autoimmune arthritis: epitope specificity and implication in pathogenesis. J Immunol 2006; 177 : 6634-41.  Back to cited text no. 68
    
69.Kim EY, Moudgil KD. Regulation of autoimmune inflammation by pro-inflammatory cytokines. Immunol Lett 2008; 120 : 1-5.  Back to cited text no. 69
    
70.Laan M, Cui ZH, Hoshino H, Lotvall J, Sjostrand M, Gruenert DC, et al. Neutrophil recruitment by human IL-17 via C-X-C chemokine release in the airways. J Immunol 1999; 162 : 2347-52.  Back to cited text no. 70
    
71.McNamee KE, Alzabin S, Hughes JP, Anand P, Feldmann M, Williams RO, et al. IL-17 induces hyperalgesia via TNF-dependent neutrophil infiltration. Pain 2011; 152 : 1838-45.  Back to cited text no. 71
    
72.Tran CN, Lundy SK, Fox DA. Synovial biology and T cells in rheumatoid arthritis. Pathophysiology 2005; 12 : 183-9.  Back to cited text no. 72
    
73.Szekanecz Z, Kim J, Koch AE. Chemokines and chemokine receptors in rheumatoid arthritis. Semin Immunol 2003; 15 : 15-21.  Back to cited text no. 73
    
74.Venkatesha SH, Astry B, Nanjundaiah SM, Yu H, Moudgil KD. Suppression of autoimmune arthritis by Celastrus-derived Celastrol through modulation of pro-inflammatory chemokines. Bioorg Med Chem 2012; 20 : 5229-34.  Back to cited text no. 74
    
75.Paleolog EM. Angiogenesis in rheumatoid arthritis. Arthritis Res 2002; 4 (Suppl 3): S81-90.  Back to cited text no. 75
    
76.Marrelli A, Cipriani P, Liakouli V, Carubbi F, Perricone C, Perricone R, et al. Angiogenesis in rheumatoid arthritis: a disease specific process or a common response to chronic inflammation? Autoimmun Rev 2011; 10 : 595-8.  Back to cited text no. 76
    
77.Paleolog EM. The vasculature in rheumatoid arthritis: cause or consequence? Int J Exp Pathol 2009; 90 : 249-61.  Back to cited text no. 77
    
78.Lu J, Kasama T, Kobayashi K, Yoda Y, Shiozawa F, Hanyuda M, et al. Vascular endothelial growth factor expression and regulation of murine collagen-induced arthritis. J Immunol 2000; 164 : 5922-7.  Back to cited text no. 78
    
79.Lu Q, Lu S, Gao X, Luo Y, Tong B, Wei Z, et al. Norisoboldine, an alkaloid compound isolated from Radix linderae, inhibits synovial angiogenesis in adjuvant-induced arthritis rats by moderating Notch1 pathway-related endothelial tip cell phenotype. Exp Biol Med (Maywood) 2012; 237 : 919-32.  Back to cited text no. 79
    
80.Oliver SJ, Cheng TP, Banquerigo ML, Brahn E. Suppression of collagen-induced arthritis by an angiogenesis inhibitor, AGM-1470, in combination with cyclosporin: reduction of vascular endothelial growth factor (VEGF). Cell Immunol 1995; 166 : 196-206.  Back to cited text no. 80
    
81.Tanaka K, Morii T, Weissbach L, Horiuchi K, Takeuchi K, Toyama Y, et al. Treatment of collagen-induced arthritis with recombinant plasminogen-related protein B: a novel inhibitor of angiogenesis. J Orthop Sci 2011; 16 : 443-50.  Back to cited text no. 81
    
82.Yoo SA, Bae DG, Ryoo JW, Kim HR, Park GS, Cho CS, et al. Arginine-rich anti-vascular endothelial growth factor (anti-VEGF) hexapeptide inhibits collagen-induced arthritis and VEGF-stimulated productions of TNF-alpha and IL-6 by human monocytes. J Immunol 2005; 174 : 5846-55.  Back to cited text no. 82
    
83.Szekanecz Z, Besenyei T, Paragh G, Koch AE. New insights in synovial angiogenesis. Joint Bone Spine 2010; 77 : 13-9.  Back to cited text no. 83
    
84.Westra J, Brouwer E, Bos R, Posthumus MD, Doornbos-van der Meer B, Kallenberg CG, et al. Regulation of cytokine-induced HIF-1alpha expression in rheumatoid synovial fibroblasts. Ann NY Acad Sci 2007; 1108 : 340-8.  Back to cited text no. 84
    
85.Hitchon C, Wong K, Ma G, Reed J, Lyttle D, El-Gabalawy H. Hypoxia-induced production of stromal cell-derived factor 1 (CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum 2002; 46 : 2587-97.  Back to cited text no. 85
    
86.Brahn E, Banquerigo ML, Lee JK, Park EJ, Fogler WE, Plum SM. An angiogenesis inhibitor, 2-methoxyestradiol, involutes rat collagen-induced arthritis and suppresses gene expression of synovial vascular endothelial growth factor and basic fibroblast growth factor. J Rheumatol 2008; 35 : 2119-28.  Back to cited text no. 86
    
87.Lainer DT, Brahn E. New antiangiogenic strategies for the treatment of proliferative synovitis. Expert Opin Investig Drugs 2005; 14 : 1-17.  Back to cited text no. 87
    
88.Miotla J, Maciewicz R, Kendrew J, Feldmann M, Paleolog E. Treatment with soluble VEGF receptor reduces disease severity in murine collagen-induced arthritis. Lab Invest 2000; 80 : 1195-205.  Back to cited text no. 88
    
89.Schoettler N, Brahn E. Angiogenesis inhibitors for the treatment of chronic autoimmune inflammatory arthritis. Curr Opin Investig Drugs 2009; 10 : 425-33.  Back to cited text no. 89
    
90.Egginton S. Activity-induced angiogenesis. Pflugers Arch 2009; 457 : 963-77.  Back to cited text no. 90
    
91.Fong GH. Mechanisms of adaptive angiogenesis to tissue hypoxia. Angiogenesis 2008; 11 : 121-40.  Back to cited text no. 91
    
92.Maruotti N, Cantatore FP, Crivellato E, Vacca A, Ribatti D. Angiogenesis in rheumatoid arthritis. Histol Histopathol 2006; 21 : 557-66.  Back to cited text no. 92
    
93.Szekanecz Z, Koch AE. Angiogenesis and its targeting in rheumatoid arthritis. Vascul Pharmacol 2009; 51 : 1-7.  Back to cited text no. 93
    
94.Berse B, Hunt JA, Diegel RJ, Morganelli P, Yeo K, Brown F, et al. Hypoxia augments cytokine (transforming growth factor-beta (TGF-beta) and IL-1)-induced vascular endothelial growth factor secretion by human synovial fibroblasts. Clin Exp Immunol 1999; 115 : 176-82.  Back to cited text no. 94
    
95.Jackson JR, Minton JA, Ho ML, Wei N, Winkler JD. Expression of vascular endothelial growth factor in synovial fibroblasts is induced by hypoxia and interleukin 1beta. J Rheumatol 1997; 24 : 1253-9.  Back to cited text no. 95
    
96.Cunnane G, FitzGerald O, Hummel KM, Gay RE, Gay S, Bresnihan B. Collagenase, cathepsin B and cathepsin L gene expression in the synovial membrane of patients with early inflammatory arthritis. Rheumatology (Oxford) 1999; 38 : 34-42.  Back to cited text no. 96
    
97.Li Z, Hou WS, Escalante-Torres CR, Gelb BD, Bromme D. Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate. J Biol Chem 2002; 277 : 28669-76.  Back to cited text no. 97
    
98.Lin EA, Liu CJ. The role of ADAMTSs in arthritis. Protein Cell 2010; 1 : 33-47.  Back to cited text no. 98
    
99.Maciewicz RA, Wotton SF. Degradation of cartilage matrix components by the cysteine proteinases, cathepsins B and L. Biomed Biochim Acta 1991; 50 : 561-4.  Back to cited text no. 99
    
100.Malemud CJ. Matrix metalloproteinases (MMPs) in health and disease: an overview. Front Biosci 2006; 11 : 1696-701.  Back to cited text no. 100
    
101.Rengel Y, Ospelt C, Gay S. Proteinases in the joint: clinical relevance of proteinases in joint destruction. Arthritis Res Ther 2007; 9 : 221.  Back to cited text no. 101
    
102.Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003; 92 : 827-39.  Back to cited text no. 102
    
103.Volin MV, Woods JM, Amin MA, Connors MA, Harlow LA, Koch AE. Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis. Am J Pathol 2001; 159 : 1521-30.  Back to cited text no. 103
    
104.Pickens SR, Chamberlain ND, Volin MV, Pope RM, Talarico NE, Mandelin AM, 2 nd , et al. Role of the CCL21 and CCR7 pathways in rheumatoid arthritis angiogenesis. Arthritis Rheum 2012; 64 : 2471-81.  Back to cited text no. 104
    
105.Poole AR, Kobayashi M, Yasuda T, Laverty S, Mwale F, Kojima T, et al. Type II collagen degradation and its regulation in articular cartilage in osteoarthritis. Ann Rheum Dis 2002; 61 (Suppl 2): ii78-81.  Back to cited text no. 105
    
106.Huet G, Flipo RM, Colin C, Janin A, Hemon B, Collyn-d′Hooghe M, et al. Stimulation of the secretion of latent cysteine proteinase activity by tumor necrosis factor alpha and interleukin-1. Arthritis Rheum 1993; 36 : 772-80.  Back to cited text no. 106
    
107.Kaneko M, Tomita T, Nakase T, Ohsawa Y, Seki H, Takeuchi E, et al. Expression of proteinases and inflammatory cytokines in subchondral bone regions in the destructive joint of rheumatoid arthritis. Rheumatology (Oxford) 2001; 40 : 247-55.  Back to cited text no. 107
    
108.Li X, Yuan FL, Lu WG, Zhao YQ, Li CW, Li JP, et al. The role of interleukin-17 in mediating joint destruction in rheumatoid arthritis. Biochem Biophys Res Commun 2010; 397 : 131-5.  Back to cited text no. 108
    
109.Luyten FP, Lories RJ, Verschueren P, de Vlam K, Westhovens R. Contemporary concepts of inflammation, damage and repair in rheumatic diseases. Best Pract Res Clin Rheumatol 2006; 20 : 829-48.  Back to cited text no. 109
    
110.Kousidou OC, Roussidis AE, Theocharis AD, Karamanos NK. Expression of MMPs and TIMPs genes in human breast cancer epithelial cells depends on cell culture conditions and is associated with their invasive potential. Anticancer Res 2004; 24 : 4025-30.  Back to cited text no. 110
    
111.Tezuka K, Tezuka Y, Maejima A, Sato T, Nemoto K, Kamioka H, et al. Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts. J Biol Chem 1994; 269 : 1106-9.  Back to cited text no. 111
    
112.Takaishi H, Kimura T, Dalal S, Okada Y, D′Armiento J. Joint diseases and matrix metalloproteinases: a role for MMP-13. Curr Pharm Biotechnol 2008; 9 : 47-54.  Back to cited text no. 112
    
113.Murphy G. Tissue inhibitors of metalloproteinases. Genome Biol 2011; 12 : 233.  Back to cited text no. 113
    
114.Greene J, Wang M, Liu YE, Raymond LA, Rosen C, Shi YE. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 1996; 271 : 30375-80.  Back to cited text no. 114
    
115.Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 2010; 1803 : 55-71.  Back to cited text no. 115
    
116.Burger D, Rezzonico R, Li JM, Modoux C, Pierce RA, Welgus HG, et al. Imbalance between interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon direct contact with stimulated T lymphocytes: involvement of membrane-associated cytokines. Arthritis Rheum 1998; 41 : 1748-59.  Back to cited text no. 116
    
117.Zhou H, Wong YF, Wang J, Cai X, Liu L. Sinomenine ameliorates arthritis via MMPs, TIMPs, and cytokines in rats. Biochem Biophys Res Commun 2008; 376 : 352-7.  Back to cited text no. 117
    
118.Lee L, Buckley C, Blades MC, Panayi G, George AJ, Pitzalis C. Identification of synovium-specific homing peptides by in vivo phage display selection. Arthritis Rheum 2002; 46 : 2109-20.  Back to cited text no. 118
    
119.Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 1993; 36 : 1681-90.  Back to cited text no. 119
    
120.Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41 : 1552-63.  Back to cited text no. 120
    
121.Seymour HE, Worsley A, Smith JM, Thomas SH. Anti-TNF agents for rheumatoid arthritis. Br J Clin Pharmacol 2001; 51 : 201-8.  Back to cited text no. 121
    
122.Zwerina J, Redlich K, Polzer K, Joosten L, Kronke G, Distler J, et al. TNF-induced structural joint damage is mediated by IL-1. Proc Natl Acad Sci USA 2007; 104 : 11742-7.  Back to cited text no. 122
    
123.Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Bijlsma JW, et al. Updated consensus statement on biological agents, specifically tumour necrosis factor {alpha} (TNF{alpha}) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2005. Ann Rheum Dis 2005; 64 (Suppl 4): iv2-14.  Back to cited text no. 123
    
124.Nakae S, Saijo S, Horai R, Sudo K, Mori S, Iwakura Y. IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist. Proc Natl Acad Sci USA 2003; 100 : 5986-90.  Back to cited text no. 124
    
125.Genovese MC, Van den Bosch F, Roberson SA, Bojin S, Biagini IM, Ryan P, et al. LY2439821, a humanized anti-interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study. Arthritis Rheum 2010; 62 : 929-39.  Back to cited text no. 125
    
126.Tanaka Y, Maeshima Y, Yamaoka K. In vitro and in vivo analysis of a JAK inhibitor in rheumatoid arthritis. Ann Rheum Dis 2012; 71 (Suppl 2): i70-4.  Back to cited text no. 126
    
127.Venkatesha SH, Berman BM, Moudgil KD. Herbal medicinal products target defined biochemical and molecular mediators of inflammatory autoimmune arthritis. Bioorg Med Chem 2011; 19 : 21-9.  Back to cited text no. 127
    
128.Venkatesha SH, Rajaiah R, Berman BM, Moudgil KD. Immunomodulation of autoimmune arthritis by herbal CAM. Evid Based Complement Alternat Med 2011; 2011 : 986797.  Back to cited text no. 128
    
129.Kim HR, Rajaiah R, Wu QL, Satpute SR, Tan MT, Simon JE, et al. Green tea protects rats against autoimmune arthritis by modulating disease-related immune events. J Nutr 2008; 138 : 2111-6.  Back to cited text no. 129
    
130.Tong L, Moudgil KD. Celastrus aculeatus Merr. suppresses the induction and progression of autoimmune arthritis by modulating immune response to heat-shock protein 65. Arthritis Res Ther 2007; 9 : R70.  Back to cited text no. 130
    
131.Yang YH, Rajaiah R, Lee DY, Ma Z, Yu H, Fong HH, et al. Suppression of ongoing experimental arthritis by a chinese herbal formula (huo-luo-xiao-ling dan) involves changes in antigen-induced immunological and biochemical mediators of inflammation. Evid Based Complement Alternat Med 2011; 2011 : 642027.  Back to cited text no. 131
    
132.Nanjundaiah SM, Lee DY, Ma Z, Fong HH, Lao L, Berman BM, et al. Modified huo-luo-xiao-ling dan suppresses adjuvant arthritis by inhibiting chemokines and matrix-degrading enzymes. Evid Based Complement Alternat Med 2012; 2012 : 589256.  Back to cited text no. 132
    


    Figures

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    Tables

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    Abstract
   Introduction
    Subsets of T hel...
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