JCR: Journal of Clinical Rheumatology:
Immunologic Mechanisms in the Pathogenesis of Rheumatoid Arthritis
Firestein, Gary S. MD
From the Department of Medicine and the Division of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, La Jolla, California.
Reprints: Gary S. Firestein, Professor of Medicine, Chief of Rheumatology, Allergy, and Immunology, University of California, San Diego School of Medicine, 9500 Gilman Drive BSB, Room 5098, Mail Code 0656, La Jolla, CA 92093. E-mail: firstname.lastname@example.org.
Although much is known about the etiology and pathogenesis of rheumatoid arthritis (RA), our understanding of the immune pathways remains incomplete. The observed clinical and pathologic manifestations result from activation of several interrelated immune pathways. Current concepts of RA pathogenesis, supported by animal models, laboratory studies, and clinical observation, have reestablished and revised some of the original views. Early proposals emphasized the importance of autoantibodies and immune complexes in the initiation of RA, suggested a role for T cells in the inflammatory response characteristic of RA, and based disease perpetuation on an imbalance in the cytokine networks. We now recognize that each of these interrelated mechanisms significantly contributes to RA pathogenesis, including T cells that can help initiate and perpetuate the disease. This article reviews the major components and immune pathways involved in RA and briefly discusses the animal models that contribute to our understanding. Although a unified theory of RA pathogenesis may not be possible at this time, a paradigm is presented that considers the immune pathways that contribute to disease progression and joint destruction. These pathways may have important implications for treatment, because their modulation by biologic response modifiers (BRMs) directed toward specific targets provides benefits to patients with RA. BRMs are a new class of therapeutic agents derived from biologically active molecules and designed to modulate specific immune or inflammatory pathways. Although currently approved BRMs still have limitations, choosing an appropriate target, possibly early rather than late in the immune response, might result in new and improved therapies for RA.
Rheumatoid arthritis (RA) is a complex inflammatory disease of synovial joints, especially the small joints of the hands and feet, that is characterized by joint destruction and chronic disability. With a population point prevalence of 1%,1 RA is responsible for a significant socioeconomic burden.2 This burden results not only from direct medical costs associated with substantial health resource utilization, but also from high indirect and intangible costs related to lost productivity and decreased quality of life. Recent estimates suggest that indirect costs may account for as much as two thirds of the almost $16 billion annual cost of RA.2
Although rheumatic diseases were recognized at the time of Hippocrates, what has come to be known as RA was first recognized in the 17th century and named by Garrod in 1859. It was definitively described as a clinical entity by Charles Short in 1957. Its complexity was immediately recognized, but despite much immunologic research and the identification of multiple cells and pathways that contribute to its pathogenesis, the underlying etiology and pathogenesis are still not completely understood.
This review discusses our present knowledge of the pathogenic mechanisms of RA. Although we have revisited some of the early views regarding the mechanisms that support inflammation and joint destruction, significant progress has been made in our understanding of the disease. This understanding can be of benefit in developing appropriate therapy through modulation of immune pathways.
EARLY EVOLUTION OF OUR CONCEPTS OF RHEUMATOID ARTHRITIS PATHOGENESIS
Initial Theories: Autoimmunity and T-Cell Involvement
Views of RA have undergone several incarnations as new mechanisms and pathways have been uncovered and added to the growing immunologic literature regarding its pathogenesis. RA was initially considered an autoimmune disease based in large part on the identification of rheumatoid factor (RF) in the sera of patients with RA and the characterization of these factors as autoantibodies.3 Zvaifler4 and others subsequently proposed that RA represents a localized immune complex disease characterized by production of RF in the synovium, the formation of RF-immune complexes that fix complement with the ensuing consumption of complement within the joint, and the recruitment of a variety of cells (eg, T cells, B cells, macrophages) that become activated and contribute to inflammation and joint damage. The immune-complex hypothesis was reasonable, especially because the presence of RF was determined to be predictive of more aggressive disease. However, it did not account for the absence of RF in some patients with RA, the presence of RF in patients with other diseases, the presence of RF in a proportion of normal individuals, and other features of the disease.
The search for additional mechanisms implicated a role for T cells in RA pathogenesis and resulted in the identification of immunogenetic components. Using allogeneic mixed lymphocyte reactions, Stastny et al5 demonstrated a relationship between RA and specific human leukocyte antigen (HLA)-DR genes of the major histocompatability complex (MHC). This was the first evidence of a genetic component, and it was a notable finding because HLA is a key molecule responsible for the presentation of antigen to T cells by antigen-presenting cells (APCs) such as macrophages and dendritic cells. Antigen presentation is also one of the signals required for T-cell costimulation and activation, early events in the adaptive immune response.
It subsequently became clear that not only is HLA integral to the immune response, but that the RA associate maps to a specific gene locus coding for the third hypervariable region of the DRβ chain.6 This epitope may predict susceptibility and disease severity.7 One possible mechanism is that this molecule binds an arthritogenic peptide resulting in T-cell activation and inflammation in susceptible individuals. However, caveats associated with this mechanism included the lack of identification of a specific reactive peptide, the existence of heterogeneous allele associations, and the multiple functions of HLA in the immune response. Nevertheless, the implication of T cells in the orchestration of RA pathogenesis was a major breakthrough and is supported by the fact that many of the animal models of arthritis are T cell-dependent (eg, collagen- and adjuvant-induced arthritis).
By the mid-1980s, cytokines produced in a variety of immune and inflammatory cells had been identified, and these molecules were considered prominent in the RA disease process. A chaotic cytokine network was simplified by the characterization of a regulatory network that took into account the major cell types in the synovium, their products, and their actions. For instance, the production of the T cell–associated cytokines interferon-γ (IFN-γ) and interleukin-2 (IL-2) within the synovium is relatively low in RA.8 The fibroblast- and macrophage-like synoviocytes in the intimal lining of the synovium produce factors that activate adjacent cells to maintain the inflammatory response, with T cells as well as B cells and macrophages accumulating in the sublining layer.9 The predominance of these macrophage- and fibroblast-derived cytokines8 pointed to a non-T-cell mechanism for rheumatoid synovitis. The cytokine network was subsequently proposed as a perpetuating mechanism in RA,10 and the imbalance between proinflammatory and antiinflammatory cytokines became the focus of pathogenic mechanisms in RA.
Strong support for the role of the cytokine network in RA was provided by the development and approval of the first biologic response modifiers (BRMs). These BRMs, which specifically target cytokines involved in the inflammatory response, include the anti–tumor necrosis factor (TNF-α) agents etanercept, infliximab, and adalimumab, and the IL-1 inhibitor anakinra. That these BRMs are effective in the management of RA and have been beneficial in a proportion of patients, providing not only symptomatic relief, but also slowing radiographic progression, confirms the importance of cytokines. However, these agents are dramatically effective in only approximately 40% of patients, and even in these patients, the requirement for continuous therapy suggests that additional stimuli are required to orchestrate the regulation of cytokine production.
CURRENT VIEWS OF RHEUMATOID ARTHRITIS PATHOGENESIS: BACK TO THE FUTURE
Renewed interest in autoantibodies as precipitating factors in RA pathogenesis resulted in part from the serendipitous development of a spontaneous mouse model of arthritis that is mediated by immune complex formation. The K/BxN mouse is a transgenic mouse characterized by a chronic erosive polyarthritis that shows similarities to human inflammatory RA, including pannus formation, synoviocyte proliferation, and synovitis.11 Propagation of this arthritis is dependent on B-cell secretion of arthritogenic autoantibodies.12 These autoantibodies bind to the self-antigen glucose-6-phosphate isomerase (GPI), a ubiquitously expressed cytosolic enzyme involved in glycolysis.13 The disease in these mice initially starts as a T cell-dependent response to GPI in which autoreactive T cells recruit anti-GPI B cells, which then differentiate into plasma cells producing arthritogenic autoantibodies (anti-GPI-IgG). The subsequent initiation of synovitis is solely dependent on these autoantibodies, because transfer of sera or purified anti-GPI antibody from K/BxN mice into naive mice results in the transient development of arthritic joints.11,12,14 Repeated administration of K/BxN serum or antibody is required to maintain the disease. The proposed mechanism for these effects is induction of the inflammatory cascade resulting from the formation of GPI–anti-GPI immune complexes on articular surfaces.15 The inflammatory cascade appears to be primarily mediated by the alternative complement pathway,15 but the K/BxN model is also clearly dependent on the cytokine network. In vivo studies in cytokine knockout mice suggest an absolute requirement for IL-1 and a lesser role for TNF in disease development.16 This model not only demonstrates the importance of autoantibodies as a catalyst for the inflammatory response, but also highlights the role of T cells and shows that there is a clear relationship among the various proposed pathogenic mechanisms.
Although the presence of these autoantibodies suggests a role of B cells in RA (Fig. 1), a joint-specific self-antigen may not be a prerequisite for induction of RA. In the case of GPI, its actual role in human RA is unclear, because there is a low prevalence and an absence of specificity of GPI antibodies in RA.17 Hence, GPI–anti-GPI immune complexes are not likely to be a major driving force in disease pathogenesis. There are many other putative antigens implicated in RA, including heat shock proteins, collagen, heavy chain binding protein, and cyclic citrullinated peptides (CCPs).18 These molecules could contribute to the pathogenesis of RA, because the resulting immune complex formation can potentially promote complement fixation and activation of immune cells (Fig. 1). However, autoantibodies are not likely to be the sole etiologic agents, because autoreactivity often precedes clinical RA by many years.19 In particular, anti-CCP antibodies might be predictive of RA, with presence in sera predating onset of symptoms.20 Anti-CCP antibodies also have >90% specificity for RA21 with a high predictive value for development of clinical disease, disease severity, and radiographic damage.19,20,22–24
Just as autoantibodies and immune complexes are being reestablished in the hierarchy of immunoinflammatory events in RA, T cells have also been implicated as primary mediators in the orchestration of RA. This role for T cells represents one of the latest developments in our understanding of RA and is important not only from the mechanistic standpoint, but also from the clinical perspective.25
In a manner similar to that of autoantibodies discussed here, the concept of a central role for T cells was supported by another spontaneous mouse model. The SKG mouse is a T cell-dependent model of inflammatory arthritis that has clinical and histologic similarities with human RA.25,26 In the SKG mouse, a mutation in the ZAP-70 signal transduction gene involved in T-cell activation results in abnormal thymic selection of autoreactive T cells. Instead of being deleted to prevent autoimmunity, there is positive selection of these autoreactive T cells, which survive and become arthritogenic.
Although the SKG model suggests that T cells can spontaneously cause inflammatory arthritis in RA, to understand how this occurs, it is important to understand that activation of naive T cells requires 2 distinct but contemporaneous ligation events (Fig. 2). 27 The first event consists of presentation by an APC of an MHC–antigen complex with reciprocal binding to the T-cell receptor. The second signal occurring in temporal proximity is ligation of a costimulation molecule on the APC with its cognate receptor molecule on the T cell. Binding of the MHC–antigen complex to the T cell without costimulation results in hyporesponsive T cells (ie, anergy).28 In contrast, binding of both costimulatory signals results in T-cell activation with the consequences of T-cell antigen responsiveness. Several costimulatory pairs have been described, some of which activate T cells and some of which attenuate the T-cell response. Of the pairs that activate T cells, CD28 and CD80/CD86 are among the best characterized.27 This pathway is the target for abatacept, a new BRM that interferes with costimulation. Although this approach and its clinical implications are discussed elsewhere in this supplement,29 the clinical efficacy observed using costimulation modulation supports a role of T cells in many patients with RA.
T cells may contribute to the inflammatory response because they not only have specific effector functions, but they also activate or interact with other cells that perpetuate inflammation and joint destruction (Fig. 3). These interactions include those with B cells, which may then be induced to produce autoantibodies; macrophages, fibroblast-like synoviocytes, and chondrocytes, all of which can release proteases and other effector molecules; and osteoclasts.9 These latter cells are of particular importance because they are responsible for bone resorption and their activation accelerates joint destruction in patients with RA.30
There is also intersection between T cells and the cytokine pathway through T cell-derived cytokines and cytokines released by other T cell-activated immune cells. Two T cell-derived cytokines of potential importance in RA are IFN-γ and IL-17. Although only small amounts of IFN-γ are produced by synovial T cells,8,31 the presence of this cytokine could be important. First, IFN-γ serves as a marker for the subset of activated T cells known as TH1 helper cells. These cells promote and amplify autoimmune diseases, and it may be a shift in the ratio of TH1 and TH2 cells that helps perpetuate pathogenic mechanisms.32,33 IFN-γ also has a direct effect on inflammation by increasing MHC class II expression as well as priming macrophages to produce inflammatory and tissue-damaging mediators such as TNF-α, proteases, reactive oxygen species, and nitric oxide.34
Another notable T cell-derived cytokine detected in RA synovium is IL-17. This cytokine, which shares many functions with IL-1 and TNF-α, is produced in rheumatoid synovium by T cells.35,36 The consequences of IL-17 action have led to the suggestion that it might serve as a “missing link” between T-cell accumulation/activation and the downstream mechanisms leading to inflammation and joint destruction.35 IL-17 can amplify the production of proinflammatory cytokines by fibroblasts and macrophages and can also promote cell adhesion molecules, thereby enhancing infiltration of inflammatory cells into the joint. It also induces production of matrix metalloproteinases (MMPs) and shifts the balance of bone metabolism toward osteoclastogenesis with subsequent bone resorption.35
Although IL-17 by itself can induce MMP production and cause cartilage destruction, suboptimal concentrations are synergistic when combined with the proinflammatory cytokines TNF-α and IL-1.37 Based on this range of activities, IL-17 has been considered a potential target for therapy. In fact, treatment of a mouse model of arthritis with a neutralizing antibody against IL-17 results in reduced inflammation and joint damage.38
If T cells produce cytokines and perform other effector functions in the joint, the inciting antigen is clearly relevant. Although many identified antigens have been considered such as RF, GPI, CCP, and others as previously mentioned, no single antigen fits all the requirements for explaining the disease.9 Indeed, initiating antigens might be distinct from perpetuating epitopes. Either antigen spread or antigen replacement might be a driving force in established disease. Furthermore, as also previously suggested with regard to GPI, the inciting stimulus need not be a joint-associated antigen. Although some of the currently identified autoantibodies are joint-specific such as type-2 collagen and proteoglycans, RF and CCP are systemic antigens that have been implicated.9
The Significance of Synoviocytes
In addition to the previously mentioned immune cells, recent work has identified a subpopulation of activated synovial fibroblasts that are present in RA and have characteristics that clearly distinguish them from other synovial fibroblasts.39,40 These fibroblasts within the RA synovium are more aggressive than normal or osteoarthritis synoviocytes. Their activation induces an increase in adhesion molecules, which enhances their attachment to articular cartilage and increases their invasiveness into the extracellular matrix. When activated, they also release MMPs and other proteolytic enzymes, which contribute to joint degradation by digesting matrix proteins such as collagen and proteoglycans. Additionally, the RA synovial fibroblasts appear to enhance T- and B-cell survival in the synovium by preventing apoptosis, potentially prolonging the immune effector functions of these cells.
Evidence suggests that in RA, this subpopulation of synovial fibroblasts might become permanently imprinted to express the more aggressive phenotype. When coimplanted with normal human cartilage in severe combined immunodeficient mice, they retain their aggressive behavior even in the absence of other inflammatory cells.41 The factors initiating activation and imprinting have not been fully characterized, although cytokine-dependent and -independent mechanisms have been described.40
CONCLUSIONS: A UNIFIED THEORY OF RHEUMATOID ARTHRITIS PATHOGENESIS?
After many years of experimental and clinical investigation into the pathogenesis of RA, we have a better, albeit still incomplete, understanding of the disease process. Interestingly, we have come full circle in our concepts, with the roles of immune complexes and T cells that were initially postulated to be central to RA pathogenesis again coming into focus as primary mediators in the initiation and perpetuation of the disease.
Although RA is a complex disease with multiple interacting mechanisms that contribute to inflammation and joint destruction, a possible paradigm that takes into account the major features can be described as shown in Figure 4. In this model, both predetermined and random events contribute to the initiation of the disease. The predetermined aspect is the genetic component, which suggests that certain individuals carry a genotype for autoreactivity that may precede disease onset. The random aspect is represented by environmental influences that might activate innate immunity. This primordial defense system is an evolutionary adaptation that enables rapid recognition and elimination of pathogens and is considered the first line of an organism's immune defense.
Processing an unspecified but not necessarily rheumatoid-specific antigen by dendritic cells and presentation to T cells in conjunction with the costimulatory signal activates the T cells that then help orchestrate many of the downstream pathways. This processing and presentation of antigen likely occurs in central lymphoid organs and initiates the adaptive immune response, an organism's second line of defense that results in expansion of cell populations recognizing specific antigens. The initiation of adaptive immunity produces a clonal expansion of T cells with subsequent migration to the synovium where cytokines are produced and where the T cells interact with synoviocytes, macrophages, and B cells to promote inflammation. Under appropriate conditions, loss of tolerance related to either genetic predisposition or the T-cell repertoire can result in an autoimmune response to particular antigens newly exposed during inflammatory degradation of the joint.
With the identification of multiple cell types and various cytokines providing opportunities for new interventions, these concepts have therapeutic implications and have shaped our current approach to RA management. Furthermore, the complexity and redundancy of the regulatory mechanisms combined with the observed interpatient variability in the disease process explains why some patients may respond to a particular therapy whereas others do not, especially when targeting pathways downstream of key regulators of immunologic events.
The ability to construct biologically active molecules has resulted in the introduction of BRMs as therapeutic agents. By modulating immune and cellular responses, BRMs have expanded our resources for therapy as well as for further investigation of the disease process. Although currently approved BRMs represent a major step forward in the treatment of RA, demonstrating both symptomatic efficacy and disease modification, they are not without limitations. Choosing an appropriate therapeutic target is crucial to bringing greater benefits to more patients. It is possible that modulation of selected events early rather than late in the immune response can have the effect of modulating pathways that are of particular importance in the pathogenic process. Agents currently in clinical trials such as abatacept (discussed in this supplement by Kremer29), as well as many still in development (reviewed in this supplement by Genovese42), have generated optimism that we may eventually control the progressive course of RA, reducing both the economic and patient burden.
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rheumatoid arthritis; pathogenesis; autoimmunity; immune complexes; T cells; B cells; cytokines
© 2005 Lippincott Williams & Wilkins, Inc.
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