B cells: a fundamental role in the pathogenesis of rheumatoid arthritis?

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1 Rheumatology 2005;44(Suppl. 2):ii3 ii7 B cells: a fundamental role in the pathogenesis of rheumatoid arthritis? doi: /rheumatology/keh616 The role of T cells in the pathogenesis of RA is well established, whereas to date the precise contribution of B cells is less well defined. B cells have many potential key roles: they can act as antigen-presenting cells, secrete pro-inflammatory cytokines (including tumour necrosis factor-a), produce rheumatoid factor (RF) and other autoantibodies and activate T cells. B cells act as antigen-presenting cells by processing and presenting antigenic peptides to T cells, which become activated, proliferate and exert pro-inflammatory activities. RF may also play a role in perpetuating B-cell activation and antigen presentation to T cells, thus leading to sustained production of RF. This, combined with RF immune-complex-mediated complement activation, may contribute to the sustained inflammatory response. Studies have shown that the use of an anti-cd20 monoclonal antibody in RA depletes circulating B cells, resulting in improvement in disease activity for up to 1 yr. It is thus evident that B cells play a central role in the pathophysiology of RA and therefore merit further investigation as a therapeutic target. KEY WORDS: B cells, Rheumatoid arthritis, Rheumatoid factor, Rituximab, T cells. Recently, there has been a significant increase in our understanding of the pathogenesis of RA; however, its aetiology remains to be fully elucidated. RA is an autoimmune disease characterized by infiltration of inflammatory cells in the synovial membrane of affected joints, leading to pannus formation. The precise induction and progression of this process remains unclear. However, the presence of T- and B-cell infiltrates in the inflamed synovial tissue is a consistent histological finding in RA [1]. Genetic studies have demonstrated that RA is strongly correlated with the major histocompatibility complex class II antigen HLA-DR4 [2]. The main function of HLA-DR molecules is to present antigenic peptides to T cells. The synovial membrane contains a large number of CD4þ helper T cells, which when activated are known to play an important role in the pathogenesis of RA. Furthermore, autoantibodies, such as RF, appear to be associated with more aggressive articular disease, a higher frequency of extra-articular manifestations and increased mortality and morbidity [2]. Role of T cells in the pathogenesis of RA The role of T cells in the pathogenesis of RA is well established. The RA disease process is summarized in Fig. 1 and is thought to be dependent on a trimolecular complex consisting of antigenic peptides, T-cell receptors and HLA-DR4. In RA, the antigenpresenting cells (APCs) take up one or more unknown antigens and process them into peptides that are inserted into the groove of HLA-DR4 located on the surface of the APC. T cells with the appropriate T-cell receptors then engage with this complex (forming a trimolecular complex) to become activated. Subsequently, this causes a number of events including the production of interleukin-2 (IL-2), which leads to the clonal expansion of T cells [3]. After the T cells become activated, in addition to the release of cytokines (such as IL-2), a number of other changes occur to the T cells. The T cells begin to grow larger and start to express a number of surface molecules, such as CD69, tumour necrosis factor- (TNF-) and rank ligand (RANKL). CD69, a cellsurface signalling molecule, is involved in the activation of macrophages, TNF- is involved in the activation of synovial fibroblasts and RANKL plays a role in osteoclast activation. Following these surface changes, T cells produce the soluble mediators IL-17 and interferon- (IFN-) [2]. IL-17 has been implicated in osteoclast activation causing bone resorption in RA [3]. IFN- stimulates macrophages to secrete a large number of pro-inflammatory cytokines. IL-1, IL-6 and TNF- are the key cytokines thought to be responsible for stimulation of the synovial fibroblasts or synoviocytes [4, 5]. These key inflammatory cytokines induce inflammation and the release of matrix metalloproteinases that degrade the connective tissue and are involved in pannus formation [2]. The activated T cells also express osteoprotegerin ligand which, together with cytokines such as IL-1, stimulate osteoclast activation leading to bone erosion. This sequence of events leads to the chronic inflammation that causes damage to cartilage and bone in RA. Although there has been controversy surrounding the evidence for T-cell-stimulated cytokine release in RA synovial membrane, the early research work of Dayer and colleagues [6, 7] and, more recently, that of McInnes and colleagues [8, 9] can help to shed some light on this issue. They have demonstrated that activated T cells found in the synovial fluid and membrane of patients with RA can directly engage with and activate the macrophages, synoviocytes and osteoclasts by cell-to-cell interactions. The role of B cells in RA Although the role of T cells and APCs in the pathogenesis of RA has been studied extensively, the precise role of B cells is still not well characterized. An important characteristic of RA is chronic inflammation of the synovial tissue in the affected joints. In contrast to normal synovial tissue, infiltrating lymphocytes are commonly seen in the inflamed synovial tissue [1]. These infiltrates Guy s, King s and St Thomas School of Medicine, King s College, London, UK. Submitted 2 July 2004; revised version accepted 24 February Correspondence to:, Department of Rheumatology, Guy s, King s and St Thomas Medical School, Guy s Hospital, St Thomas Street, London SE1 9RT, UK. gabriel.panayi@kcl.ac.uk ii3 ß The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oupjournals.org

2 ii4 FIG. 1. T cell-mediated pathways in rheumatoid arthritis (MMP, matrix metalloproteinase). within the synovial membrane may be diffuse or follicular in structure (Fig. 2). The diffuse infiltrate lacks a distinct structural organization, whereas the follicular infiltrate consists of a perivascular aggregation of T cells peripherally surrounded by B cells. One of the main cellular components of the follicular infiltrates are B cells, which can differentiate into plasma cells [1]. Approximately 30% of patients with RA have synovia that show follicular infiltrates [10]. B-cell development initiates in the bone marrow, where stem cells progress through various stages of differentiation to become immature B cells. Immature B cells express functional surface immunoglobulin (Ig) M whilst still in the bone marrow, before migrating (as mature B cells) to peripheral lymphoid tissues including the lymph nodes [11]. Within the lymphoid follicles (follicular infiltrates) mature B cells can then be induced by antigens to proliferate and express IgA, IgG and IgE in addition to IgM (germinal centre cells). These germinal centre cells can further differentiate into plasma cells, which secrete immunoglobulins. The development of germinal centres within affected tissues is a frequent finding in organ-specific and generalized autoimmune disorders. Pro-inflammatory cytokines, including TNF- and lymphotoxin-, may play a major role in promoting the organization of germinal centres in inflammatory lymphoid tissues [1, 10]. Hence in RA there is an abundance of B cells present within the synovial membrane of affected joints and these lymphocytes can be organized into lymphoid structures. B cells can play a number of potentially critical roles in the pathogenesis of RA and these are summarized in Fig. 3. They may function as APCs by processing and presenting antigenic peptides to the T cells [2, 12 15]. The T cells then proliferate and exert pro-inflammatory activities (Fig. 4). It is well known that B cells can bind antigens through their immunoglobulin receptor. The immunoglobulin receptor lies on the surface of the B cell and can bind a very low level of antigen from the environment. The antigen is degraded by the B cell into antigenic peptides. These antigenic peptides are then presented in the groove of the HLA-DR4 molecule to activate the T cells, which in turn undergo various processes, including proliferation, cytokine production and cell-to-cell interaction, which contribute to the pathogenic process in RA [13]. Is T-cell activation B-cell dependent? The activation of T cells is considered to be the key component in the pathogenesis of RA. Previous evidence [16] and, more recently, data from Takemura et al. [15] suggest that this sustained activation in the rheumatoid synovium may be dependent on the presence of B cells. In the latter study, samples of synovial membrane from the joint of a patient with RA were transplanted under the skin of severe combined immunodeficient (SCID) mice that have no T or B cells and are unable to reject allografts. The transplanted synovial membrane continued to secrete cytokines as the SCID mice were not able to reject them. Twelve days after transplantation, an anti-cd20 monoclonal antibody (rituximab; MabThera Õ /Rituxan Õ ) was administered three times daily at doses ranging between 300 g/day and 600 g/day; after 8 days the synovial implants were extracted and examined by immunohistology. The results showed that the anti-cd20 antibody depleted the B-cell levels in the synovial membrane and had a downstream effect in suppressing production of IFN- and IL-1 (Fig. 5). Therefore, it appears that B cells are directly involved in maintaining inflammation within the synovial membrane, and that T-cell activation can be B-cell dependent. The role of RF RF is an antibody reactive against antigenic determinants on the Fc fragment of the IgG molecule [11, 17]. Approximately 80% of patients with RA develop circulating RF antibodies [11, 18]. A wealth of historical evidence supports involvement of RF in the pathogenesis of RA. Furthermore, the severity and activity of RA has been correlated with RF levels, and seropositive RA is associated with more aggressive articular disease, a higher frequency of extra-articular manifestations and increased mortality and morbidity [11, 19].

3 Role of B cells in RA ii5 A FIG. 2. Diffuse (A) and follicular (B) infiltrates in synovial tissue. B The activation of B cells plays a critical role in the synthesis of RF and the rheumatoid synovial membrane contains an abundance of B cells with RF specificity [17]. It is thought that B cells with RF specificity may migrate into the synovium of patients with RA, therefore presenting a variety of complex antigens to relevant T cells. This causes perpetuation of the local inflammatory responses and amplification of RF production in the synovium [11]. These autoantibodies may prolong B-cell survival and hence maintain their own production. This self-perpetuating stimulus in conjunction with RF immune complex-mediated complement activation may collectively contribute to the propagation of the inflammatory cascade [18]. Support for this concept is provided from clinical intervention studies with the targeted anti-cd20 monoclonal antibody rituximab [20]. The observed drop in autoantibody production suggests a particular role for CD20þ B cells. Consequently, therapies that deplete or suppress B cells could be very valuable in the treatment of RA. Conclusions There is clear evidence that T and B cells play an integral part in the inflammation process associated with RA. B cells also have the potential to play a number of underlying roles in the pathogenesis of RA. Research suggests that targeted B-cell therapy in RA may operate via numerous potential mechanisms. Taken together with the evidence of their involvement as APCs in the activation of T cells, the production of RF and further immunoregulatory effects through dendritic cells, it seems appropriate that B cells should be investigated as a specific therapeutic target in RA.

4 ii6 FIG. 3. Possible roles of B cells in RA. FIG. 4. Pathway for B cells as antigen-presenting cells. (Courtesy of Professor.) FIG. 5. Effect of anti-cd20 antibody administration on cytokine transcript levels in synovial grafts from two patients with follicular synovitis. Tissue cytokine transcription was quantified by polymerase chain reaction enzyme linked immunsorbent assay (PCR-ELISA) following extraction of synovial grafts from SCID mice 6 days after the last antibody injection. Reproduced from Takemura et al. [15] with permission from the American Association of Immunologists. ß2001 The American Association of Immunologists, Inc.

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