The Pathogenic Role of Rheumatoid Factor in Rheumatoid Arthritis

Review

The pathogenic role of rheumatoid factor in rheumatoid arthritis

Rheumatoid factors (RFs) are the first autoantibodies described in rheumatoid arthritis (RA), which target the Fc region of IgG. Since their discovery, RFs have been the subject of extensive studies not just because of their association with RA, but also because they serve as an excellent model for the regulation and induction of disease-related autoantibodies. Although RFs are normally induced during secondary immune responses, isotype switching and affinity maturation are confined to RA patients and are not observed in normal individuals. Therefore, the emergence of high-affinity RFs, which are believed to depend on ‑T cell help, is under strict control in normal subjects, whereas these control mechanisms appear to be bypassed in RA. In this article, we provide an overview of the current knowledge of how pathologic RFs are induced and discuss the mechanisms by which RFs contribute to RA disease process.

†1 keywords: immune complex n rheumatoid arthritis n rheumatoid factor n Toll-like Yeong Wook Song receptor & Eun Ha Kang2 1Division of Rheumatology, + Department of Internal Medicine, The first autoantibody in rheumatoid arthritis natural antibodies produced by CD5 B1 cells Seoul National University College of (RA), rheumatoid factor (RF), was described (B1 cells). B1 cells are a subclass of B cells that Medicine, Seoul, Republic of Korea 2Division of Rheumatology, by Waaler in 1940, who reported the hemag spontaneously secrete IgM antibodies (natural Department of Internal Medicine, glutinating activity of a serum from a patient antibodies) of low-affinity and polyspecificity. Seoul National University Bundang Hospital, Seongnam-si, Republic of with RA [1]. RFs were named by Pike in 1949 They are different from conventional B2 cells Korea due to their association with RA [2] and were in that they do not undergo somatic hyper †Author for correspondence: later found to be autoantibodies targeting the mutation and memory formation. B‑cell sub Department of Internal Medicine, Seoul National University Hospital, Fc region of IgG in the g2–3 cleft. Although sets capable of secreting RFs are likely to include 28 Yongun-dong, Chongno-gu, Seoul, frequently observed in diseased conditions both B1 and B2 cells, but the culprit subset may 110–744, Republic of Korea Tel.: +82 220 722 234 including RA, RFs are also observed in normal be variable depending on the biological condi Fax: +822 762 9662 subjects [3], which implies that they have both tion that induces RF production. B1 cells have [email protected] pathological and physiological roles that depend been shown to compose a major fraction that on the circumstances under which they are secretes large amounts of IgM RFs against the induced. In this article, we provide an overview stimulation with Staphylococcus aureus [12]; RF of current knowledge regarding the induction of secretion from B1 cells was found to occur at pathologic RFs and discuss the mechanisms by comparable levels in RA patients and normal which RFs contribute to the RA disease process. subjects. Thus, it seems that the production of polyclonal low-affinity IgM RFs is not disease Characteristics of RFs & RF-producing specific, but rather a physiological response that B cells in normal individuals & in may serve in host defense by facilitating the RA patients formation and clearance of immune complexes. Rheumatoid factors are normally produced However, larger numbers of B1 cells are present during secondary immune responses against in RA patients compared with normal subjects infections or immunizations [4–6]. This find [13], and a correlation between peripheral blood ing is in line with the observation that RFs are B1 cell frequency and RF titer has been reported frequently found in chronic infectious condi in RA [14]. Therefore, the significance of these tions [7] and that immune-complexed rather than findings remains to be resolved, although these monomeric IgG is an efficient inducer of RF findings may mean that RA patients are more response [8]. In addition, RFs themselves bind readily triggered to produce RF and, thus, prone with much greater affinity to aggregated IgG or to RA development. Alternatively, these could be immune complex than to monomeric IgG [9–11]. secondary findings unrelated to disease patho RFs produced during the secondary immune genesis, because in patients with infectious dis response are generally polyclonal IgMs of low- eases, RF production is not correlated with the affinity, which resemble the characteristics of development of arthritis.

Nucleotide sequence analysis of RF genes mice expressing human IgM demonstrated from normal immunized hosts and RA that RF-producing B cells are deleted in the patients has shown that RFs in normal indi absence of T‑cell help and that complete B‑cell viduals are frequently encoded by a limited activation involving GC formation only occurs set of IgV genes, do not appear to switch iso with T‑cell help [20]. Another finding that fur type and have few replacement mutations in ther supports the role of T cells in the produc complementary determinant regions, which tion of pathologic RFs is that a critical contact results in little affinity maturation[15] . On the residue of RF from a RA patient was found other hand, the synovial RFs of RA patients to be derived from somatic hypermutation [21]. are encoded by a wider range of IgV genes, To date, T‑cell clones reactive to autologous undergo isotype switching and exhibit exten IgG have not been detected in RA patients, sive nucleotide changes in complementary most likely owing to clonal deletion. T cells determinant regions, which lead to affinity that infiltrate RA synovium have been shown maturation [15]. Although the precise pheno to be polyclonal and to lack specificity for any types of RF-producing B cells in lymph nodes particular autoantigen [22,23]. Nevertheless, any and tissue germinal centers (GCs) have not T cells that recognize antigen-derived peptides been determined in RA patients, the pres presented by RF-producing B cells have the ence of accumulated somatic mutations and potential to activate these B cells; the ability of isotype switching makes it plausible that of RF-expressing B cells to take up immune pathologic RFs are produced by T‑cell-driven complexes and to present trapped antigens to B2 cells in RA. ubiquitous T cells [24] may enable these cells to bypass the need for specific ‑T cell help, and How are RFs produced? could, ultimately, lead to the emergence of The mechanisms responsible for the activation autoreactive T cells that can trigger RF synthe of RF-producing B cells have been elusive for sis. On the contrary, recent studies on the role decades. In normal individuals, RF-producing of TLRs in B‑cell activation and differentiation B cells are not activated despite abundant self harbor questions whether T‑cell help is indis IgGs. The finding that monomeric IgGs, pensible (or whether TLR signaling is vital) for unlike immune-complexed IgGs, are poor the production of pathologic RFs. Emerging inducers of RF production suggests that effec data suggest that TLR and BCR co-activation tive B‑cell receptor (BCR) crosslinking is induces isotope switching without T‑cell help critical to transfer the B‑cell activation signal. [25–27], although little is known regarding the However, it has been shown that B‑cell activat effect of TLR signaling in somatic hyper ing ability depends not only on the immune mutation and affinity maturation. In addition, complex formation, but also on the nature of TLR engagement seems to provide an essential antigens contained in the complex in the sense signal for optimal antibody response even in that the ligation of Toll-like receptors (TLRs) is the presence of T cells [28,29]. Therefore, high- critical to trigger RF production in addition to affinity RFs might be triggered in the absence BCR ligation [16]; both B1 and B2 cells express of T‑cell help in the initial phase of RA, but TLRs, particularly TLR-1 and -9 [17,18]. This their production in established RA is likely to finding represents a good example of how TLRs involve both T‑cell help and TLR signaling in provide the link between innate and adaptive a synergistic manner. immunity. The interesting aspects of the simul taneous co-ligation of BCR and TLR are that How is tolerance to self IgG lost TLRs are expressed on memory B cells and RFs in RA? are produced via TLR ligation alone in mem Evidence shows that RF-producing B cells are ory B cells [19]. However, in order to generate highly efficient antigen-presenting cells for high-affinity RFs, particularly of IgG or IgA multivalent, immune-complexed antigens [24]. isotypes, T‑cell help might be required. Although T cells reactive to human IgG are deleted by a T‑cell tolerance mechanism [20], T ‑cell requirements for T cells that recognize antigen-derived peptides RF production presented by RF-producing B cells have the It has long been believed that T‑cell help is potential to activate these B cells. Therefore, crucial for the production of pathologic RFs the generation of predominantly IgM RFs that have undergone isotype switching and during secondary immune responses (when Ig affinity maturation. Studies on transgenic isotype switching usually occurs) suggests that

652 Int. J. Clin. Rheumatol. (2010) 5(6) future science group Review Song & Kang Rheumatoid factors in rheumatoid arthritis Review

a strict control mechanism prevents the emer and in the recently proposed American College gence of high-affinity RFs. Affinity-dependent of Rheumatology (ACR)/European League B‑cell deletion has been reported to censor Against Rheumatism (EULAR) criteria for autoreactive B cells during GC reaction [30,31]. RA [47]. However, much remains to be determined The physiological roles of RFs under normal regarding how high-affinity RF-producing conditions have been shown [48–50]: B cells escape tolerance mechanisms. To enhance immune complex clearance by It has been shown that the synovial mem increasing complex avidity and size; branes of RA patients are extrafollicular sec ondary lymphoid organs that provide a micro To help B cells uptake immune complex and, environment for isotype switching and the thereby, effectively present antigens to T cells; somatic mutation of RF-producing B cells [32]. To facilitate complement fixation by binding William et al. have reported that the somatic to IgG-containing immune complexes. hypermutation in an autoimmune response could occur elsewhere to the conventional GCs Thus, high-affinity and high-titer RFs in RA in an autoimmune murine model [33]. Based synovial fluid are believed to exert such func on the concept that censoring mechanisms are tions in a pathologic manner; the capacity of unique to GCs, these authors proposed that RFs to enhance immune complex formation B cells, which have undergone hypermutation [48,51] may not only grant arthritogenicity to RF outside GCs might escape the self-censoring itself, but also potentiate the arthritogenicities mechanism that selectively eliminates auto of other autoantibodies, including anticitrul reactive B‑cell clones and that they are more linated protein antibodies (ACPAs). Moreover, prone to be autoreactive. High-affinity RFs several studies have shown that immune com are locally produced in RA by B cells in the plexes isolated from RA patients induce TNF‑a inflamed synovium [34,35] where lymphoid or other cytokines from peripheral blood mono follicle-like structures are often found [36]. nuclear cells via Fc‑g receptor IIa engagement GCs have been found in approximately 25% [52–54]. In particular, Mathsson et al. have dem of the RA synovial samples examined, with onstrated that both serum and synovial fluid RF the remaining samples showing either diffuse levels of RA patients are correlated with poly or aggregated infiltrates of T and B cells [36]. ethylene glycol-precipitated synovial fluid IgG Although a substantial amount of evidence levels, the latter being correlated with TNF‑a indicates that GCs in RA synovium are the levels of peripheral blood mononuclear cells primary sites for the affinity maturation of induced by polyethylene glycol-precipitated autoantibodies [34,35,37], neither the clinical synovial fluid immune complexes; the immune phenotype of RA nor the presence of RFs is complex-induced TNF‑a levels were signifi associated with the presence of GCs [38,39]. cantly higher in RF-positive patients than Therefore, it remains to be resolved whether RF-negative patients [54]. They have also shown self-censoring mechanisms in synovial GCs that serum/synovial fluid ACPA levels were operate in the same manner as in nodal GCs. not correlated with serum/synovial fluid poly ethylene glycol-precipitated IgG levels or with Contributions of RFs to the disease in vitro induced TNF‑a levels. On the other process in RA hand, immune complexes formed with ACPAs IgM RFs are the major RF species in RA and and citrullinated proteins have been shown to are detected in 60–80% of RA patients [40]. induce TNF‑a from peripheral blood mono Furthermore, RF specificity to RA is increased nuclear cells or in vitro differentiated macro at high titers (e.g., IgM RF ≥50 IU/ml) and phages [52]. Therefore, both RFs and ACPAs with IgA isotypes [40,41]. High titer RFs and seem to contribute to RA severity. IgA isotypes are also associated with radiologic Although clinical as well as biological evi erosion, extra-articular manifestations and, dence indicate that RFs are important players thus, poorer outcomes [40,42–45]. The associa in RA pathogenesis, there has been no clear evi tion between high titer RF status and a poor dence that RFs are involved in the initial events prognosis indicates that RFs may have a role triggering the disease process of RA rather than in the pathogenesis of RA. In addition, RF has themselves being triggered by RA. Unlike the proven to be a useful disease marker of RA, and relatively low disease specificity of RF for RA, is included in the 1987 American Rheumatism it has been shown that ACPA production in Association classification criteria for RA [46] RA patients is a disease-specific humoral

future science group www.futuremedicine.com 653 Review Song & Kang Rheumatoid factors in rheumatoid arthritis Review

auto immune response [55–57]. It has been dem facilitating further immune complex forma onstrated in studies that retrospectively utilized tion, complement fixation, cytokine release and preclinical serum samples that both RF and tissue damage. Ultimately, exaggerated inflam ACPAs are present in the sera of RA patients mation will result in tissue citrullination and months to years prior to disease onset [58–60]. more ACPA production. Interestingly, the majority of RF-positive RA A number of studies have proved that effec patients are also positive for ACPA [55], and tive disease-modifying antirheumatic drug considering that immune complexes are strong therapy can decrease serum RF levels [61]. In inducers of RFs, immune complexes containing particular, reduction of IgM RF levels seems to citrullinated antigens and ACPA might facili be correlated with clinical improvement [62–64]. tate RF production. In support of this notion, Moreover, TNF‑a inhibitors have been shown the onset of RF was found by Nielen et al. to to decrease serum RF levels [65–68], which follow the onset of ACPA by a few years when was correlated with clinical improvement RF and ACPA titers were serially examined [65,66,68]. However, pretreatment RF positiv during the preclinical period [60]. Furthermore, ity was not different between responders and RF titers in ACPA-positive RA patients were nonresponders [67]. Rather, high basal levels found to be much higher than those in ACPA- of IgA RFs but not of ACPAs were associated negative patients in their study and vice versa. with poor response to TNF‑a inhibitors in a Therefore, a vicious cycle between ACPA and recent prospective study on 131 longstand RF is expected; ACPA-containing immune ing RA patients [67]. Unlike RF levels, reduc complexes induce RF production and RFs, in tion of anti-cyclic citrullinated peptide levels return, amplify the inflammatory response by after disease-modifying antirheumatic drug or

Genetic Environmental stimuli susceptibility

Isotype switching and Induction affinity Immune of ACPAs maturation complexes of RFs formed within the joint or trapped into the joint Induction Complement fixation of RFs or cytokine release via FcγRIIa More generation of ACPAs and RFs Joint damage

Clinical RA

Figure 1. Hypothetical model for rheumatoid factor synthesis and rheumatoid arthritis development. (A) ACPAs are induced in genetically susceptible individuals in response to protein citrullination caused by environmental stimuli. (B) RFs may be induced either by ACPA-containing immune complexes (in ACPA-positive and RF-positive patients) or by other inducers (in ACPA-negative and RF-positive individuals). (C) RF-producing B cells undergo isotype switching and somatic hypermutation upon chronic exposure to immune complexes. (D) Immune complexes, of which formation is facilitated in the presence of RFs, are preferentially formed within the joints where ACPAs and RFs are locally produced. Those formed outside the joints might be trapped into the joints. (E) Joint damage/inflammation begins with immune complex deposition, complement fixation and cytokine release.(F) Protein citrullination as a result of joint damage drives further ACPA production followed by further RF production. This causes a vicious cycle between joint damage and autoantibody production. RA is diagnosed when joint inflammation results in clinical symptoms. ACPA: Anticitrullinated protein antibody; RA: Rheumatoid arthritis; RF: Rheumatoid factor.

654 Int. J. Clin. Rheumatol. (2010) 5(6) future science group Review Song & Kang Rheumatoid factors in rheumatoid arthritis Review

TNF ‑a treatment has been controversial but patients [77]. Moreover, RFs have been shown to reported to occur in early RA patients with less be a better predictor of a good response to ritux than 1 year of disease duration [64,69], which, imab than ACPAs [78]. These findings provide however, was not correlated with clinical sound information regarding the actual and improvement. The close relationship between critical roles of RFs in the pathophysiology of serum RF levels (but not ACPA levels) and RA and suggest that RF-producing B cells and clinical response to TNF‑a therapy might their activation mechanisms may be important suggest that RFs play a distinguished patho therapeutic targets in RA. logic role from that of ACPAs. Alternatively, it might suggest that autoantibody-producing Conclusion & future perspective cells are differently regulated for RFs and Since RF was first described, substantial evi ACPAs; a number of factors are known to be dence has been accumulated from both basic important in plasma cell survival, including and clinical studies to suggest that RFs are cytokines such as TNF‑a and the cell adhesion key players in the pathogenesis of RA. This molecule CD44 [70]. concept has been further corroborated by the Recent advances in RA treatment include results of recent clinical trials adopting B‑cell the introduction of rituximab, an anti-CD20 depleting agents. The current hypothesis is that monoclonal antibody. CD20 is expressed RFs are induced by immune complexes derived by B‑cell precursors and mature B cells, but from disease-specific autoantibodies, which, not by stem cells or end-stage plasma cells. in turn, further potentiate immune complex Rituximab is interesting in that it directly formation, complement fixation, tissue dam targets autoantibody-producing B cells. Trials age and more disease-specific autoantibody of rituximab have shown that the agent is production (Figure 1). Since simultaneous TLR highly effective at reducing RA activity [71–73]. ligation is required in addition to BCR ligation Following B‑cell depletion by rituximab, to activate B cells to secrete RFs, the nature of a large and rapid decrease in RF titers was autoantigens contained in the immune com observed, whereas immunoglobulin concen plex might be a critical factor to elicit RF pro trations remained within normal ranges [73]. duction. Future studies on the mechanisms by Decrease of ACPA levels tended to be delayed which RF-producing B cells are activated and and modest compared with that of RF levels bypass tolerance mechanisms will help refine [74,75] and decreased levels of RFs and ACPAs crucial therapeutic targets. were only observed in responders [74]. The dif ferent kinetics of RF and ACPA levels during Financial & competing interests disclosure rituximab treatment implies that the produc This study was supported by a grant from the Korea tion of RFs is more dependent on short-lived Healthcare technology R&D Project, Ministry for Health plasma cells, while that of ACPAs on long-lived and Welfare, Republic of Korea (A084794). The authors plasma cells. In fact, spontaneous RF response have no other relevant affiliations or financial involvement has been shown to occur by continuous genera with any organization or entity with a financial interest in tion of short-lived plasmablasts in a transgenic or financial conflict with the subject matter or materials animal model with autoimmune background discussed in the manuscript apart from those disclosed. [76]. The effect of rituximab has been more No writing assistance was utilized in the production of beneficial in RF-positive than in RF-negative this manuscript.

E xecutive summary The production of the polyclonal low-affinity IgM rheumatoid factor (RF) is not disease specific, but rather a physiological response that may serve host defenses by facilitating the formation and clearance of immune complexes. RF-producing B cells secrete RFs when co-ligated on Toll-like receptors together with B‑cell receptors, reflecting the link between innate and adaptive immunity in the humoral immune response. T‑cell help is believed to be required to enable RF-producing B cells to undergo isotype switching and somatic hypermutation, a process that is responsible for the production of high-affinity pathologic RFs in rheumatoid arthritis (RA). However, the emergence of such RFs is strictly prevented in normal individuals via tolerance mechanisms that are not completely understood. Although high-affinity RFs do not seem to trigger RA themselves, they are thought to contribute actively to disease severity and chronicity by enhancing immune complex formation and complement fixation; RFs induced by immune complexes derived from disease- specific autoantibodies further potentiate immune complex formation, complement fixation, tissue damage and more disease-specific autoantibody production. Therefore, RF-producing B cells and their activation mechanisms, including Toll‑like receptor ligation may be important targets for RA treatment.

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65 Chen HA, Lin KC, Chen CH et al.: The 70 Cassese G, Arce S, Hauser AE et al.: Plasma mechanism of action and identification of effect of etanercept on anti-cyclic citrullinated cell survival is mediated by synergistic effects biomarkers of response. Ann. Rheum. Dis. peptide antibodies and rheumatoid factor in of cytokines and adhesion-dependent signals. 67(7), 917–925 (2008). patients with rheumatoid arthritis. J. Immunol. 171(4), 1684–1690 (2003). n Investigated the kinetics of changes of Ann. Rheum. Dis. 65(1), 35–39 (2006). 71 Vita S, Zaja F, Sacco S, De Candia A, different subsets of immune cells in the 66 Alessandri C, Bombardieri M, Papa N et al.: Fanin R, Ferraccioli G: Efficacy of selective peripheral blood and in the synovial of RA Decrease of anti-cyclic citrullinated peptide B cell blockade in the treatment of patients during rituximab treatment. The antibodies and rheumatoid factor following rheumatoid arthritis: evidence for a result of this study demonstrated that synovial anti-TNF‑a therapy (infliximab) in pathogenetic role of B cells. Arthritis Rheum. B‑cell depletion can occur with rituximab rheumatoid arthritis is associated with clinical 46(8), 2029–2033 (2002). treatment. Persistence of synovial plasma cells improvement. Ann. Rheum. Dis. 63(10), 72 Leandro MJ, Edwards JC, Cambridge G: was related to persistence of synovial B cells 1218–1221 (2004). Clinical outcome in 22 patients with and the reduction of synovial plasma cells was 67 Bobbio -Pallavicini F, Caporali R, Alpini C rheumatoid arthritis treated with B associated with clinical improvement. et al.: High IgA rheumatoid factor levels are lymphocyte depletion. Ann. Rheum. Dis. 76 William J, Euler C, Shlomchik MJ: associated with poor clinical response to 61(10), 883–888 (2002). Short-lived plasmablasts dominate the early tumour necrosis factor‑a inhibitors in 73 Edwards JC, Szczepanski L, Szechinski J et al.: spontaneous rheumatoid factor response: rheumatoid arthritis. Ann. Rheum. Dis. 66(3), Efficacy of B-cell-targeted therapy with differentiation pathways, hypermutating cell 302–307 (2007). rituximab in patients with rheumatoid arthritis. types, and affinity maturation outside the 68 De Rycke L, Verhelst X, Kruithof E et al.: N. Engl. J. Med. 350(25), 2572–2581 (2004). germinal center. J. Immunol. 174(11), Rheumatoid factor, but not anti-cyclic nn One of the largest studies that investigated the 6879–6887 (2005). citrullinated peptide antibodies, is modulated therapeutic effect of rituximab in RA patients. 77 Edwards JC, Cambridge G: Prospects for by infliximab treatment in rheumatoid arthritis. Significant improvement was observed in B-cell-targeted therapy in autoimmune Ann. Rheum. Dis. 64(2), 299–302 (2005). clinical parameters, which proves that B cells disease. Rheumatology (Oxford) 44(2), 69 Rönnelid J, Wick MC, Lampa J et al.: are critical players in RA pathogenesis. 151–156 (2005). Longitudinal analysis of citrullinated protein/ 74 Cambridge G, Leandro MJ, Edwards JC et al.: 78 Quartuccio L, Fabris M, Salvin S et al.: peptide antibodies (anti-CP) during 5 year Serologic changes following B lymphocyte Rheumatoid factor positivity rather than follow up in early rheumatoid arthritis: depletion therapy for rheumatoid arthritis. anti-CCP positivity, a lower disability and a anti-CP status predicts worse disease activity Arthritis Rheum. 48(8), 2146–2154 (2003). lower number of anti-TNF agents failed are and greater radiological progression. associated with response to rituximab in Ann. Rheum. Dis. 64(12), 1744–1749 (2005). 75 Thurlings RM, Vos K, Wijbrandts CA, Zwinderman AH, Gerlag DM, Tak PP: rheumatoid arthritis. Rheumatology (Oxford) Synovial tissue response to rituximab: 48(12), 1557–1559 (2009).

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