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 low­affinity 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. B­cell 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 low­affinity 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 form ation 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 immune­complexed 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. 10.2217/IJR.10.62 © 2010 Future Medicine Ltd Int. J. Clin. Rheumatol. (2010) 5(6), 651–658 ISSN 1758-4272 651 REVIEW Song & Kang Rheumatoid factors in rheumatoid arthritis REVIEW Nucleotide sequence ana lysis of RF genes mice expressing human IgM demonstrated from normal immunized hosts and RA that RF­producing B cells are deleted in the patients has shown that RFs in normal indi­ absence of T­cell help and that complete B­cell viduals are frequently encoded by a limited activation involving GC formation only occurs set of IgV genes, do not appear to switch iso­ with T­cell 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, T­cell 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 RF­producing B cells in lymph nodes particular autoantigen [22,23]. Nevertheless, any and tissue germinal centers (GCs) have not T cells that recognize antigen­derived peptides been determined in RA patients, the pres­ presented by RF­producing 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 RF­expressing B cells to take up immune pathologic RFs are produced by T­cell­driven 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 RF­producing B cells have been elusive for sis. On the contrary, recent studies on the role decades. In normal individuals, RF­producing of TLRs in B­cell activation and differentiation B cells are not activated despite abundant self harbor questions whether T­cell help is indis­ IgGs. The finding that monomeric IgGs, pensible (or whether TLR signaling is vital) for unlike immune­complexed IgGs, are poor the production of pathologic RFs. Emerging inducers of RF production suggests that effec­ data suggest that TLR and BCR co­activation tive B­cell receptor (BCR) crosslinking is induces isotope switching without T­cell help critical to transfer the B­cell activation signal. [25–27], although little is known regarding the However, it has been shown that B­cell 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 Toll­like 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 T­cell help in the initial phase of RA, but TLRs, particularly TLR­1 and ­9 [17,18]. This their production in established RA is likely to finding represents a good example of how TLRs involve both T­cell help and TLR signaling in provide the link between innate and adaptive a synergistic manner. immunity. The interesting aspects of the simul­ taneous co­ligation 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 RF­producing B cells are ory B cells [19]. However, in order to generate highly efficient antigen­presenting cells for high­affinity RFs, particularly of IgG or IgA multivalent, immune­complexed antigens [24]. isotypes, T­cell help might be required. Although T cells reactive to human IgG are deleted by a T­cell tolerance mechanism [20], T -cell requirements for T cells that recognize antigen­derived peptides RF production presented by RF­producing B cells have the It has long been believed that T­cell 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 high­affinity RFs. Affinity­dependent of Rheumatology (ACR)/European League B­cell deletion has been reported to censor Against Rheumatism (EULAR) criteria for auto reactive B cells during GC reaction [30,31].