Although identification of the central antigens in a number of rheumatic diseases is still lacking, formation of T cell/B cell aggregates and the formation of germinal centre-like structures can be correlated with increasing disease activity, including the production of autoantibodies (Leadbetter et al. 2002; Shlomchik et al. 2001). It needs to be shown whether apparent differences in the underlying pathologic process, with the disease activity likely escalating from 1) non-organized infiltrate to 2) T/B aggregates through 3) ectopic germinal centre formation. Such distinctions might indicate differences in the course of the disease correlating with the degree of B cell activity and may provide the benefit of tuning therapeutic strategies.
Despite the role of T cell help in the differentiation of B cells, recent studies suggest that B cells not only play an interactive role between the innate and adaptive immune system, but can also be activated without additional T cell help using either TLR- or BAFF-dependent activation pathways. This emphasizes the central role of B cells in immune responses and the need for B cell-directed therapies. A recent study (Leadbetter et al. 2002) showed that effective activation of rheumatoid factor-positive B cells can be mediated by IgG2a-chromatin immune complexes via engagement of the B cell receptor and TLR9, a member of the MyD88-dependent toll-like receptor (TLR) family. Bacterial and vertebrate DNAs differ by the absence of CpG methylation in bacteria and therefore TLR9 can detect unmethylated CpG dinucleotides as a signal of infection initiating B cell activation. In humans, the expression of TLR9 appears to be relatively restricted to B cells and CD123+ dendritic cells. After ligation of CpG motifs to TLR9, B cells are induced to proliferate and secrete Ig, and DCs secrete a wide array of cytokines, interferons and chemokines that activate TH1 cells. Bacterial DNA or CpG motifs co-stimulate B cell activation through cell membrane Ig and thereby promote an early antigen-specific response. This study (Leadbetter et al. 2002) found that immune complexes containing self-DNA activate rheumatoid factor-specific B cells as a result of two distinct signals: (a) engagement of the B cell antigen receptor (BCR) and (b) activation of TLR9 through the histone/DNA portion of the immune complex. Although the implications of these findings for certain autoimmune diseases need further studies, the evidence that TLR9 activation co-stimulates autoreactive B cells provides a mechanism of action for an established therapy for systemic autoimmune diseases. Decades ago, it was found that chloroquine is an effective therapy for systemic autoimmu-nity, but the mechanism of its activity was not identified. Chloroquine and other compounds that interfere with endosomal acidification and maturation specifically block all the CpG-mediated signals (Yin et al. 1998). The established efficacy of chloroquine and related compounds in treating autoimmune diseases could be related to a requirement for continuous co-stimulation of the BCR and TLR9 pathways in sustaining disease activity. Chloroquine also blocks antigen presentation, interleukin-6 production and directly binds DNA, which could contribute to its effectiveness. Moreover, it has been shown that sulfasalazine also has effects on reducing B cell activity, which further indicates that known disease-modifying antirheumatic drugs may have the capacity to influence the biologic activity of these cells (Cambridge et al. 2003). Moreover, other TLRs can also be considered as candidates in rheumatoid arthritis pathogenesis, i.e. TLR4 recognizing LPS, but this needs further investigation.
Therapy for severe autoimmune disease has primarily relied on broadly immunosuppressive agents such as cyclophosphamide, methotrexate, cy-closporine, leflunomide, mycophenolate mofetil and corticosteroids (Hiro-hata et al. 2002). Although survival rates have improved dramatically, none of these therapies offers a cure and most have significant toxicity. With the advent of monoclonal antibody and specific small-molecule-based therapies, more specific and effective therapies are possible. Therapy directed at specifically reducing B cell numbers has recently gained attention and enthusiasm (Cambridge et al. 2002; Dorner and Burmester 2003). Based on the ability of the chimerized anti-CD20 monoclonal antibody (rituximab) to reduce B cell numbers without significant toxicity, it is also being evaluated in human clinical trials for patients with a number of autoimmune diseases (Cambridge et al. 2002; De Vita et al. 2002; Edwards et al. 2000, 2004; Leandro et al. 2001, 2002a, b; Leandro, 2003). Rituximab functions by binding the membrane-embedded CD20 surface molecule on B cells, leading to B cell elimination by host immune effector mechanisms such as ADCC, inducing apoptosis and cell-mediated cytotoxicity.
A further humanized antibody directed to CD22 previously applied in non-Hodgkin's patients is also under evaluation in early clinical studies of patients with autoimmune disease (J. Kaufmann et al., personal communication).
Considering our current understanding of the role of B cells in the patho-genesis of autoimmune disease, the potential specificity of monoclonal antibodies with minimal toxicity, and the encouraging preliminary results in human clinical trials, one can expect to see a significant expansion in the use of B cell-directed therapy. Notably, however, most autoimmune patients that have benefited from rituximab therapy have not manifested remarkable decreases in measurable Ig levels, but have been associated with some—but not uniform—decreases in autoantibody titres, such as rheumatoid factor, an-tineutrophil cytoplasmic antigen, cryoglobulins. These data suggest that the therapeuticeffectmay notsimplyrelyondeleting precursors of autoantibody-producing cells, but possibly also by interfering with the life-cycle of specific antigen-presenting B cells.
Beyond overall B cell depletion allowing common targeting of T cell-dependent and -independent B cell activation, future therapies need to identify the most important common pathways of B cell activation that provide similar efficiency but avoid complete loss of B cells. Other potential targets for treating B cell-mediated human autoimmune diseases include BAFF antagonists and decoy receptors utilizing BMCA-Ig or TACI-Ig. Recent trials of CTLA-4-lg fusion proteins that disrupt T-B cell interactions (Kremer et al. 2003) and T cell activation have been promising in the treatment of rheumatoid arthritis, showing moderate efficacy with no evidence of significant toxicity. The development of therapeutic monoclonal antibodies that block certain ligand engagement or intracellular pathways may have considerable benefit for the treatment of autoimmunity, without the risk of eliminating bulk B cell populations, as with anti-CD20-directed therapies. Since CD19 deficiency ameliorates autoimmunity in mice, a further understanding of the molecular aspects of CD19-Src-family kinase interactions may lead to the identification of target molecules for therapeutic intervention during human autoimmunity.
Rapidly advancing molecular understanding of regular and disturbed immune responses will provide abundant targets appropriate for drug development. It is expected and likely that many of these drugs will target B cell function directly since it is becoming more obvious that abnormally activated B cells contribute substantially to many human autoimmune diseases.
Acknowledgements Supported by Sonderforschungsbereich 421 and 650, and DFG grants 491/4-7, 5-3,4.
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