Protective autoantibodiesRole in homeostasis clinical importance and therapeutic potential.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 52, No. 9, September 2005, pp 2599–2606 DOI 10.1002/art.21252 © 2005, American College of Rheumatology REVIEW Protective Autoantibodies Role in Homeostasis, Clinical Importance, and Therapeutic Potential Yehuda Shoenfeld1 and Elias Toubi2 antigens by masking their antigenic determinants. Humoral autoimmune protection is a growing field of study in which protective autoantibodies are thought to play a role in preventing many autoimmune diseases, such as systemic lupus erythematosus (SLE). IgM anti–doublestranded DNA (anti-dsDNA) antibodies have a negative correlation with the severity of glomerulonephritis (GN) in SLE. The administration of IgM anti-dsDNA antibodies into SLE-prone mice prevented the development of nephritis, suggesting a protective role for these antibodies. In addition, the presence of rheumatoid factor (RF) in SLE was suggested by many investigators to be protective against the development of lupus nephritis. Beneficial autoimmunity against proinflammatory cytokines has also been reported to play a role in the immunomodulation of autoimmune diseases, such as rheumatoid arthritis (RA). Autoantibodies to various oxidation-specific neoepitopes on oxidized low-density lipoprotein (oxLDL) have been demonstrated to attenuate inflammation and plaque formation in atherosclerosis. Thus, protective autoantibodies may be utilized for therapeutic purposes, e.g., IgM anti-dsDNA and antioxLDL antibodies might serve as useful treatments for patients with SLE and patients with atherosclerosis, respectively. Thus, it seems that the protective role of autoimmunity is not limited to the cellular processes of the immune system, since the humoral process (autoantibodies) has also been found to be involved. In the present report, we summarize the current knowledge on protective autoantibodies, the existence of which seems to lead to their application for therapeutic purposes. Introduction Paul Eherlich, a Nobel prize laureate, believed that the existence of autoantibodies is always associated with fatal conditions, referring to the idea as the horror autotoxicus. However, this notion of fatal autoimmunity was later refuted by him when he suggested that antiautotoxin antibodies may exist. The dogma that autoimmunity leads to continuous damage of organisms has since been challenged by a mass of data in which autoimmunity is demonstrated to be protective in many situations. Previous studies have shown that central nervous system (CNS) trauma spontaneously evokes a beneficial T cell–dependent immune response that reduces neuronal loss. Injuries to the CNS induce self-destructive processes, leading to the degeneration of initially spared neurons. This destruction is mediated by increased amounts of glutamate, a neurotransmitter that becomes cytotoxic when presented in excessive amounts but which can recruit and activate a T cell–dependent self-protective immune mechanism (1–3). This protective autoimmunity was shown to be a Th1-mediated response that could be experimentally achieved by passive transfer of autoreactive Th1 cells (4–6). Natural autoantibodies are found in the sera of healthy individuals. They are polyreactive, mostly of the IgM isotype, and react with both self and non-self antigens. Nonspecific and low-affinity binding of these natural autoantibodies to self antigens may prevent autoreactive clones from reacting vigorously with self 1 Yehuda Shoenfeld, MD, FRCP (Hon): Sheba Medical Center, Tel-Aviv University, Tel-Hashomer, Israel; 2Elias Toubi, MD: Bnai Zion Medical Center, Haifa, Israel. Address correspondence and reprint requests to Yehuda Shoenfeld, MD, FRCP (Hon), Department of Medicine “B,” Sheba Medical Center, Tel-Hashomer 52621, Israel. E-mail: Shoenfel@post.tau.ac.il. Submitted for publication January 19, 2005; accepted in revised form May 24, 2005. Natural autoantibodies as protective immunoglobulins Natural autoantibodies derive their name from the fact that they are generated in the absence of specific immunization and exist independent of exposure to 2599 2600 foreign antigens (i.e., belong to the innate immune system) (7). Although natural autoantibodies may belong to all isotypes, IgM antibodies constitute the major component. Moreover, natural autoantibodies are primarily polyreactive, encoded by germline V-gene segments, and have low affinities but broad specificities to both foreign and self structures (8). Depending on the conditions encountered, natural autoantibodies are able to exert either a physiologic (beneficial, protective) or a pathologic (harmful) role. When they transform into a higher affinity, become self specific, and are produced in excess, natural autoantibodies might participate in the formation of pathogenic immune complexes (9). Natural autoantibodies are characterized by their reactivity against well-conserved public epitopes. They fulfill the definition of autoantibodies, since they are self reactive but not self specific. The nonspecific and lowaffinity binding of natural autoantibodies to self antigens may prevent autoreactive clones from reacting vigorously with self antigens by binding and masking their antigenic determinants (10). Early studies shared the concept that natural autoantibodies act to remove circulating products, some of which are immunogenic autoantigens, before they can elicit a damaging autoimmune response (11). This is consistent with their reported participation in the clearance of altered self constituents, such as aged erythrocytes and keratinocytes, by enabling multivalent binding of natural IgG antikeratin antibodies and the subsequent phagocytosis of the immune complexes formed (12). The recent availability of secreted IgM–deficient (sIgM⫺/⫺) mice has provided a model to test the importance of natural IgM in autoimmune diseases. In this model, mice bear a deletion of the coding sequence for sIgM; therefore, IgM is expressed, but not secreted, on the surface of B cells. When MRL/lpr mice were crossed with sIgM⫺/⫺ mice, they developed a more severe form of disease, suggesting that deficiency of natural IgM antibodies could be the predisposing factor for accelerated SLE (13). Natural IgM antibodies pooled from the normal circulating IgM repertoire have recently been shown to induce apoptosis of lymphoblastoid cell lines and human peripheral blood mononuclear cells. The IgM-induced cell death involved classic features of apoptosis, such as nuclear fragmentation and activation of caspases (14). Soluble Fas molecules inhibited this natural autoantibody–induced apoptosis, suggesting that the Fas pathway is involved. These results allude to a role for normal IgM antibodies in controlling cell death and proliferation, and imply a possible therapeutic role for SHOENFELD AND TOUBI IgM antibodies in autoimmune and lymphoproliferative disorders. In some autoimmune situations, the inhibition of certain IgG autoreactive responses to histone or dsDNA by natural polyreactive IgM monoclonal antibodies (mAb) does not function, leading to the expression or expansion of autoreactive IgG-producing clones. The inhibitory effect of IgM mAb is mediated by V-region– dependent interactions with the autoreactive IgG, as shown by the ability of these antibodies to block the binding of F(ab⬘)2 fragments of autoreactive IgG to their respective autoantigens (15). The blocking activity was found to be dose-dependent, with maximal inhibition occurring at a specific molar ratio between the patient’s IgG and a given mAb, supporting the concept of a functional idiotypic network regulating autoimmune responses. The interaction between IgM mAb and F(ab⬘)2 fragments of autoreactive IgG might involve several sites and could be dependent on 3-dimensional configurations (16). Nevertheless, it is conceivable that many of the natural autoantibodies may act protectively by being immunoregulatory. Observed qualitative differences would imply that there are modifications in the mechanisms of natural autoantibody synthesis, leading to the development of monospecific autoantibodies that possess high affinities for self structures. Autoimmunity after infections by parasites or viruses could lead to permanent immune activation, due to dysregulation of natural autoantibody production. Anti–single-stranded DNA, antithyroglobulin, and anti-IgG antibodies are demonstrated after stimulation of CD5⫹ B lymphocytes from healthy humans by viruses such as the Epstein-Barr virus (17). Thus, natural autoantibodies act as a filter, preventing autoantigens from inducing autoimmunity by cross-reaction with antigens on infectious organisms. Natural autoantibodies may also act by blocking the receptors on autoreactive CD5⫹ cells and by downregulating their own synthesis (18). It has been demonstrated that 10–20% of the total IgG molecules isolated from immune and nonimmune sera are asymmetrically glycosylated, in such a way that they fail to trigger immune effector mechanisms and to form insoluble complexes with antigens (19). In contrast to symmetrically glycosylated IgG autoantibodies, asymmetric IgG antibodies are self specific but have no deleterious effect in normal individuals, and therefore may act as autoprotective antibodies. Asymmetric IgG antibodies act in a competitive way when they are mixed with precipitating or symmetric antibodies of the same specificity, and the action of these antibodies ROLE OF PROTECTIVE AUTOANTIBODIES 2601 therefore depends on their respective proportion in the mixture (20). The increased ratio of asymmetric to symmetric IgG in sera from older rats suggests that asymmetric antibodies may exert a beneficial effect by protecting self antigens from inducing severe immune responses (21). Protective antibodies in autoimmune diseases It seems that natural autoantibodies are not the only molecules that entail protective characteristics. Protective autoantibodies may also be detected among the regular repertoire of autoantibodies in a disease process. IgM anti-dsDNA antibodies. Anti-dsDNA antibodies differ with respect to their avidity, isotype, antigen specificity, charge, idiotypes, and V-region sequences. The IgM class of anti-dsDNA antibodies appears in disease states other than SLE, such as RA, Sjögren’s syndrome, and autoimmune liver disease (22). The presence of IgM anti-dsDNA antibodies in SLE was found to be significantly associated with milder disease activity, namely, a negative correlation with lupus nephritis (23). In contrast, immune complexes containing IgG autoantibodies against dsDNA are deposited in the renal vasculature, which results in organ damage, and this has been correlated with the severity of GN in SLE (24). In a recent study, absence of lupus nephritis was suggested to be a consequence of a predominance of the IgM isotype of anti-dsDNA antibodies (25). SLE patients with a permanent ratio of IgG to IgM of ⬍0.8 did not develop lupus nephritis, despite high levels of antidsDNA antibodies. The greater ability of antibodies of the IgM class to bind more circulating antigen could explain the phenomenon of a decrease in the formation of IgG-class immune complexes via competitive inhibition. It is also possible that IgM anti-dsDNA antibodies may down-regulate autoreactive B cells and decrease the production of pathogenic IgG anti-dsDNA antibodies. Thus, higher titers of IgM compared with IgG antidsDNA antibodies, as well as the impaired switchover of IgM to IgG, might indicate a protective effect against lupus nephritis. In addition, it has been suggested that IgM anti-dsDNA–dsDNA complexes are cleared more effectively by phagocytes and are therefore minimally deposited in the glomerular basement membrane (Figure 1). Thus, it was logical to investigate whether IgM antidsDNA antibodies can be used to prevent immune complex–mediated organ damage. In a group of un- Figure 1. Protective and pathogenic roles of anti–double-stranded DNA (anti-dsDNA) antibodies. A, IgM anti-dsDNA are efficent in binding and neutralizing dsDNA. In addition, IgM–dsDNA immune complexes undergo efficient phagocytosis instead of being deposited on the glomerular basement membrane. B, Pathogenic IgG antidsDNA antibodies remain soluble and therefore escape efficient phagocytosis and are deposited on the glomerular basement membrane. Color figure can be viewed in the online issue, which is available at http://www.arthritisrheum.org. treated NZB ⫻ NZW mice, which are prone to develop SLE, typical signs of GN, including glomerular IgG deposits and infiltration of mononuclear cells, were evident; in contrast, when age-matched mice were treated with IgM anti-dsDNA antibodies, absence or only mild signs of GN and only a minimal glomerular deposition of IgG could be determined (26). These results demonstrate that IgM anti-dsDNA antibodies may protect against immune complex–mediated organ damage in murine lupus and may explain why human SLE patients with higher titers of IgM anti-dsDNA are partially protected against GN. Protective RF. There is no agreement on whether the presence of RF exerts protection, induces injury, or is an epiphenomenon with regard to kidney disease in SLE. The presence and isotype distribution of RF in SLE patients in relation to some clinical parameters, including renal function, was not found to be protective (27). However, many other studies demonstrated RF to be protective against the development of lupus nephritis. In one study, a highly significant correlation between the presence of IgM-RF and the absence of kidney disease was noted (28). In that same study, elevated levels of IgG-RF indicated active SLE disease, suggesting that there is the potential for various RF isotypes to interact differently with immune complexes in vitro and in vivo. In another study, it was shown that IgM-RF could block attachment of C3b, which is capable of reacting with glomeruli receptors, indicating that IgM-RF can inhibit binding of immune complexes to human glomer- 2602 uli (29). This in vitro phenomenon may represent a possible protective mechanism of RF in vivo in immune complex diseases. Furthermore, it was shown that the presence of only IgA-RF defined a subgroup of SLE patients in whom high disease activity, but a lower incidence of SLE nephropathy, was present (30). It is speculated that immune complexes are enlarged by the presence of RF and are therefore more efficiently phagocytosed, or cannot penetrate the glomerular basement membrane, thereby decreasing their nephritogenic potential. An interesting negative association between IgG-RF and IgG–anticardiolipin (aCL) antibodies has been reported, suggesting that the presence of IgG-RF in SLE may lower the risk of developing the clinical manifestations of the antiphospholipid syndrome (APS) (31). Further confirmatory studies are needed to establish the above observations. Protective anticytokine antibodies. Anticytokine antibodies have been shown to play an important role in the regulation of the immune response, both under normal conditions and in several autoimmune disorders. It has recently been demonstrated that the immune system, which can attack self components, also generates beneficial autoimmunity against proinflammatory mediators. A well-defined model of RA was used to elaborate the contribution of beneficial autoimmunity to the regulation of the disease, demonstrating that during the disease, autoantibody production is elicited against a few inflammatory, but not regulatory, mediators. Epitope mapping has revealed that anti–tumor necrosis factor ␣ (anti-TNF␣) immunity is highly restricted and shows no cross-reactivity to other known gene products (32). The occurrence and clinical significance of natural neutralizing antibodies against interferons (IFNs) has been investigated in patients with myasthenia gravis (MG). Natural antibodies against any of the IFNs were not detected in healthy subjects, whereas 21% of patients with MG had natural antibodies against IFN␣ and 9% had natural antibodies against IFN␤ (33). The role of these natural antibodies in MG needs to be further investigated. Protective anti–T cell receptor (anti-TCR) antibodies. The nonresponsiveness of T cells to self antigens is controlled by several mechanisms, including clonal deletion, T cell ignorance, and existence of specific regulatory T cells. Anti-TCR antibodies may constitute another significant level of regulation, but their occurrence and regulatory role have been poorly investigated. Natural autoantibodies specific for the TCR are produced spontaneously at low levels in some healthy SHOENFELD AND TOUBI human sera, and at higher levels in patients with RA and SLE (34). There are also variations in isotype and in the particular variable region that is recognized. IgM autoantibodies directed against a few peptide-defined determinants were elevated in RA, whereas SLE patients’ sera showed higher IgG binding to a broad spectrum of TCR peptides. Naturally occurring, circulating regulatory anti-TCR antibodies have also been detected in patients with MG (35). These antibodies were reactive against a dominant T cell population expressing the V␤5.1 TCR gene, which is responsible for the production of the pathogenic anti–acetylcholine receptor antibodies in HLA–DR3–positive patients with early-onset MG. Anti-TCR antibodies specifically bound the native TCR on intact V␤5.1-expressing cells and specifically inhibited the proliferation and IFN␥ production of purified V␤5.1-expressing cells to alloantigens in the mixed lymphocyte reaction, indicating regulatory functions for these antibodies. The occurrence of anti-TCR antibodies has been associated with less severe disease, but the effects are not sufficient to prevent a chronic exacerbated autoimmune process. Protective autoantibodies in atherosclerosis. Anti-oxLDL antibodies. Atherosclerosis is a chronic inflammatory disease whose pathogenesis involves disrupted lipoprotein metabolism and the formation of proinflammatory lipid perioxidation products. The oxidation of LDL generates a variety of oxidatively modified lipids and proteins that represent highly immunogenic neodeterminants of the immune system (36). In murine models of atherosclerosis, such as apolipoprotein E–deficient (ApoE⫺/⫺) mice, atherosclerosis is correlated with the development of high titers of autoantibodies to various oxidation-specific neoepitopes of oxLDL (37). IgG-oxLDL immune complexes facilitate increased uptake of oxLDL via Fc␥ receptors on macrophages, the formation of foam cells, and the release of IFN␥ and TNF␣, thus contributing to endothelial cell dysfunction and the development of atherosclerosis (38,39). In contrast, IgM anti-oxLDL antibodies were suggested, in many studies, to play a protective role against the development of atherosclerosis. In ApoE⫺/⫺ mice, a panel of oxLDL-specific B cell lines that secrete IgM antibodies were defined as natural autoantibodies with a protective role against atherosclerosis (40). All were IgM antibodies that bound strongly to malondialdehyde (MDA)–modified LDL or to LDL previously oxidized by exposure to copper. These antibodies have been shown to bind to the phosphorylcholine (PC) head group of oxidized phos- ROLE OF PROTECTIVE AUTOANTIBODIES pholipids (oxPLs) and to be structurally and functionally identical to the natural T15/EO6 IgM anti-PC antibodies (of B-1 cell origin and reported to provide optimal protection from virulent pneumococcal infection) (41). Immunization of mice with MDA-modified LDL induced the expansion of innate B-1 cells and the secretion of IgM antibodies that bind the PC of oxPLs, thus reducing atherogenesis (42). Anti-oxLDL antibodies have been shown to be inversely related to intima-media thickening (IMT) of the carotid arteries when studied in a healthy population with no clinical signs of atherosclerosis (43). In a population-based cohort of 1,022 middle-age men and women, the relationship between different isotypes of autoantibodies to copper-oxidized LDL and MDAmodified LDL and the development of carotid artery IMT was investigated (44). Circulating IgM autoantibodies to MDA-modified LDL had a stronger, inverse correlation with subclinical atherosclerosis (determined by IMT of the carotid artery) than that of autoantibodies to copper-oxidized LDL. In a recent study, a significant inverse correlation between the presence of anti-oxLDL autoantibodies and the degree of LDL or LDL oxidation was demonstrated (45), suggesting that the increase in anti-oxLDL antibodies and the extent of the LDL oxidation ratio is protective against atherosclerosis. The findings are indeed conflicting, since some anti-oxLDL autoantibodies seem to be protective, whereas many others are found to be correlated with the extent of atherosclerosis; thus, antioxLDL can be characterized as either predictive or pathogenic. This contradiction is explained by the possibility that there are, in fact, at least 2 different types of antibodies produced in vivo. One is a protective antibody that is induced by active immunization and is able to clear oxLDL cholesterol from the circulation, whereas the other types of antibody are pathogenic and play a role in the formation of foam cells. This could be due to the heterogeneous nature of these antibodies, which differ both in Ig subclass and in their epitope specificity and affinity (46). A number of protective mechanisms of IgM anti-oxLDL antibodies have been proposed. 1) Natural IgM antibodies can inhibit the scavenger receptor– mediated binding and uptake of oxLDL by macrophages in a dose-dependent manner. 2) The ability of apoptotic cells and blebs to induce monocyte adhesion by endothelial cells was inhibited by protective IgM anti-oxLDL antibodies, indicating that apoptotic and oxidized membrane blebs contain the same biologically active oxPLs present in oxLDL (47). By binding to these proathero- 2603 Figure 2. Protective role of anti–oxidized low-density lipoprotein (anti-oxLDL) antibodies (Abs) against atherosclerosis. A, Uptake of oxLDL by phagocytes increases the formation of foam cells and atherosclerotic plaques. B, Protective IgM anti-oxLDL antibodies bind oxidation-specific epitopes on apoptotic cells, preventing their uptake by macrophages and decreasing the formation of foam cells. genic epitopes, natural IgM antibodies promote their clearance away from vascular sites to distant sites, such as the spleen. 3) Anti-oxLDL antibodies may retain potentially proatherogenic oxLDL particles that are largely intravascular, which prevents their interaction with the vessel wall (Figure 2). Interleukin-5 (IL-5). IL-5 has been shown to be stimulatory on innate B-1 cells, leading to increased secretion of T15/EO6 IgM antibodies, whereas IL-5 deficiency leads to decreased titers of these antibodies and accelerated atherosclerosis. Thus, IL-5 links adaptive and natural immunity specifically to epitopes of oxLDL and protects from atherosclerosis, in part by the expansion of atheroprotective natural IgM antibodies specific for oxLDL (48). Naturally occurring antibodies to cholesterol in normal human plasma also contribute to turnover of LDL cholesterol by opsonizing LDL and other lipoproteins containing bad cholesterol, thus enabling removal by complement receptors (49). Antiphospholipid antibodies (aPL). Patients with APS are at a higher risk of developing atherosclerosis, and individuals with primary atherosclerosis have an increased prevalence of both aPL and anti-oxLDL (50). Several studies indicate that some aPL can cross-react with oxLDL, indicating that similar antigenic determinants can be created by the oxidation of PLs and LDLs. It has been assumed that aPL, similar to antioxLDL, may play a protective role against atherosclerosis. To further investigate this theory, the CL-reactive mAb FB1 was obtained from an (NZW ⫻ BXSB)F1 mouse (a strain with features of SLE and APS) and 2604 passively administered to atherosclerosis-prone mice (51). The antibody was found to cross-react with both native LDL and oxLDL and significantly reduced plaque formation in these mice, indicating that some aPL may play a protective role in atherogenesis. In addition to its possible effect on cleaning oxLDL from the circulation and preventing its uptake by macrophages, it has been proposed that the FB1 mAb could modify lipoproteins and inhibit expression of adhesion molecules in the aortic vasa vasorum. In addition, the presence of aPL that cross-react with oxLDL immune complexes can crosslink Fc receptors on macrophages and induce IL-10 production, a protective factor against atherosclerosis (52). Protective autoimmunity as a future therapy Among the many immunomodulatory therapeutic regimens in autoimmune diseases, high-dose intravenous immunoglobulin (IVIG) has been shown to be beneficial, without being immunosuppressive or toxic (53). IVIG contains a wide range of natural autoantibodies that reflect the exposure of the donor population to different immunopathogens. These natural autoantibodies are directed against the constant heavy- and light-chain domains of autoantibodies. Natural antiidiotype autoantibodies may also bind to variable regions of antigen receptors, rendering cell activation by autoantigens impossible (54). Natural anti–hinge region autoantibodies may also block autoreactive B cell proliferation, especially when autoantigen is bound to the B cell antigen receptor (55) (Figure 3). Natural anti-CD4 and anti–class I major histocompatibility complex autoantibodies have been affinity-purified from IVIG preparations, inhibiting CD4 T cell proliferation in a mixed lymphocyte culture and hindering the function of CD8 T cells. These data suggest that IVIG might modulate T cell–mediated autoimmune diseases (56). IVIG has been shown to contain agonistic anti–Fas receptor autoantibodies that mediate antiinflammatory effects by inducing apoptosis of inflammatory cells such as activated CD4⫹ T cells and autoreactive B cells. Natural antiidiotype autoantibodies were also found to block Fas ligand–Fas receptor interactions, thus preventing apoptosis of some immunomodulatory cells. Therefore, both mechanisms are relevant in IVIG-induced immunomodulation in SLE (57). In order to evaluate the clinical response of SLE patients to IVIG, 20 patients were treated with highdose (2 gm/kg) IVIG monthly, in a 5-day schedule for SHOENFELD AND TOUBI Figure 3. Protective role of natural autoantibodies in intravenous immunoglobulin (IVIG). A, Natural autoantibodies in IVIG prevent autoimmunity by binding apoptotic cells and increasing their efficient phagocytosis. B, Natural antibodies may bind self antigens expressed in blebs on apoptotic cells and prevent their recognition by autoreactive cells. C, Natural autoantibodies have also been shown to downregulate autoreactive B cells, especially when autoantigens are bound to the B cell antigen receptor. Color figure can be viewed in the online issue, which is available at http://www.arthritisrheum.org. 1–8 treatment courses (58). A beneficial clinical response was seen in 17 of 20 patients (85%). Mainly manifestations such as arthritis, fever, thrombocytopenia, and neuropsychiatric lupus responded to the treatment. Responders tended to have a significant normalization of their abnormal C4 and anti-SSA/Ro antibody levels following IVIG treatment. Assuming that the idiotype network is an important mechanism for maintaining self tolerance, we investigated the effects of modulation by antiidiotype antibodies by using concentrated, specific natural polyclonal anti-dsDNA antiidiotype antibodies (IVIG-Id) that were obtained from commercial IVIG in (NZB ⫻ NZW)F1 mice (59). The IVIG-Id–treated mice showed a decline in the titer of anti-dsDNA antibodies during the treatment. Improvement in the renal immunohistologic condition was significant and the survival time was much longer in the IVIG-Id–treated mice compared with controls (59). Conclusion The protective role of IgM anti-dsDNA antibodies in ameliorating renal involvement in murine lupus and the protective effects of the naturally existing antibodies to proinflammatory cytokines support the idea that natural autoantibodies could become one of the future therapies in several autoimmune diseases. These antibodies could be boosted either by specific immuni- ROLE OF PROTECTIVE AUTOANTIBODIES zation or by utilizing hybridoma techniques with selection for specific protective IgM antibodies. As we have discussed, there is the potential to harness this knowledge for therapeutic purposes, utilizing active immunization with the relevant autoantigens as a means to stimulate the immune therapeutic response (e.g., active immunization with oxLDL to protect against atherosclerosis) or utilizing passive transfer of protective antibodies (e.g., IVIG or specific protective autoantibodies such as IgM anti-dsDNA, aCL, and anti-TCR) (60,61). Defining the characteristics of these protective autoantibodies and the conditions of their generation brings us closer to the potential for prevention of autoimmune diseases such as RA and SLE. 2605 16. 17. 18. 19. 20. 21. REFERENCES 1. Nevo U, Kipnis J, Golding I, Shaked I, Neumann A, Akselrod S, Schwartz M. 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