the therapeutic potential of targeting b cells and anti-oxldl antibodies in atherosclerosis
TRANSCRIPT
Autoimmunity Reviews 9 (2009) 53–57
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Autoimmunity Reviews
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The therapeutic potential of targeting B cells and anti-oxLDL antibodiesin atherosclerosis
M. van Leeuwen, J. Damoiseaux, A. Duijvestijn, J.W. Cohen Tervaert ⁎Department of Internal Medicine, Section Clinical & Experimental Immunology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, The Netherlands
⁎ Corresponding author. Department of InternalExperimental Immunology, Maastricht University MediMD Maastricht, The Netherlands.
E-mail address: [email protected]
1568-9972/$ – see front matter © 2009 Elsevier B.V. Aldoi:10.1016/j.autrev.2009.03.001
a b s t r a c t
a r t i c l e i n f oArticle history:Received 22 February 2009Accepted 3 March 2009Available online 11 March 2009
Keywords:AtherosclerosisB cellAnti-oxLDL antibodiesTherapyPassive immunization
While the involvement of T cells in atherosclerosis is nowadays well accepted, little is known about the roleof B cells. Obviously, B cells as the source of antibodies, in particular antibodies to oxLDL, have gained a lot ofattention in atherosclerosis. In addition, B cells do harbour other functions in adaptive immunity. In thisreview, we provide an overview of the current knowledge on both the role of B cells and antibodies, i.e., anti-oxLDL antibodies, in atherosclerosis. It appears that B cells and also anti-oxLDL antibodies may comprise pro-and anti-atherogenic effects. Therefore, the establishment of effective therapy, targeting B cells or anti-oxLDLantibodies, warrants further research to unravel these opposite effects.
© 2009 Elsevier B.V. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 532. Cellular effects of B cells in atherosclerosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 543. The role of antibodies to oxidized LDL in atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 544. B cell depletion and atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 555. Antibody modulation as therapy for atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
1. Introduction
Atherosclerosis is a multi-factorial disease that is recognized as achronic inflammatory disease [1]. Furthermore, atherosclerosis isnowadays thought to be an autoimmune disease [2]. Severalautoantigens have been identified including heat shock proteins, β2glycoprotein I and oxidized LDL (oxLDL) [3]. The focus in athero-sclerosis has mainly been on the immune response of macrophagesand T cells, which are abundantly present in atherosclerotic plaques.
Medicine, Section Clinical &cal Center, P.O. Box 616, 6200
.nl (J.W.C. Tervaert).
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The role of B cells in atherosclerosis has not been clarified yet,although in many studies antibodies, the most abundant B cellproduct, have been investigated. In particular antibodies to oxLDLhave been studied for their potential association with the outcome ofcardiovascular diseases [4]. In various autoimmune diseases, the roleof B cells and autoantigen specific antibodies are well established.Therefore, B cells and autoantibodies may serve as targets fortreatment. For instance, B cell depletion appears as an effectivetherapy in many of these autoimmune diseases. Since only few studieshave been performed on the cellular function of B cells inatherosclerosis, the possible role of B cell depletion with respect tocardiovascular disease development is not well known. Cardiovascularclinical events such as myocardial infarction and stroke are primarilycaused by disruption of the atherosclerotic plaque and are still majorcauses of death inwestern society [1], despite optimal use of currentlyavailable treatment. Due to global expansion of cardiovasculardiseases, there is a strong need to develop new strategies. In thisreview, we summarize the current literature regarding both B cells as
Fig. 1. Protective IgM vs pro-atherogenic IgG anti-oxLDL antibodies. (A) Encounter of oxLDL and IgM anti-oxLDL (1) enables the formation of immune complexes (2). The oxLDL–IgMimmune complex does not bind to the Fcγ-receptor on the macrophage. Fcγ-receptor mediated activation cascades do not occur (3). (B) Encounter of oxLDL and IgG anti-oxLDL (1)enables the formation of immune complexes (2) that subsequently bind to Fcγ-receptors on themacrophage (3). Binding to the Fcγ-receptor triggers signal transduction pathways inthe macrophage (4) resulting in foam cell formation (5a) and the release of inflammatory cytokines (5b).
54 M. van Leeuwen et al. / Autoimmunity Reviews 9 (2009) 53–57
well as anti-oxLDL antibodies in atherosclerosis. Furthermore, wediscuss the possible therapeutic potential of targeting these entities inatherosclerosis.
2. Cellular effects of B cells in atherosclerosis
B cells arewell recognized as essential players in humoral immunity.Besides being precursors of antibody-producing cells, B cells act asimportant regulators of T-cell activation via antigen presentation andcytokine production [5]. Our knowledge on the potential role of B cellsin human atherosclerotic lesion development is limited. An importantreason is that in humans the existence of B cell subsets has not beenclearly established. In mice, distinct B cell subsets like B1, B2, and B10cells have been described [5]. B1 cells, preferentially localized in theperitoneal cavity, have been recognized as producers of naturalantibodies. These natural antibodies are produced without stimulationwith exogenous antigen and are T-cell independent. Natural antibodiesprovide a first line of defence against invading pathogens [6]. Incontrast, B2 cells require cognate T-cell interaction for activation andproduction of antibodies. Antibodies produced by B2 cells can undergoisotype switching and somatic hypermutation during an immuneresponse. Recently, a third subset called B10 cells has been described.These IL-10 producing B cells function as negative regulators ofinflammatory immune responses [7].
B cells are only occasionally detected in the intima of humanatherosclerotic plaques [8]. In contrast, early plaques contain largeamounts of IgM and IgG [9]. Tertiary lymphoid tissue, a structureresembling germinal centres, is found in the adventitial layer nearadvanced atherosclerotic plaques. The majority of the lymphocytes inthese structures are B cells. This is in contrast to the minor presence ofT cell and macrophages. These sites are thought to be important in thelocal generation of humoral immune responses [10]. It is currently notknown which B cell subset is the most prominent in these tertiarystructures. Also, B cells and antibodies could be detected in all stagesof atherosclerosis in experimental models [9,11]. Several studiesindicated that B cells act as protective players in experimental modelsof atherosclerosis [12,13]. Caligiuri et al. showed that splenectomyinduced a partial depletion of B and T cells and this resulted in adramatic increase of atherosclerosis in atherosclerotic ApoE−/− mice.Subsequently, the disease process could be protected by the transfer ofsplenic B cells from atherosclerotic ApoE−/− mice [12]. It can bespeculated that in particular splenic marginal zone B cells harbour theprotective effect. These marginal zone B cells are, like B1 cells, known
to respond to non-protein and T-cell independent antigens. Further-more, B cell deficient (μMT) LDLr−/− mice developed 30–40%increased lesion size in the distal and proximal aortas compared toconventional LDLr−/− mice [13]. These studies reveal a protectiveeffect of B cells on atherosclerosis, but do not discriminate between apossible cellular function of B cells and protection by antibodies. Thisissuemight be solved in future studies by the passive transfer of serumfrom atherosclerotic mice or anti-oxLDL antibodies to B cell depletedatherosclerosis-prone mice.
3. The role of antibodies to oxidized LDL in atherosclerosis
Oxidation of LDL is suggested as one of the first events in theinitiation of atherosclerosis, and oxLDL is thought to be highlyimmunogenic [14]. Consequently, anti-oxLDL antibodies can befound in animal and human lesions. Salonen et al. [15] correlatedanti-oxLDL IgG antibody titers for the first time with carotidatherosclerosis inmen. Palinksi et al. [16] showed in an atheroscleroticmouse model a correlation between antibodies specific for oxLDL andthe development of atherosclerotic plaques. To assess the functionalrole of IgM antibodies the group of Witztum has cloned monoclonalIgM antibodies from atherosclerotic mice. These IgM antibodies werecharacterized as natural antibodies with specificity for the phospho-choline epitope (T15 IgM) [17]. These natural IgM antibodies havegained a lot of interest in mouse atherosclerosis and it is plausible thatthey play a protective role [18–20]. For example, IL-5 deficientatherosclerotic mice showed a decreased secretion of T15 IgMantibodies and a subsequently accelerated atherosclerosis. Interest-ingly, IL-5 provides non-cognate stimulation to innate B cells.However, IL-5 has also stimulatory effects on B cells itself, whichcannot exclude a primary B cell effect with subsequent antibodyinduction [18]. Very recently Lewis et al. [21] reported a dramaticincrease in plaque size in an atherosclerotic model which lacks serumIgM, supporting a protective role of IgM. In humans, circulatingantibodies to oxLDL have been extensively studied in healthypopulations as well as in different patient populations with cardio-vascular diseases. In well-powered clinical studies [22–24] an inverserelationship between IgM anti-oxLDL levels and the outcome ofcardiovascular disease was observed while high IgG antibody levels tooxLDL were positively associated with clinical cardiovascular events[22,24]. However, all of these associations were not independent ofother risk factors. Also, an unstable plaque phenotype has beenassociated with high levels of IgG to oxLDL in contrast to high IgM
Fig. 2. Possibilities for passive immunization with different antibody structures. Antibody molecules directed to oxLDL like Fab fragments (A) IgMmolecules (B) and IgG4 molecules(C) prevent the binding of oxLDL immune complexes to Fcγ-receptors on macrophages.
55M. van Leeuwen et al. / Autoimmunity Reviews 9 (2009) 53–57
levels to oxLDL which were associated with a stable plaque phenotype[25]. A recent study revealed a protective role for natural IgMantibodies specific for the phosphorylcholine (PC) epitope since lowlevels of IgM anti-PC were associated with ischemic stroke [26]. Asmentioned above, IL-5 may induce these anti-PC natural IgMantibodies and this could explain the observed atheroprotective effectof IL-5. Indeed, IL-5 levels are positively related to plasma levels of IgManti-oxLDL antibodies and to reduced subclinical atherosclerosis [27].In summary, a protective role of anti-oxLDL IgM antibodies issuggested not only in animal studies, but also in human athero-sclerosis. At present, it is therefore hypothesized that the IgMresponse to oxLDL is anti-atherogenic, while the antigen-driven IgGresponse is pro-atherogenic [6,28]. IgG antibodies bound to oxLDLmay promote atherosclerosis by inducing macrophage activation viaFcγ-receptors (FcγR) (Fig. 1) [29]. This results in the release ofinflammatory cytokines and the transformation from macrophage tofoam cell. In contrast, IgM-oxLDL immune complexes cannot bind toFcγRs on macrophages and therefore macrophage activation isprevented (Fig. 1). In addition, IgM autoantibodies to oxLDL areproposed to clear oxLDL particles in an anti-inflammatory way [6].
4. B cell depletion and atherosclerosis
B cell depletion, in particular via anti-CD20 monoclonal antibody,has proven to be a very effective treatment of various autoimmunediseases. The cell surface CD20 molecule is expressed after the pre-Bcell stage and remains expressed throughout B cell differentiationstages, except for the plasma cell stage [5]. Since plasma cells are notdepleted, the efficacy of anti-CD20 therapy is due to B cell mediatedmechanisms and is not the result of the elimination of the antibody-producing machinery. The increased application of B cell depletion insystemic autoimmune diseases that are prone to accelerated athero-sclerosis enables to study the role of B cells in human atherosclerosis.Given the detrimental effect of B cell depletion in murine models,atherosclerotic patients may not benefit from B cell depletion by anti-CD20 therapy, unless distinct B cell subsets are differentially affectedby anti-CD20 therapy. In mouse models conventional B2 cells aredepleted effectively due to their preferential localization in lymphoidorgans and the circulation. CD20 mAb treatment seems much lessefficient for depletion of B cells localized in the peritoneal cavity. Thesurvival of B1 cells in the peritoneal cavity may be due to the specificmicroenvironment or to an intrinsic survival mechanism of thesepredominating B1 cells [30]. CD20 mAb treatment, finally, alsodepletes the CD1dhiCD5+ B cell subset that includes regulatory B10
cells [30]. Evidently, further research regarding the depletion onspecific B cell subsets is warranted [5]. Also other anti-B cell therapies,like anti-CD19 treatment, deserve attention. CD19 is expressed on thesame development stages as the CD20 marker, but it is additionallypresent on pre-B cells. Anti-CD19 therapy depletes B1 and B2 cells, butthe effect on B10 cells is not yet defined. Altogether, preclinical mousemodels should reveal if B cell subsets can be differentially depletedand how this affects development of atherosclerosis.
5. Antibody modulation as therapy for atherosclerosis
The use of immunoglobulins is currently widely applied in theclinical setting for treatment of various diseases. The intravenousadministration of total IgG (IVIg), isolated from pooled plasma ofthousands of healthy individuals, has been shown to be effective inmodulating disease activity in various autoimmune diseases. Also inmurine atherosclerosis, beneficial effects of IVIg have been reported[31]. Various mechanisms have been suggested for the protectiveeffect of IVIg in autoimmune diseases [32]. Importantly, the anti-inflammatory properties of IVIg may be due to the blocking of theFcγR function and dampening macrophage activation throughengaging the inhibitory FcγRIIb.
OxLDL plays a pivotal role during atherosclerosis development.Therefore, antibody-mediated therapy, targeting oxLDL could play animportant role in future therapeutic strategies. The focus of antibodytherapy should be based either on increasing the level of protectiveantibodies, or on preventing the effector mechanisms of the pathogenicantibodies. This might be achieved by passive immunization which iseffectively accomplished in various infectious and/or autoimmunediseases. Passive immunization strategies with human IgG1 antibodiesspecific for oxLDL are successful in mice. A reduction of 50 and 90% inplaque size was reported [33,34]. Interestingly, the human IgG–oxLDLcomplexes were incapable to initiate FcγR-mediated macrophageactivation due to species incompatibility. Also the absence of FcγRs inmice has an anti-atherogenic effect [35]. These studies identify the FcγRas a key player in atherosclerosis, which should be taken into accountwhen considering antibody therapy. Firstly, human IgG anti-oxLDL Fabfragments can inhibit uptake of oxLDL bymacrophages (Fig. 2A). Furtherexperiments should be designed to examine its clinical utility [36]. Anobvious disadvantage of therapies with Fab fragments is the short half-life of these reagents. An alternative therapeutic strategy aims at theinduction of protective IgM antibodies (Fig. 2B). Immunization of LDLr−/− with S. pneumoniae resulted in increased circulating levels of IgMspecific for the PC epitope and a concomitant decrease in the extent of
56 M. van Leeuwen et al. / Autoimmunity Reviews 9 (2009) 53–57
atherosclerosis [19]. As alreadymentioned, the PCepitope is sharedwithoxLDL. Also the administration of IgM antibodies against the PC epitopein a murine atherosclerosis model resulted in significantly reduced veingraft lesion size [20]. When humans were vaccinated against pneumo-coccal infection, however, no increase in IgM anti-oxLDL antibodies wasobserved [37]. On the other hand, a recent report demonstrated areduction in the incidence of myocardial infarction after pneumococcalvaccination [38]. The reduced incidence of myocardial infarction mightbe explained by the induction of protective IgM anti-oxLDL antibodies,but the levels of these antibodies were not reported. Alternatively, theprotective effect of pneumococcal vaccination could be due to areduction of bacterial infections and subsequent dampening of abruptinflammatory changes in coronary plaques [39]. Finally, an interestingtherapeutic approach would be the administration of IgG4 anti-oxLDLantibodies. IgG4 also lacks the ability to bind to FcγR (Fig. 2C), butadditionally has anti-inflammatory properties due to dynamic Fab-armexchange which prevents the formation of large immune complexes.Proof principle of IgG4 antibody therapy comes fromamonkeymodel ofmyasthenia gravis [40].
6. Conclusion
The importance of B cells and anti-oxLDL antibodies in thedevelopment of atherosclerosis opens opportunities for therapeuticapproaches. However, the fact that B cells on one side have protectivefunctions and on the other side are deleterious in atherosclerosishampers progress in therapeutic strategies. With regard to approachesaiming at B cell targeting it will be essential to develop B cell subset-specific strategies that deplete B2 cells but do not affect non-cognate B1and regulatory B10 cells. So far, other than anti-CD20 antibodies shouldbe studied in this respect. At present, little is known about the effect of Bcell targeting therapy in humans on different B cell subsets and thereforeB cell therapy is still far away from clinical practice for atherosclerosis.However, since depletion of B cells in experimental models is pro-atherogenic, the current use of anti-B cell approaches in otherautoimmune diseases known to be associated with accelerated athero-sclerosis may be detrimental on the long term. Nevertheless, a straightforward therapeutic approach will be passive immunization withprotective (anti-inflammatory) IgM or IgG4 antibodies to oxLDL. Thefirst studies in mice with IgM anti-oxLDL are promising in this respect,but more studies are needed to evaluate potential clinical application.The use of anti-inflammatory IgG4 antibodies with oxLDL specificitycould be a good alternative to treat human atherosclerosis since theseIgG4moleculesdonotbind to FcγRsonphagocytes and lack complementactivation. We believe that these immunomodulatory B cell or anti-oxLDL based approaches in combination with current treatment formnew perspectives for the treatment of cardiovascular diseases.
Take-home messages
• Adaptive immunity is important in the involvementof atherosclerosis.• Little is known about the exact role of B cells in atherosclerosis, butpro- and anti-atherogenic effects have been suggested.
• It has been hypothesized that IgM anti-oxLDL antibodies are anti-atherogenic, whereas IgG anti-oxLDL antibodies are pro-atherogenic.
• Depletion of B cells in autoimmune disease should spare potentiallyprotective B1 cells, the classical producers of protective IgMantibodies, and the more recently described B10 regulatory B cellsand should target conventional B2 cells.
• Binding of oxLDL containing immune complexes to Fcγ-receptors isconsidered a factor for triggering pro-inflammatory macrophageresponses.
• Prevention of oxLDL containing immune complex binding to the Fcγ-receptor can be achieved via IgM anti-oxLDL antibodies, polyclonalIVIg, Fab fragments directed to oxLDL, and IgG4 anti-oxLDL.
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European population substructure is associated with mucocutaneouerythematosus
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Studies of cell-mediated immune responses to influenza vaccination in
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ncluding mucocutaneous phenotypes, autoantibody production, andwith with SLE has not been explored. Therefore Chung SA, et al.some differences in the clinical manifestations according with the754) from 8 case collections were genotyped for N1,400 ancestrybstructure. Using the Structure program, the authors characterized) European ancestry based on these genetic markers. Nonparametrictween Northern European ancestry and specific SLE manifestations.try were significantly associated with photosensitivity, P (trend)=ersus lowest quartile [OR(high-low)] 1.64, 95% confidence interval1.93, 95% CI 0.98-3.83). In contrast, increasing levels of Northernticardiolipin autoantibodies (P(trend)=1.6×10(-4), OR(high-low)P(trend) = 0.017, OR(high-low) 0.67, 95% CI 0.46-0.96). This studyrn versus Southern European ancestry. Thus, genetic ancestry mayes among SLE patients of European descent. Moreover, these resultsaddress issues of population substructure based on genetic ancestry.
s manifestations and autoantibody production in systemic lupus
e against influenza. In patients with systemic lupus erythematosusbeen demonstrated, but cell-mediated responses have not yet beensed the cell-mediated responses to influenza vaccination in patientsontrol subjects received subunit influenza vaccine. Peripheral bloodcination. Cell-mediated responses to A/H1N1 and A/H3N2 vaccinesked immunospot assay and flow cytometry. Antibody responsesination, patients with SLE had fewer IFNgamma spot-forming cellsf IFNgamma-positive CD8+ T cells. After vaccination, the number ofjects, although the number remained lower in patients. In addition,terleukin-2 were lower in patients after vaccination compared withion did not induce a CD8+ T cell response. For A/H3N2-specificnses to influenza vaccination were associated with the use of
H3N2-specific antibody titers after vaccination was lower in patientsion to a decreased antibody response, cell-mediated responses toect the effects of the concomitant use of immunosuppressive drugs.enza infections.
systemic lupus erythematosus