Scavenger receptors as regulators of natural antibody responses and B cell activation in autoimmunity

Molecular Immunology 48 (2011) 1307–1318

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Molecular Immunology journal homepage: www.elsevier.com/locate/molimm

Review

Scavenger receptors as regulators of natural antibody responses and B cell activation in autoimmunity Emilie Domange Jordö ∗ , Fredrik Wermeling, Yunying Chen, Mikael C.I. Karlsson ∗∗ Karolinska Institutet, Department of Medicine, KS L2:04, 17176 Stockholm, Sweden

a r t i c l e

i n f o

Article history: Received 17 July 2010 Received in revised form 5 January 2011 Accepted 17 January 2011 Available online 18 February 2011 Keywords: B cells Scavenger receptors Apoptotic cells Autoantibodies Natural antibodies Oxidation specific epitopes

a b s t r a c t Innate immune activation is crucial in defense against invading pathogens, including recognition by pattern recognition receptors, such as scavenger receptors. The scavenger receptor family was originally defined by their ability to bind oxidized LDL and thus the majority of research on this set of receptors has been done in association with cardiovascular disease. However, these receptors also bind an array of other modified self and foreign ligands and have for this reason the ability to regulate the immune response, including B cell activation. In this respect, increasing evidence suggests that these receptors are involved in autoimmunity and might provide a link between autoimmune disease and atherosclerosis. In this review, we will summarize how scavenger receptors can regulate activation of B cells both through their expression on this cell type but also by functions mediated by expression on cells interacting with B cells. Recent evidence of scavenger receptor function reveals how the transition from natural and polyreactive antibody responses towards potentially pathogenic B cell activation occurs. This translates to a new role for scavenger receptors in atherosclerosis and autoimmune disease, such as systemic lupus erythematosus. © 2011 Elsevier Ltd. All rights reserved.

1. Introduction In the early innate immune response against pathogens, phagocytes, such as macrophages (Ms) and dendritic cells (DCs), play a crucial role. These phagocytes express pattern recognition receptors (PRRs), including scavenger receptors (SRs), Toll-like receptors (TLRs) and Nod-like receptors (NLRs), which recognize and mediate clearance of pathogens along with directing the immune system to a proper response. These receptors also recognize host-derived ligands, such as apoptotic cells and modified low density lipoprotein, e.g. oxidized LDL (oxLDL) (Pluddemann et al., 2007). It is therefore

Abbreviations: ␤2GPI, beta-2-glycoprotein I; CRP, C-reactive protein; FDC, follicular DC; FOB, follicular B cells; iNKT, invariant NKT cells; LAMP, lysosomeassociated membrane protein; LOX-1, lectin-like oxLDL receptor-1; LysoPC, lysophosphatidylcholine; MARCO, macrophage receptor with collagenous structure; MDA, malonaldehyde; MZB, marginal zone B cell; MZM, marginal zone M; NP, 4-hydroxy-3-nitrophenyl acetyl; NLR, nod-like receptors; oxLDL, oxidized LDL; OxPL, oxidized phospholipids; PC, phosphorylcholine; PPAR␥, peroxisome proliferators-activated receptor gamma; S1P, sphingosine-1-phosphate; SR, scavenger receptors; SR-PSOX, scavenger receptor for phosphatidylserine and oxLDL; SLE, systemic lupus erythematosus; SRCR, Scavenger Receptor Cysteine-Rich; TWEAK, tumor necrosis factor-like weak inducer of apoptosis. ∗ Corresponding author. Tel.: +46 8 517 766 98; fax: +46 8 33 57 24. ∗∗ Corresponding author. Tel.: +46 8 517 761 35; fax: +46 8 33 57 24. E-mail addresses: [email protected] (E. Domange Jordö), [email protected] (M.C.I. Karlsson). 0161-5890/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.molimm.2011.01.010

important that the recognition and response to different ligands is tightly regulated in order to avoid inflammatory disease, e.g. in the form of atherosclerosis and systemic lupus erythematosus (SLE). The term scavenger receptor has been primarily used to describe two overlapping groups of pattern recognition receptors; first, receptors which bind modified LDL and other polyanionic ligands (Pluddemann et al., 2007), second, receptors that contain a highly conserved ancient version of the immunoglobulin (Ig) domain – the scavenger receptor cysteine-rich (SRCR) domain (Sarrias et al., 2004). The SRCR superfamily overlaps with the oxLDL-binding SR family, in which most class A SRs also have SRCR domains. The oxLDL-binding SRs are further subdivided into classes depending on their structure, where class B–H use a number of different structural motifs, such as lectin domains (Pluddemann et al., 2007). A common feature of all SRs is that they bind both foreign- and selfderived ligands (Table 1). This review highlights SRs that influence B cell function, with focus on how they could affect the interplay between natural and potentially harmful autoreactive antibody responses. The concept of pattern recognition was first described more than 10 years ago and great advances have been made in describing TLRs and NLRs as pattern recognition receptors and how signals from these receptors are integrated to regulate inflammatory responses in health and disease (Janeway and Medzhitov, 2002; Martinon et al., 2009). An important mechanism through which this takes place occurs in two steps; first, TLR engagement leads to production

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Table 1 Scavenger receptors on B cells and APC subtypes. Class; oxidized LDL-binding scavenger receptor (SR) class. SRCR domain; SR either contain scavenger receptor cystein-rich domain (+) or not (−). Expression pattern. Specificity; receptor ligands. TLR association; SR known to affect the function of stated TLRs. Disease association; suggested to be important for pathology of stated diseases. Abbreviations; acetylated low density lipoprotein (acLDL), apoptotic cells (AC), atherosclerosis (Athero), bacteria (bact), Creactive protein (CRP), dendritic cells (DC), haemoglobin-haptoglobin complexes (HbHp), heat chock protein 70 (HSP70), high density lipoprotein (HDL), lipopolysaccharide or derivatives (LPS), lipoteichoic acid (LTA), Lectin-like oxLDL receptor-1 (LOX-1), macrophages (M), macrophage receptor with collagenous structure (MARCO), multiple sclerosis (MS), oxidized low density lipoprotein (oxLDL), phosphatidylcholine (PC), rheumatoid arthritis (RA), SR for phosphatidylserine and oxLDL (SR-PSOX), systemic lupus erythomatosus (SLE) and TNF-like weak inducer of apoptosis (TWEAK). References: 1–6 (Becker et al., 2006; Chen et al., 2010; Kunjathoor et al., 2002; Luoma et al., 1994; Platt and Gordon, 2001; Wermeling et al., 2007). 7–10 (Chen et al., 2010; Elomaa et al., 1995; Kraal et al., 2000; Wermeling et al., 2007) 11–15 (Corcoran et al., 2002; Kuchibhotla et al., 2008; Kunjathoor et al., 2002; Stewart et al., 2010; Won et al., 2008). 16–21 (Fukasawa et al., 1996; Guo et al., 2009; Watanabe et al., 2010; Covey et al., 2003; Zhang et al., 2003; Zhu et al., 2009). 22–23 (Ramprasad et al., 1996; Zhang et al., 2007). 24–26 (Delneste et al., 2002; Fujita et al., 2010; Nakagawa et al., 2002). 27–31 (Gursel et al., 2006; Matloubian et al., 2000; Minami et al., 2001; Nakayama et al., 2003; Nanki et al., 2005). 32–34 (Bover et al., 2007; Moreno et al., 2009). 35–38 (Axtell et al., 2004; Brown and Lacey, 2010; Hippen et al., 2000; Vera et al., 2009). 39–40 (Sarrias et al., 2007; Bowen et al., 1995). Name

Class

SRCR

Expression pattern

Specificity

TLR association

Disease association

References

SR-A (CD204) MARCO CD36 SR-B1 CD68 (macrosialin) LOX-1 CXCL16 (SR-PSOX) CD163 CD5 CD6

A A B B D E G I – –

+ + − − − − − + + +

M, DC M, DC M, DC, B cell B cell, M M, DC, B cell M, DC M, DC, B cell M B cell B cell

LPS, CRP, AC, oxLDL, acLDL bact, LPS, LTA, AC bact, glycerides, LTA, acLDL, oxLDL, AC bact, oxLDL, acLDL, HDL, PC, AC oxLDL bact, oxLDL, CRP, HSP70 oxLDL, PC, bact, CXCR6 HbHp, TWEAK CD5, fungi LPS, LTA, CD166

TLR-4 TLR-2,4 TLR-1,2,4,6 TLR-4,9 – TLR-2,4 TLR-9 TLR-4 – –

Athero, SLE SLE Athero Athero Athero Athero, RA Athero, SLE, RA Athero, SLE MS –

1–6 7–10 11–15 16–21 22–23 24–26 27–31 32–34 35–38 39–40

of pro-forms of cytokines, second, these are cleaved by activated complexes of NLRs, called inflammasomes. TLR-signaling is thus coupled to inflammasome-dependent secretion of active IL-1, IL-18 and IL-33 (Martinon et al., 2009). However, the role for SRs in this network of regulators is just now starting to emerge. TLRs have been studied in their regulation of autoreactive B cells (reviewed in (Crampton et al., 2010; Marshak-Rothstein, 2006)). Subpopulations of B cells differ in TLR expression profiles, and TLR ligands have been shown to activate subtypes of B cells differently, partly because of differences in their activation threshold (Barr et al., 2007). TLRs have also been shown to interact with SRs, mostly in pathogen recognition (Areschoug and Gordon, 2009). Furthermore, TLRs play a regulatory role in SLE and atherosclerosis pathology (Lundberg and Hansson, 2010; Means and Luster, 2005). Nevertheless, how and in which context TLRs and SRs co-operate in these settings and especially on B cells is an emerging field of investigation. While TLRs are expressed throughout the body on many types of cells, SRs have more restricted expression profiles. For instance, in the marginal zone of the spleen, marginal zone macrophages (MZMs) express the class A SRs SR-A and macrophage receptor with collagenous structure (MARCO). These SRs bind apoptotic cells and are in close proximity to marginal zone B cells (MZBs), thereby being able to provide them with autoantigens. In the same manner, other subtypes of Ms are present at anatomical sites where innate B cell activation occurs, such as subcapsular Ms in the lymph nodes (LNs), metallophilic Ms around the follicles in the spleen and peritoneal Ms, limiting access to or providing antigen to LN B cells, splenic B cells and B1 B cells, respectively (Gonzalez et al., 2010; Kraal, 1992; Phan et al., 2007). Thus, M could potentially be connected to early stages of B cell activation and regulation, something that is further discussed in Section 2.2.1. Also DCs contribute to B cell activation, where CD11chigh plasmablast-associated DCs in the red pulp of the spleen support early B cell activation (MacLennan et al., 2003). Aside from regulating antigen availability, Ms and DCs can provide additional signals regulating B cell function, e.g. through cytokines. Subtypes of B cells play different roles in immune responses, due to location and expression levels of receptors such as TLRs and SRs (Viau and Zouali, 2005). Innate type B cells, MZB and B1 B cells, both express distinct patterns of TLRs and SRs compared to conventional (follicular) B cells (FOB) (Barr et al., 2007). For example,

MZBs were recently shown to express CD36 (class B SR) and CD68 (class D SR) (Won et al., 2008; Zhang et al., 2007). Other molecules of interest expressed on B cells are the class B SR-BI, and the MHClike molecule CD1d, capable of mediating presentation of modified lipids present in both atherosclerosis and SLE (Barral and Brenner, 2007). Interestingly, also IL-1R mRNA was found to be preferentially expressed in MZBs, suggesting a differential response by FOBs and MZBs to IL-1 after inflammasome activation (Zhang et al., 2007). B1 B cells originate, in contrast to B2 B cells, from the fetal liver, even though recent data from mice with inducible RAG expression show that they can develop from bone marrow (BM) precursors (Duber et al., 2009). B1 B cells can be found in the peritoneum as well as in secondary lymphoid organs, while their function has mainly been studied using cells isolated from the peritoneum (Duan and Morel, 2006). This innate type of B cell can be subdivided into the B1a and B1b type, where both are B220low , IgDlow , IgMhigh , CD9+ , CD43+ , CD11b+ and CD23low . The B1a B cells are further defined by expression of CD5 and CD6, which belong to the SRCR family (Sarrias et al., 2004). B1 B cells have traditionally been described to be the main producers of natural antibodies, but MZBs carry the same reactivities and both these subtypes are believed to contribute to the natural antibody pool (Chou et al., 2009; Martin and Kearney, 2000; Martin et al., 2001). Natural antibodies have been defined as antibodies that are present in the circulation prior to antigenic stimuli, essentially of the IgM subtype (Hooijkaas et al., 1984). Part of the evidence for this is that they are found in germ-free mice as well as human cordblood (Chou et al., 2009). The variable regions of natural antibodies are germline-encoded with no or very few mutations, providing these antibodies with broad specificity. Some natural antibodies have therefore been described as polyreactive (Dighiero et al., 1983; Satoh et al., 1983), meaning that they react to a number of unrelated antigens including lipopolysaccharide (LPS) and self-antigens, such as dsDNA and insulin (Wardemann et al., 2003). On the other hand, many antigens can be modified during enhanced oxidation processes in inflammation, and polyreactivity has been explained by the fact that antibodies can recognize the same oxidation-specific epitope, although they recognize different antigens (Chou et al., 2009). As an example, the E06/T15 antibody binding oxLDL in fact binds the lipid moiety, i.e. the phosphorylcholine (PC) headgroup of oxidized phospholipid (oxPL) components of oxLDL, also present on the surface of bacteria as well as apoptotic cells.

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Fig. 1. Scavenger receptors regulate B cell activation in response to modified self. Self-antigens are modified during inflammation-induced oxidation processes. This gives rise to ligands for scavenger receptors (SRs) expressed on B cells as well as antigen presenting cells (APC). These receptors include the Class A SRs SR-A and MARCO, Class B SRs CD36 and SR-BI, Class D SR CD68, Class E SR LOX-1, Class G SR-PSOX and SRCR family members CD5, CD6 and CD163. Together these could regulate and interact with the B cell receptor (BCR) and/or an array of toll like receptors (TLRs), depending on which cell type they are expressed on.

Even though pathogenic autoantibodies have specificity for the same epitopes as their natural counterparts, they have usually undergone class switch recombination and affinity maturation in germinal centres. Production of these antibodies could occur after activation of B1 B cells and MZBs in a pro-inflammatory environment. It was recently shown that the extent to which B cells react to self-antigens, is in part set in the periphery after B cells have left the BM and gone through transitional stages (Wardemann and Nussenzweig, 2007). Another reactivity enriched in the natural B cell pool is directed to haptens, such as 4-hydroxy-3-nitrophenyl acetyl (NP). The preimmune B cell pool is thus enriched for these reactivities, which are inherently immunostimulatory, unlike reactivities against most foreign protein antigens (Palm and Medzhitov, 2009). When mice deficient in soluble IgM were injected with the T-dependent antigen NP-KLH, the mice produced significantly delayed antigen specific IgG with lower affinity (Ehrenstein et al., 1998). In these mice, antigen bound to follicular DC (FDC) was greatly reduced, showing the need for natural IgM-containing immune complexes in the response to NP-KLH. A later report showed that MZBs transport antigen to FDCs and that this transport is dependent on CD21/35 (Barrington et al., 2009; Cinamon et al., 2008; Phan et al., 2007). Also, this shows how natural antibodies are needed for the subsequent adaptative antibody response. Natural IgM is also thought to assist in clearance of apoptotic cells thus preventing secondary necrosis, which is pro-inflammatory and can potentially induce autoreactive responses (Grabar, 1975; Peng et al., 2005; Silverman et al., 2008). Here, we discuss how SRs may influence and be influenced by natural antibody responses, and how this could affect the development of inflammatory diseases such as SLE and atherosclerosis.

2. Effect of scavenger receptors on B cell activation Although SR functions have been thoroughly investigated in other cell types, their presence on B cells was only recently described and so far relatively little data is available on their intrinsic effect on B cell activation and function (Fig. 1). In this section we summarize the current data existing on SRs’ intrinsic (when expressed on B cells) and extrinsic (when expressed on adjacent cells) effect on B cells.

2.1. Intrinsic effect of scavenger receptors on B cells Class B SRs CD36 and SR-BI have been shown to be expressed on mouse and human B cells (Zhu et al., 2009). CD36 is expressed on MZB cells, but not on B1 B cells (Won et al., 2008), while the subtype of B cell on which SR-BI is expressed on has not been described. Aside from CD36, the class D SR CD68 was found to be selectively expressed on MZBs (Zhang et al., 2007), while the members of the SRCR superfamily CD5 and CD6 have been described to be expressed on B1a B cells (Alonso et al., 2010; Carsetti, 2004). Finally, the class G SR for phosphatidylserine and oxLDL (SR-PSOX/CXCL16) is expressed on naïve B cells.

2.1.1. Class B scavenger receptor CD36 CD36 is expressed on antigen-presenting cells (APC) and the expression is differently regulated depending on the cell type. While the expression of CD36 is dependent on the transcriptional activator Oct-2 in B cells, this is not the case in DCs or Ms (Corcoran et al., 2002), suggesting that CD36 could have different functions depending on which cell it is expressed on. CD36 deficiency has been reported not to affect B cell development (Won et al., 2008) and does not directly affect homeostatic B cell function (Corcoran et al., 2002). However, absence of CD36 affects specific antibody responses in vivo. CD36−/− mice infected with Leishmania major showed higher levels of specific IgG, smaller lesions and faster recovery after infection (Corcoran et al., 2002). CD36 expression on Ms was not the limiting factor for parasite invasion and survival in this model, suggesting a role for this receptor on B cells. CD36 has been reported to interact with TLR2 in vivo in response to heat-killed S. pneumoniae, a T-independent antigen (Won et al., 2008). CD36−/− mice mounted a reduced anti-PC antibody response, which was due to absence of CD36 on B cells, as shown by ex vivo co-cultures of B cells with DCs pulsed with S. pneumoniae, where the absence of CD36 on DCs or Ms did not affect the antibody response. The difference in phenotype seen in specific antibody responses in these two studies might be due to different binding of antigen to CD36, and the possible requirement for cooperation with different TLRs. CD36 has also been shown to interact with TLR2-TLR1 and TLR2–TLR6 heterodimers, as well as the recently discovered TLR4–TLR6 heterodimer (Stewart et al., 2010). CD36 was shown to recruit the latter to bind oxLDL and cause inflammation by activating Ms. The presence of TLR4 and TLR6 as

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well as CD36 on MZB cells suggests that CD36 could induce signaling in response to oxLDL also in B cells. CD36 has been shown to mediate antigen uptake in other cells (see Section 2.2.2.1), but whether this occurs in B cells remains to be determined. The nuclear hormone receptor, peroxisome proliferatorsactivated receptor gamma (PPAR␥) has been shown to regulate expression of CD36 (Nicholson, 2004). Interestingly, PPAR␥ ligands enhance human B cell antibody production and differentiation in response to stimulation with anti-IgM and CpG (Garcia-Bates et al., 2009). Only CpG-stimulated memory B cells, with higher levels of PPAR␥, could respond to PPAR␥ ligands and a PPAR␥ antagonist decreased PPAR␥ ligand-induced IgG but not IgM. These data indicate that PPAR␥ could, rather than regulate the primary response, regulate the ability of B cells to class-switch. CD36 was shown to be expressed on a small population of human normal peripheral CD19+ lymphocytes (Rutella et al., 1999). CD36 expression was further found to be increased on B cells in chronic B cell malignancies and this was associated with adverse prognostic factors (Muroi et al., 1992; Rutella et al., 1999). Also modified expression patterns of TLRs have been shown to be involved in the pathogenesis of these malignancies (Muzio et al., 2009). This indicates that CD36 needs to be tightly regulated also in human B cells, and that modified expression leads to increased B cell reactivity associated with disease. 2.1.2. Class B scavenger receptor SR-BI SR-BI has been shown to be expressed on Ms (Hirano et al., 1999) and B cells (Zhu et al., 2009). CpG-signaling was shown to trigger calcium entry into primary B cells, as well as cell adhesion to VCAM-1, in a SR-BI-dependent TLR9-independent manner (Zhu et al., 2009). This was verified through the inhibitory effect of antiSR-BI antibodies, while antibodies against CD36 did not affect the response. In the same study, SR-BI was also shown to negatively regulate TLR9-dependent IL-6, IL-10 and IgM production in primary B cells. Furthermore, sphingosine-1-phosphate (S1P) is a lipid moiety of high density lipoprotein (HDL) that when bound to SR-BI may modulate S1P receptor-mediated MZB shuttling between the marginal zone and the follicle (Cinamon et al., 2008). Interestingly, the S1P receptor expression on MZB cells has been shown to be downregulated by TLR agonists (Rubtsov et al., 2008). This suggests that MZB shuttling of antigen to FDCs is tightly connected to TLR and SR functions. 2.1.3. Class D scavenger receptor CD68 The oxLDL-binding SR CD68 (macrosialin) is expressed on Ms and is upregulated on activated mouse peritoneal Ms and monocytes (Ramprasad et al., 1996). It is also expressed on MZB cells (Zhang et al., 2007), but its function on these cells remains to be determined. CD68 on B cells may be an interesting candidate for regulation of natural antibody responses, since it could attract self and foreign antigen to MZBs. 2.1.4. Class G scavenger receptor PSOX SR-PSOX has been reported to be expressed on DCs, Ms and T cells, as well as a subset of human CD19+ B cells in tonsils but not in peripheral blood (Matloubian et al., 2000; Shashkin et al., 2003; Wilbanks et al., 2001). This SR is identical to CXCL16 and has therefore mostly been studied as a chemokine. IFN␥- and TNF␣induced CXCL16 can be cleaved of the cell surface by a disintegrin and metalloproteinase (ADAM)10, which is the same enzyme that cleaves CD23 of the surface of B cells (Abel et al., 2004; Gibb et al., 2010). This suggests that CXCL16 could be regulated during B cellmediated inflammatory responses. However, the role of CXCL16 on B cells has not been examined. CXCL16 has also been shown to modulate TLR-9 function and responses to CpG (Gursel et al., 2006). One could envision a similar

mechanism on CXCL16-expressing tonsil B cells. TLR9 is a known modulator of B cell activation in autoimmunity (Avalos et al., 2010), but the potential of CXCL16 to modulate these responses is yet to be explored. 2.1.5. SRCR superfamily members CD5 and CD6 CD5 and CD6 are close relatives in the SRCR superfamily. They are expressed on thymocytes, mature T cells and the B1a subset of B cells (Sarrias et al., 2004). CD5 is used as a marker to define the B1a subpopulation (Carsetti, 2004), but is also found to be increased on anergic B2 B cells (Hippen et al., 2000). CD5 co-localizes in the immunological synapse with the BCR and has a negative effect on BCR signaling (Dalloul, 2009; Lankester et al., 1994). Furthermore, B1a cells from CD5-deficient mice respond better to anti-IgM stimulation, while no difference was seen when stimulating with anti-CD40 antibody or LPS. Several endogenous ligands for CD5 have been proposed, including CD72, gp150 and the Ig heavy chain, but the definitive motif remains to be determined (Calvo et al., 1999; Pospisil et al., 1996; Van de Velde et al., 1991). A recent publication shows that CD5 is its own ligand, thus suggesting that it can mediate interaction between adjacent CD5 expressing cells (Brown and Lacey, 2010). CD5 can also function as a PRR, recognizing conserved fungal glucan ligands, and thereby protects mice from zymosan-induced septic shock (Vera et al., 2009). CD5 is suggested to have a role in B cell tolerance, as shown in adoptive transfer experiments of CD5−/− B cells, where reduced signs of anergy were accompanied by elevated IgM in serum (Hippen et al., 2000). An endogenous ligand for CD6 has been identified in the Ig superfamily transmembrane protein ALCAM/CD166 that mediates leukocyte adhesion and migration (Bowen et al., 1995). Although the specifics of the interaction between CD6 and CD166 have been extensively studied, its biological effects on immune responses are not well understood, especially for B cells. CD6 has an affinity for foreign ligands derived from bacteria, such as LPS and lipoteichoic acid (LTA). The relevance for this interaction was suggested in experiments where soluble CD6 increased survival rates in experimental septic chock (Sarrias et al., 2007). Given the expression of CD5 and CD6 on B1a B cells, it is likely that they regulate the signaling threshold of this B cell subset specifically. Evidence for this exists for CD6, where its engagement by an antibody protects human lymphocytic leukemia B cells from anti-IgM induced apoptosis (Osorio et al., 1997). It was recently discovered that also mature and memory B cells express CD6 (Alonso et al., 2010). CD6 expression was increased in mature B cells from Sjögren’s syndrome patients and this was believed to mediate migration of B cells to CD166-expressing epithelial cells in salivary glands, in a similar manner to other leukocytes contributing to the pathogenesis in these patients (Masedunskas et al., 2006). It has also been shown that FOBs express CD166 (Zhang et al., 2007), which could mediate interaction with other B cells in the follicle and facilitate antigen delivery. Also, since CD166 is upregulated on activated monocytes and expressed on T cells, CD6 expression on innate B cells could be involved in their recruitment to sites of inflammation as well as in their activation. In conclusion, SRs have important functions for the innate types of B cells they are expressed on. They are most probably involved in modulating signaling as well as antigen uptake and transport (Fig. 2). SRs on innate B cells with natural reactivities could in turn affect the natural antibody levels, as well as activate autoreactive B cells to produce pathogenic antibodies. 2.2. Extrinsic effect of scavenger receptors on B cell activation While data on SR function on B cells is just emerging, their function on Ms have been extensively studied since they were

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Fig. 2. Possible ways through which scavenger receptors expressed by B cells could regulate their function: (1) Cell to cell interactions influencing migration and antigen presentation (SR-B1, SR-PSOX (CXCL16), CD5, CD6); (2) Function as a co-receptor for the B cell receptor (CD36, SR-B1, CD5, CD6); (3) Binding of antigen for transport and/or uptake and presentation (CD36, SR-B1, CD68, SR-PSOX (CXCL16), CD5, CD6); (4) Regulation of TLR-mediated function (CD36, SR-B1, SR-PSOX (CXCL16)).

described in the 1970s (Goldstein et al., 1979). SRs have been recognized as PRRs of the innate immune response, playing a role both in host defense and mechanisms leading to pathogen virulence by allowing pathogen entry into host cells (Areschoug and Gordon, 2009). They also bind self-antigens, such as apoptotic cells (Jeannin et al., 2008). By mediating binding, uptake and signaling in response to their various ligands, SRs expressed on “non-B cells”, such as Ms and DCs, have the ability to affect B cell activation and the subsequent humoral response. We here describe how different SRs (SR-A, MARCO, CD36, SR-BI, CD68, LOX-1, SR-PSOX/CXCL16 and CD163) could play such a role. 2.2.1. Class A scavenger receptors The class A SRs SR-A and MARCO are expressed on M subtypes, including MZMs mentioned earlier (Kraal and Mebius, 2006). They bind a variety of self and foreign ligands, including modified LDL and bacterial components (Elomaa et al., 1995; Kraal and Mebius, 2006). The expression of these receptors regulate clearance of their ligands and can therefore also limit antigen availability for B cells in close proximity, as well as regulating them through the induction of cytokine responses. 2.2.1.1. SR-A. SR-A is mainly expressed on myeloid cells. Although not found on monocytes, it is upregulated during M differentiation (Platt and Gordon, 2001). SR-A is also expressed on mast cells (Brown et al., 2007), bone marrow-derived DCs and splenic DCs (Becker et al., 2006). The receptor has been found to be present on M in atherosclerotic lesions and SR-A has therefore been extensively studied in foam cell formation and atherosclerosis (Geng et al., 1995; Luoma et al., 1994). Interestingly, SR-A does not only serve as an oxLDL receptor, but also mediate other functions, such as modulating M activation (reviewed in (de Winther et al., 2000)). The aggravated atherosclerosis phenotype seen with SR-A deficiency (Kuchibhotla et al., 2008) may also be due to decreased M adhesion to extracellular matrix, since SR-A mediates adhesion of Ms to human smooth muscle cells (Santiago-Garcia et al., 2003). SR-A was discovered to be important for M uptake of apoptotic cells in vitro (Platt et al., 1996). While no apparent difference in removal of apoptotic thymocytes was seen after irradiation in SR-A-deficient mice (Platt et al., 2000), the autoantibody response towards intravenously injected apoptotic cells was significantly increased in SR-A−/− mice (Wermeling et al., 2007). Ligand-binding to SR-A leads to internalization and activation of signaling pathways that induce cytokine production, including TNF␣ and IL-1␤ (Coller and Paulnock, 2001; Hsu et al., 2001), which could affect B cell activation. Even though these studies may seem contradic-

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tory, the pro-inflammatory environment created by an overload of apoptotic cell could override the lack of SR-A-derived cytokines. SR-A expression on differentiated Ms can be inhibited in activated Ms by PPAR␥ upregulation (Ricote et al., 1998). PPAR␥ regulates the inflammatory response through the inhibition of gene expression, in part by antagonizing the activities of the transcription factors AP-1, STAT and NF-kB, leading to the subsequent inhibition of nitric oxide synthase (Ricote et al., 1998). Furthermore, SR-A on Ms mediates adhesion of activated B cells, recruiting them to LN and inflammatory lesions (Yokota et al., 1998). Class A SRs mediate antigen transfer from human B cells to Ms. B cells can through this mechanism amplify or edit the immune response to specific antigens by supporting antigen presentation (Harvey et al., 2008). In oxLDL-immunized mice, SR-A was shown to mediate the uptake of modified antigens for presentation to antigen-specific T cells. This suggests that SR-A could play an important role in the presentation of autoantigens to, and activation of, specific T and B cells and could therefore affect the production of autoantibodies, and contribute to autoimmunity. Interestingly, SR-A can mediate internalization of lysophosphatidylcholine (lysoPC), present in oxLDL particles, and the mitogenic effect of lysoPC on Ms is mediated through this uptake (Sakai et al., 1996). This directly links SR-A to the immune response to modified lipid antigens important for SLE pathogenesis. Spleen cells were also seen to proliferate in a SR-A-dependent manner in response to maleylated murine serum albumin (Nicoletti et al., 1999). 2.2.1.2. MARCO. MARCO (Elomaa et al., 1995) is constitutively expressed on subpopulations of Ms located in the peritoneum, lung, medullary cord of LNs, and the marginal zone of the spleen (Arredouani et al., 2005; Kraal et al., 2000). In the peritoneum and spleen, MARCO-expressing Ms are in close contact with innate B1 B cells and MZBs, respectively (Kraal and Mebius, 2006). Upon cell activation, MARCO can be upregulated on DCs and M subpopulations such as F4/80 positive red pulp Ms (Chen et al., 2010; Granucci et al., 2003; Grolleau et al., 2003). However, MARCO is not present on thioglycollate-elicited Ms, suggesting that its upregulation on activated cells is not universal (Chen et al., 2005). We have recently shown that on red pulp Ms, the MARCO upregulation in response to LPS is dependent on both MyD88dependent and independent TLR4-signaling (Chen et al., 2010). Little is known about the function of MARCO on DCs, but ligation on bone marrow-derived DCs increases their migration and ability to stimulate cytotoxic T cells in vivo (Matsushita et al., 2010). The strategic position of the MARCO positive MZMs makes them competent collectors of antigen from the blood and thus important components in MZB activation. In agreement with this, we have recently found that MARCO is important for clearance of apoptotic cells in the marginal zone and that in the absence of MARCO and SR-A, mice develop symptoms of SLE. In addition, autoantibodies that block MARCO can be found in both SLE-prone mice before onset of disease and in SLE patients in early stages of their disease (Wermeling et al., 2007). In the response to the cell wall glycolipids from Mycobacterium tuberculosis, MARCO interaction with TLR2 and CD14 regulates cytokine (TNF␣, IL-6 and IL1␤) responses (Bowdish et al., 2009). This suggests that MARCO interacts with TLRs in a similar manner to CD36 (see Section 2.2.2.1) on Ms (Nilsen et al., 2008). When wild type, MARCO- and SR-A-deficient mice were primed with a low dose of LPS followed by a high dose, the SR-deficient mice were protected from septic death. This effect was associated with increased production of IL-10 and anti-LPS antibodies as well as upregulation of activation markers on B cells, including MHC II and the MHC-like molecule CD1d. In mice deficient in MARCO and SR-A, MZMs failed to focus injected bacteria to the marginal zone (Chen et al., 2010).

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Thus, MARCO and SR-A are involved in capture and presentation of antigens for MZB activation in vivo. MZMs have also been shown to control the retention and trafficking of MZBs through direct interaction between MARCO and MZBs (Karlsson et al., 2003). Together, these studies show that MARCO expression on MZMs is capable of regulating MZB function through different mechanisms. 2.2.2. Class B scavenger receptors 2.2.2.1. CD36. The SRs SR-A and CD36, from class A and B, respectively, have been thought to be the most important receptors for M uptake of oxLDL and subsequent foam cell formation, since none of these events could be detected in SRA−/− CD36−/− Ms in vitro (Kunjathoor et al., 2002). In order to investigate their role in vivo, SRA−/− and CD36−/− mice were back-crossed onto an atherosclerosis-prone ApoE−/− background. Absence of CD36 was shown to be protective, with no additional effect in the absence of SR-A, implicating a major role for CD36 in atherogenesis (Kuchibhotla et al., 2008). Not only uptake of oxLDL but also a CD36-dependent signaling cascade was found to be necessary for M foam cell formation (Rahaman et al., 2006). Binding of oxLDL to CD36 (Nicholson et al., 1995) leads to CD36 upregulation through activation of PPAR␥ (Han et al., 1997; Nagy et al., 1998). CD36 expression on monocytes is dependent on cytokines, including IL-4, IL-10 and TGF␤ (reviewed in (Nicholson, 2004)). CD36 can also be regulated upon adhesion to TNF-activated endothelial cells, illustrating how cytokines could have an indirect effect on SR regulation (Huh et al., 1995). Signaling through CD36 can lead to cytokine production and oxLDL-induced NF-kB activation (Janabi et al., 2000). Expression of pro-inflammatory genes was found to be reduced in monocyte-derived Ms from CD36-deficient patients (Janabi et al., 2000). CD36 signaling could therefore induce cytokines regulating its own expression. The binding of oxLDL to mouse CD36 is mediated in part by oxidized phospholipids associated with both the lipid and protein moieties of the lipoprotein. IgM directed against oxLDL block oxLDL uptake via CD36 and SR-BI (Boullier et al., 2000; Gillotte-Taylor et al., 2001), showing how these receptors bind to oxLDL, but also that natural antibodies could regulate the uptake of modified self. SR-A or CD36-mediated endocytosis of oxLDL leads to internalizaton of PPAR␥ ligands, leading to its transcriptional activation and upregulation of CD36. However, the effects of PPAR␥ ligands on upregulation of CD36 could be compensated by the inhibitory effect that PPAR␥ ligands have on SR-A expression (Ricote et al., 1998). CD36 was also shown to bind and phagocytoze apoptotic cells when expressed on immature DCs (Albert et al., 1998). In vitro stimulation of monocytes with LPS leads to the production of the pro-inflammatory cytokines TNF␣, IL-1 and IL-12 (Voll et al., 1997). This response is attenuated in the presence of apoptotic cells, also leading to the production of IL-10. This dampening effect was blocked by anti-CD36 antibodies, indicating that CD36 is involved in the anti-inflammatory effect in response to apoptotic cells. The resulting cytokine environment could further affect B cell activation. CD36 is known to associate with TLRs and be crucial for proper TLR2 signaling (reviewed in (Areschoug and Gordon, 2009)). As previously mentioned, CD36 was also recently discovered to associate with self-ligands, promoting sterile inflammation through assembly of a TLR4–TLR6 heterodimer on Ms (Stewart et al., 2010). A pro-inflammatory milieu could in turn affect B cells. Interestingly, TLR2 and TLR4 have been shown to be highly expressed in atherosclerostic lesions (Edfeldt et al., 2002; Pryshchep et al., 2008), implicating that their regulation by SRs would be of importance in this context. 2.2.2.2. SR-BI. SR-BI has been mostly studied as a receptor for HDL, thereby favoring cholesterol efflux from cells (e.g. Ms in atherosclerotic lesions) to HDL particles for transport to the liver for

excretion or recycling (reviewed in (Rigotti et al., 1997)). This has led to the investigation and discovery of SR-BI expression in lipidladen Ms in atherosclerotic lesions as well as in human monocytederived Ms. SR-BI was also found to be upregulated, together with CD36 and SR-A, during M differentiation, as well as in response to exposure with oxLDL (Hirano et al., 1999). This finding, together with the structural similarity with CD36 and the ability of SR-BI to bind apoptotic cells (Fukasawa et al., 1996), led Gillotte-Taylor et al. to hypothesize that SR-BI could act in a similar manner to CD36. SR-BI was indeed shown to bind and mediate ox-LDL uptake, possibly through binding of oxPL, suggested by the inhibitory effect of the anti-oxPL antibody E06 on binding and uptake. This inhibitory effect was also seen with 1-palmitoyl-2-(5-oxovaleroyl) phosphatidylcholine (POVPC) (Gillotte-Taylor et al., 2001). SR-BI has been shown to have a protective effect on atherosclerosis development, since attenuated or abolished expression of SR-BI in both LDLr−/− (high fat diet-induced atherosclerosis model) and ApoE−/− leads to increased atherosclerosis. This was thought to be due to its role in lipid metabolism (reviewed in (Trigatti et al., 2004)). However, transfer of SR-BI−/− BM to both LDLr−/− (Covey et al., 2003; Van Eck et al., 2004) and ApoE−/− (Zhang et al., 2003) also showed increased atherosclerosis independently of lipid profiles, indicating that SR-BI on BM cells has a protective effect in atherosclerosis. Even though it is believed that M SR-BI is the main contributor of this effect, it cannot be excluded that other cells expressing SR-BI, such as B cells, could also contribute. SR-BI also mediates binding and uptake of both gram-negative and positive bacteria (reviewed in (Areschoug and Gordon, 2009)) and could associate with TLR2 in the uptake of bacteria by trophoblast giant cells, phagocytes in mouse placenta (Watanabe et al., 2010). SR-BI was shown to protect against septic death by mediating LPS clearance, but interestingly also by suppressing TLR4-mediated NF-␬B activation and thereby the induction of the pro-inflammatory cytokines TNF␣ and IL-6 (Guo et al., 2009). Since TLR4 and MyD88 have been shown to play a role in plaque development (Michelsen et al., 2004), this could be an alternative mechanism through which SR-BI protects from atherosclerosis. Together, these studies show that SR-BI could, through the regulation of local and systemic cytokines production, affect B cell function both in lesions and peripheral immune organs. Although the phagocytic functions of SR-BI are less described in the literature compared to the previously mentioned SRs, expression of SR-BI seems to be able to contribute to the clearance of both oxLDL and apoptotic cells, thereby also limiting antigen availability. Whether TLR4-dependent cytokine production is intrinsically regulated by SR-BI also in B cells, remains to be defined. 2.2.3. Class D scavenger receptor CD68 CD68 is mostly found intracellularly in the late endosomal compartment in Ms and DCs (including Langerhans cells), and has limited surface expression on resting cells (Ramprasad et al., 1996). However, it is upregulated on the cell surface of activated Ms, such as thioglycollate-elicited peritoneal Ms, in contrast to MARCO that is not expressed on this type of M. CD68 is also part of the LAMP (lysosome-associated membrane protein) family of proteins. Of these, LAMP-1 co-localization with TLR9 to the same compartment might regulate the outcome of CpG-activation of plasmacytoid DCs (Guiducci et al., 2006). Since CD68 is localized to the same late endosomal compartments, it is possible that CD68 could regulate TLR function in a similar manner to other SRs. 2.2.4. Class E scavenger receptor LOX-1 Lectin-like oxLDL receptor-1 (LOX-1) is expressed on both Ms and DCs and binds oxLDL and the acute phase protein C-reactive protein (CRP) (Fujita et al., 2010). LOX-1 is also known to bind heat shock protein 70 (HSP70) that is secreted extracellularly by

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DCs upon pro-inflammatory stimulation and contact with invading microorganisms (Delneste et al., 2002). Other receptors for HSP70 are the TLR4-CD14 complex, as well as TLR2 (Joly et al., 2010). HSPs promote antigen uptake and transport, and can induce potent cross-presentation to T cells, thus suggesting that they could influence subsequent B cell activation. In connection to this, oxLDLuptake by DCs is mediated by LOX-1, CD36 and CD205. This leads to DC maturation and differentiation by activation of the NF-␬B pathway, which will alter cytokine production with decreased IL-10 and increase in IL-6 (Nickel et al., 2009). LOX-1 shares with SR-A the ability to bind CRP, and CRP-binding to Fc␥RIIB has been shown to induce IL-10 but downregulate IL-12 production (Mold et al., 2002). CRP also binds apoptotic cells and thus LOX-1 could facilitate uptake of apoptotic cells and thereby regulate the access of self-antigen to B cells. In relation to disease, SLE patients have increased levels of plasma CRP during flares (ter Borg et al., 1990). Also, in a mouse model of arthritis, LOX-1 is found to be expressed in the joints and seems to regulate lymphocyte infiltration, as suggested by the beneficial effect of anti-LOX-1 antibody treatment (Nakagawa et al., 2002). 2.2.5. Class G scavenger receptor PSOX (CXCL16) SR-PSOX was discovered in a monocytic cell line and was shown to be expressed in macrophages and foam cells (Minami et al., 2001). It was simultaneously identified on DCs in the T cell zone of the spleen as a CXC chemokine and was named CXCL16 (Matloubian et al., 2000). The membrane-bound CXCL16 can be shed (see Section 2.1.4) and a higher gradient of soluble CXCL16 has been shown to lead to migration of cells highly expressing CXCR6, a unique receptor for CXCL16. CXCL16 is expressed in the synovium of rheumatoid arthritis patients and anti-CXCL16 antibody treatment improves arthritis score in mice (Nanki et al., 2005). This has been suggested to be due to reduced T cell influx even though it could potentially affect B cells, known to migrate to this site of inflammation (Magalhaes et al., 2002), further suggested by the fact that plasma cells express the receptor CXCR6 and use this for migration to tissue and bone marrow (Nakayama et al., 2003). In atherosclerosis, CXCL16 can be found in lesions in both mouse and humans (Sheikine and Sirsjo, 2008). There it can, as a scavenger receptor – mediate uptake of lipoproteins and as a chemokine – drive T cell and NKT cell migration to the inflammatory site. However, in vivo studies have suggested that CXCL16 is atheroprotective, while its receptor CXCR6 is harmful. As mentioned in Section 2.1.4, CXCL16 has also been shown to modulate TLR-9 function and responses to CpG (Gursel et al., 2006) and could therefore indirectly affect CpG-reactive B cells. 2.2.6. SRCR family member CD163 CD163 contains nine SRCR domains and its expression is restricted to monocytes and Ms. CD163 binds haemoglobinhaptoglobin complexes and thus functions as an erythroblast receptor. Another identified self-ligand connected to autoimmunity is tumor necrosis factor-like weak inducer of apoptosis (TWEAK) (Bover et al., 2007; Zheng and Burkly, 2008). CD163 also binds bacteria and viruses (Van Gorp et al., 2010). CD163 expression is regulated during inflammation; where anti-inflammatory signals affecting monocytes such as IL-10 in general induce CD163 expression, pro-inflammatory signals such as IFN-␥ and TNF-␣ instead decrease its expression and LPS causes shedding of the receptor (Van Gorp et al., 2010; Yassin et al., 2011). Regulation of this receptor is dependent on the stage of inflammation and multiple cytokines will influence its expression. Thus, TLR-activation will simultaneously drive acute shedding of CD163 and induce production of IL-10 and IL-6, leading to the recovery and induction of CD163 upregulation (Weaver et al., 2007). Together,

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glucocorticoids, IL-10 and IL-6 induce a CD163+ M phenotype, referred to as “alternatively activated” (alt. wound-healing M) (Hogger et al., 1998; Mosser and Edwards, 2008; Van Gorp et al., 2010). In contrast to the classically activated M, this type of M does not make nitric oxide and is relatively poor in antigen presentation. Instead they may be part of recovery and protection from overwhelming inflammation. As part of this function, CD163 shed during activation has anti-inflammatory as well as atheroprotective activity and could function in part by being a decoy receptor for TWEAK (Moreno et al., 2009). The link between CD163 and antiinflammatory responses and the fact that it is upregulated late in the inflammatory process may in turn affect B cell regulation. However, this remains to be investigated. 3. Natural and autoreactive antibodies SLE has for long been associated with increased risk for cardiovascular disease (Bruce, 2005). However, the mechanisms behind this association have not yet been fully elucidated. The overlapping specificity for foreign and self-ligands between natural antibodies and SRs constitutes a network of recognition that regulates our ability to clear apoptotic cells and modified self-antigens without causing disease. When homeostasis cannot be maintained, this network can instead participate in disease-driving mechanisms. 3.1. Natural antibodies and autoantibodies in atherosclerosis All receptors in the SR family described in this review bind to oxLDL and could potentially induce a protective anti-oxLDL antibody response by affecting presentation to natural antigen-specific B cells. Alternatively, SRs could directly influence B cells when expressed on them. There are several B cell antigens in atherosclerosis, such as HSPs, beta-2-glycoprotein I (␤2GPI) and modified LDL, such as oxLDL. During the apoptotic process, the dying cell activates phospholipases, resulting in alteration of phospholipids (e.g. the formation of lysoPC from PC), which are also contained in modified LDL. Defects in the clearance of apoptotic cells could therefore lead to increased levels of oxLDL and oxidation specific epitopes (Chang et al., 1999). The immunogenic epitopes resulting from oxidation of phospholipids in LDL include malonaldehyde (MDA) and the reactive oxidation product of PC-rich phospholipid PAPC (1-palmitoyl2-arachidonoyl-sn-phosphatidylcholine), POVPC, which contains intact PC. Both MDA and POVPC can form adducts with the protein component of LDL, apoB. Model antigens have been used to study the specific immune responses, namely MDA-LDL (MDA-lysine epitopes) and CuSO4 -oxLDL, containing many different oxidation specific epitopes found both in lipid and protein moieties of oxLDL, as well as bacteria and apoptotic cells (Shaw et al., 2000). The reactivity against oxLDL can be directed towards the protein apoB, but the main epitope is contained in the phospholipid portion of the molecule, i.e. PC. In connection to the common oxidation specificity, anti-PC antibodies also block the uptake of apoptotic cells and oxLDL by Ms (Chang et al., 1999; Horkko et al., 1999). Accumulation of oxLDL and apoptotic cells, as well as oxLDL immune complexes, is seen in atherosclerotic lesions and vaccination strategies using Streptococcus pneumoniae (Binder et al., 2003), MDA-LDL (Palinski et al., 1995), CuSO4 -oxLDL (Ameli et al., 1996) and PC itself (Caligiuri et al., 2007), have all been shown to be effective in reducing plaque formation in animal models. Passive immunization with anti-PC antibodies has also been seen to be protective in ApoE−/− (Faria-Neto et al., 2006) and lower levels of anti-PC predict cardiovascular disease in patients, indicating an actual role in humans (de Faire et al., 2010; Frostegard, 2010). Thus, natural or induced antibodies reacting with PC might protect the

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host in response to infection, autoimmunity, and atherosclerosis (reviewed in (Binder and Silverman, 2005; Frostegard, 2010)). A protective role for B cells has been suggested in atherosclerosis models. When spleen B cells from old ApoE−/− mice were transferred to young mice, these had a protective effect on lesion size. This coincided with an increase in anti-MDA-LDL IgM (Caligiuri et al., 2002), adding to the existing evidence that natural IgM could have a protective effect, partially by blocking ox-LDL uptake and thereby foam cell formation (Boullier et al., 2000; Gillotte-Taylor et al., 2001). BM transfers from either B cell-deficient or wild type mice to LDLr−/− mice also demonstrated a protective role for B cells (Major et al., 2002). The previously mentioned protective effect seen in PCimmunized ApoE−/− mice coincided with an increase in lesioninfiltrating B cells. Furthermore, more mature B cells (IgMdull IgDhigh or IgMhigh B220+ ) were seen in the spleen but not in the peritoneum (Caligiuri et al., 2007), further suggesting that the protective population in these studies is located to the spleen. A plausible explanation is that the B cell repertoire with natural reactivity predominantly present in the spleen, i.e. the MZB cells, is the one responsible. These also express CD36, which could help to anchor antigen. The B1b B cells, also present in the spleen, could also contribute to the protective effect. However, a recent publication by Ait-Oufella et al. (2010) shows that the role for B cells in atherosclerosis might be more complex. They show in LDLr−/− and ApoE−/− mice that anti-CD20 antibody-mediated depletion of B cells ameliorates atherosclerosis. While the potentially protective anti-oxLDL IgM antibodies were preserved in this setting, the anti-oxLDL IgG antibodies were depleted, a mechanism through which harmful immune complexes could be deleted (Hernandez-Vargas et al., 2006). Another set of evidence contradicting a protective role for B cells are studies in which autoantibodies directed towards cardiolipin and ␤2GPI have a disease-driving effect. Immunization with ␤2GPI resulted in high anti-␤2GPI antibodies and larger atherosclerotic lesions (Afek et al., 1999; George et al., 1998). Furthermore, increased levels of these reactivities in patients have been associated with cardiovascular disease (Greco et al., 2009; Marai et al., 2008). CD36 and SR-BI bind the PC moiety of oxPLs in oxLDL, as prototypic E06/T15 natural antibodies block the uptake of oxLDL by these receptors (Boullier et al., 2000; Gillotte-Taylor et al., 2001), showing that natural antibodies can directly interact with SR function. Furthermore, LDL immune complexes can up-regulate SR expression. In addition, anti-PC antibodies indirectly regulate monocyte recruitment to inflammatory sites by blocking plateletactivating factor (PAF) receptors, thereby affecting VCAM- and ICAM-1 expression (Su et al., 2008). In relation to TLRs, agonists for TLR2 stimulate the production of oxidation specific IgM to a greater extent than total IgM (Chou et al., 2009). This further implies SR-TLR heterodimers in the regulation of natural antibody responses. 3.2. Natural antibodies and autoantibodies in SLE Even though there is an overlap between the specificities of autoantibodies in atherosclerosis and SLE, SLE patients display a more ubiquitously directed response. This response includes anti-DNA and anti-chromatin autoantibodies, which are used for diagnosis. In SLE, the antibodies are directly pathogenic through the formation of immune complexes (ICs) with cellular debris. These ICs accumulate in small vessels, in the glomeruli of the kidneys and in joints, where they in turn trigger pathological inflammation (Yung and Chan, 2008). SLE patients have higher levels of anti-␤2GPI antibodies, associated with cardiovascular disease (Puurunen et al., 1996), as well as lower levels of anti-PC antibodies, shown to be atheroprotective (de Faire and Frostegard, 2009). The protective effect of anti-PC

antibodies is disconnected from lipid levels, which goes together with the fact that SLE patients do not always have the classical risk factors, such as altered blood lipids (Sherer et al., 2010). Together, the altered balance of antibodies directed against different epitopes could be part of the pathology. The transition from protective to pathogenic antibody responses is related to genetic predisposition to SLE which includes a number of genes involved in clearance of apoptotic cells such as, MER (Scott et al., 2001), C1q (Botto et al., 1998), MFG-E8 (Hanayama et al., 2004) as well as MARCO (Rogers et al., 2009). In addition, autoantibodies to the MARCO receptor itself can be found in SLE-prone mice as well as SLE patients, suggesting another level of dysregulation of clearance (Wermeling et al., 2007). These defects in clearance could in turn lead to autoantigen availability and subsequent autoreactive B cell activation. Since the B cell response to apoptotic cells can give rise to both PC reactivity as well as pathogenic switched antibodies against DNA, it is likely that there is an initial protective response, followed by a pathological one. Evidence for this is suggested by the fact that IgM antibodies have been shown to mediate clearance of apoptotic cells, and that four injections of apoptotic cells are needed before IgG anti-DNA-mediated kidney pathology is evident (Mevorach et al., 1998; Peng et al., 2005). Another mechanism of regulation of apoptotic cell-derived autoantigen is connected to a unique subset of T cells called invariant NKT cells (iNKT). These cells recognize glycolipids presented on CD1d which is highly expressed on MZBs and have been suggested to have a role in both SLE and atherogenesis (Major et al., 2006). Since apoptotic cells are trapped by MZMs, MZBs have access to apoptotic material and potential CD1d ligands during activation to self-antigens. Recently, we investigated if this response was regulated by iNKT cells. Unlike responses to foreign antigens, the autoimmune response to injected apoptotic cells was greatly enhanced in mice lacking iNKT cells and we found evidence for increased kidney pathology. B cell transfer experiments and BM chimeric mice further showed that iNKT cell interaction with CD1d on B cells directly regulated B cell entry into germinal centres. Thus, iNKT cells are able to stop B cells from producing pathogenic autoantibodies (Wermeling et al., 2010). LDL-R can mediate the uptake of glycolipids for presentation to CD1d (reviewed in (Cohen et al., 2009)). Also, B cells were shown to present lipid antigen through an apolipoprotein-mediated pathway (Allan et al., 2009). Although it has not yet been studied, it is likely that the uptake of glycolipids for presentation on CD1d is regulated by SRs on the B cell itself. Furthermore, SRs expressed on other APCs, affecting uptake and subsequent presentation to B cells, could potentially regulate their activation. 4. Discussion and concluding remarks Direct regulation of antibody responses by SRs expressed by B cells is relatively unexplored, but they could potentially regulate B cells through different mechanisms (Fig. 2). The signaling events triggered by these receptors on B cells may be mediated through similar pathways as in other leukocytes, as well as lead to uptake of antigen for subsequent presentation to T cells. For example, the C terminal of CD36 binds Lyn and MEKK2, and activates JNK (Rahaman et al., 2006). In addition, Stewart et al. proposed that CD36-Lyn kinase interactions facilitate TLR4-TLR6heterodimerization and signal initiation. SRs on B cells could bind to oxPS and PC on apoptotic cells directly and affect signaling threshold of the BCR. Finally, they could mediate transport of selfantigens to the follicle and regulate the B cell’s ability to present self-antigens. In addition, DCs and Ms regulate the B cell response through SRs indirectly. One important function of these cells is to orches-

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trate either immunogenic or tolerogenic responses, depending on the antigen they phagocytose. This shows that when handling engulfed material for antigen presentation, they are able to distinguish between TLR-ligands and self-antigens, at least in the context of apoptotic cells (Torchinsky et al., 2010). Phagocytosis by APCs is thus controlled by PRRs to distinguish self from foreign antigens. Whether this control occurs also in B cells is however unknown. Since SRs associate with TLRs, the signals downstream of these receptors will be integrated in the cell and affect the outcome of antigen presentation, as well as cytokines produced in response to SR and TLR ligands. SRs can regulate intracellular TLRs which in turn control phagosome maturation through signaling mediated via MyD88 and MAPK (Torchinsky et al., 2010). SR upregulation (such as MARCO) is mediated in part via this same pathway. This means that SRs can feedback-regulate TLR responses and provide a pathway for inflammation resolution. The knowledge provided from studying SLE and atherosclerosis indicates that the components of the innate immune response, e.g. SRs and natural IgM antibodies, directed against the same oxidation-specific epitopes, serve an important protective role in early stages of disease. When balance is broken, SRs as well as natural antibody reactivities can become part of pathogenesis, where SRs instead of mediating healthy clearance and anti-inflammatory, anti-apoptotic responses, become mediators of foam cell formation and plaque instability. The ability of SRs to act with TLRs, critical in response against pathogens, could also lead to pro-inflammatory signals in response to modified self, exemplified by the formation of CD36-TLR4-TLR6 complexes binding oxLDL (Stewart et al, 2010). Also, Ms could be triggered to present self in an inflammatory milieu, no longer being able to differentiate between self and non-self. Natural antibodies also play an important role in keeping the homeostatic balance. While IgM-producing B cells with natural reactivities seem to have a protective role in SLE and atherosclerosis, activated B cells can lead to the production of switched IgG antibodies, which in turn can lead to IgG-IC formation. These could then be able to regulate SR expression (also regulated by cytokines and PPAR␥ ligands), as well as activate Ms through Fc receptors, maybe providing them with a second signal, necessary for inflammasome activation in turn leading to pro-inflammatory responses. We believe that studies of the relationship between SR function and natural antibody responses will shed light on the important underlying mechanisms of SLE and atherosclerosis, as well as regulation of immune functions beyond these two diseases. Conflict of interest None. Acknowledgement The authors would like to thank Lisa Westerberg and John Andersson for critical reading of the manuscript and Malin Winerdal for artwork. This work was supported by the Swedish Research Council, the Swedish Medical Society, King Gustaf V’s 80years foundation and the Swedish Rheumatism Association. EDJ and FW are supported by a PhD fellowship from the Karolinska Institutet. The authors declare no conflict of interest. References Abel, S., Hundhausen, C., Mentlein, R., Schulte, A., Berkhout, T.A., Broadway, N., Hartmann, D., Sedlacek, R., Dietrich, S., Muetze, B., Schuster, B., Kallen, K.J., Saftig, P., Rose-John, S., Ludwig, A., 2004. The transmembrane CXC-chemokine ligand 16 is induced by IFN-gamma and TNF-alpha and shed by the activity of the disintegrin-like metalloproteinase ADAM10. J. Immunol. 172, 6362–6372.

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