Review articleProtective Role of Natural IgM-Producing B1a Cells in Atherosclerosis
Introduction
Atherosclerosis begins with accumulation of translocated lipids in arterial intimal layers, but its development and progression, and plaque rupture, are modulated by the immune system. The presence of immune cell infiltrates in both human and animal atherosclerotic lesions supports different immune cell involvement in atherosclerosis pathogenesis. B cells are generally considered “protective” because of their ability to produce antibodies against antigens expressed by invading pathogens. Studies published a decade ago suggested that B cells protect against atherosclerosis. Unfractionated splenic B cells were reported to be atheroprotective because transferring them into splenectomized ApoE−/− mice reduced postsplenectomy aggravated atherosclerotic lesions (Caligiuri et al. 2002). To further reinforce their atheroprotective role, B cell deficiency generated in chimeric mice by B cell–deficient (μ-MT) bone marrow transplantation increased atherosclerosis in LDL-R−/− mice (Major et al. 2002).
However, we and Mallat's group have recently reported that B cells can be pathogenic because CD20-targeted B cell depletion was associated with reduced atherosclerosis in LDLR−/− and ApoE−/− mice (Ait-Oufella et al., 2010, Kyaw et al., 2010). These two reports have generated a paradigm shift in our understanding of the role of B cells in atherosclerosis. Furthermore, we identified conventional B2 cells, and not B1a cells, as the atherogenic B cell subset by their transfer into lymphocyte-deficient ApoE−/− mice as well as into ApoE−/− mice rendered B cell deficient by mu-chain gene knockout (Kyaw et al. 2010). This finding and the capacity of unfractionated splenic B cells to reduce atherosclerosis (Caligiuri et al. 2002) suggest that other B cell subsets confer a protective role in atherosclerosis pathogenesis.
To identify the atheroprotective B cell subset, we revisited the earlier splenectomy experiments in atherosclerosis (Caligiuri et al. 2002). The report that Bla B cells are depleted in splenectomized and in asplenic mice (Wardemann et al. 2012) led us to the hypothesis that the atheroprotective B cell population resided in this B1a cell subset. Indeed, our studies showed that peritoneal B1a cells are atheroprotective by producing natural IgM (Kyaw et al. 2011). The findings are consistent with the atheroprotective role of IgM (Lewis et al. 2009). Because transfer of a relatively small number of 30,000 B1a cells is sufficient to reduce atherosclerosis in splenectomized mice (Kyaw et al. 2011), we suggest that the protective effect of the transfer of large numbers (20–60 million) of unfractionated B cells to splenectomized and into ApoE−/− mice(Caligiuri et al. 2002, Doran et al. 2012) may be attributed to the presence of the atheroprotective Bla population. The opposing roles of B cell subsets were further supported by our studies in BAFFR−/− ApoE−/− mice that showed that mice lacking mature B2 but not Bla B cells had markedly reduced atherosclerosis (Kyaw et al. 2012), consistent with BAFF as a survival factor for mature B2 but not Bla B cells (Mackay and Browning 2002). Similar findings were also reported by Mallat's group in their studies of chimeric mice (Sage et al. 2012).
Thus, these studies show that B cells contain subsets with opposing roles in atherosclerosis, with the mature B2 subset being atherogenic and the B1a subset atheroprotective (Kyaw et al. 2011). In this review, we focus on the role of atheroprotective B1a cells and their product, natural IgM, in atherosclerosis.
Section snippets
B Cells Are Heterogeneous
Using surface markers, murine mature B cells can be classified into three subsets: conventional B2 cells (IgMlo IgDhi B220hi CD5−), B1 cells (IgMhi IgDlo B220lo CD5+ CD1d+), and marginal zone (MZ) cells (IgMhi IgDlo B220hi CD1d+ CD21hi) (Gorelik et al. 2004). Whereas conventional B2 cells are found in the circulation and in follicular aggregates in lymphoid organs and MZ B cells are located in the spleen, B1 cells reside primarily in peritoneal and pleural cavities.
Serosal B1 B cells are
Serosal and Spleen B1a Cells
B1 B cells, first thought to be self-renewing lymphocytes arising from the fetal liver, are also derived from bone marrow and spleen progenitors (Holodick et al., 2009, Montecino-Rodriguez and Dorshkind, 2012). They require the spleen for survival and maintenance. Mice with genetically manipulated B cell receptor (BCR) showed a strong link between BCR signaling and B1 cell development. Mutant BCR genes generate B1 cell–depleted mice, and BCR overexpression expands B1 cells in mice (Berland and
B1a Cells in Atherosclerosis
The presence of B cells in atherosclerotic lesions has been reported in human and animal studies (Ylä-Herttuala et al. 1994), but the presence of B1a cells in atherosclerotic lesions is yet to be reported. Although B1a cells normally reside in serosal cavities, these cells can migrate into local inflammatory sites. Indeed, CD22+CD5+ B1a cells are present in chronically inflamed human gingival tissues (Aramaki et al. 1998). Fluorescence-activated cell sorter and immunohistochemical analyses
A Complex Mechanism Involving Toll-Like Receptors Is Required for Peritoneal Exit and Activation of B1a Cells
The mechanism involved in B1a cell migration from serosal cavities is complex and is initiated by Toll-like receptor (TLR)-dependent signaling. TLR-4 deficiency impairs the downregulation of integrin-CD9 in B1a cells, which is required in an initial step for them to leave serosal cavities. After TLR stimulation, interaction of CXCR5-CXCL13 and sphingosine-1-phosphate (S1P) with its receptor 1 (S1P1) are next required for B1a B cell's serosal exit and homing to its destination (Ha et al. 2006).
B1a Cells Produce Natural IgM Antibodies
Natural IgM antibodies (NAbs) produced by Bla cells arise without pre-existing antigen stimulation (Coutinho et al. 1995) and are polyreactive (Baumgarth et al. 2005). In addition to having an important role in first-line defense against pathogens, NAbs also recognize modified self-antigens and/or waste material such as necrotic debris and apoptotic cells, providing a housekeeping homeostasis function. Oxidized low-density lipoprotein (oxLDL) is a major antigen in atherosclerosis that
Role of Natural IgM Antibodies in Atherosclerosis
NAbs can target oxidation-specific epitopes that are abundantly present on oxidized lipids (Hartvigsen et al. 2009), apoptotic cells (Chang et al. 2004), and necrotic cells (Binder 2010). In the course of atherosclerosis pathogenesis, accumulated antigen such as modified LDL and heat shock proteins are dominantly found in intimal lesions; however, its composition changes to inflammatory necrotic cores composed of apoptotic cell and necrotic debris as atherosclerotic lesions become advanced.
B1a Cells Also Produce Anti-Inflammatory Cytokine IL-10
In addition to IgM NAbs, B1a cells produce the majority of B cell–derived IL-10, an anti-inflammatory cytokine (O'Garra et al. 1992). IL-10 confers its anti-inflammatory actions by inhibiting synthesis of proinflammatory cytokines and suppressing antigen presentation by antigen-presenting cells to effector T cells. Using different cell lines, it has been reported that IL-10 is capable of not only inhibiting proinflammatory cytokines produced by activated macrophages but also regulating the
Role of Anti-Inflammatory Cytokine IL-10 in Atherosclerosis
In atherosclerosis, IL-10 is considered a possible candidate in predicting clinical outcome because serum IL-10 levels are directly related to cardiovascular complications in human studies (Heeschen et al. 2003). In animal studies, IL-10 knockout mice showed increased atherosclerosis (Caligiuri et al. 2003), whereas transgenic IL-10 mice had decreased atherosclerosis (Von Der Thüsen et al. 2001), indicating its protective role in atherosclerosis. Almost all leukocytes can produce IL-10,
Are B1a Cells Regulatory B Cells?
The existence of negative regulatory B cells (Bregs) is now widely accepted (Mauri and Bosma 2012). Bregs appear to modulate the inflammatory responses in autoimmunity, tumor immunity, parasitic infections, and transplantation (Mauri and Ehrenstein 2008). The origin, development, surface markers, and anatomical location of Bregs are still unclear (Mauri and Bosma, 2012, Noh and Lee, 2011). All the published data indicate that Bregs produce IL-10 (Evans et al., 2007, Fillatreau et al., 2002),
In Vivo Expansion of B1a Cells
In contrast to mature B2 cells that primarily recognize T-dependent antigens, B1 cells strongly respond to self-antigens such as phosphatidylcholine, DNA and membrane proteins from erythrocytes and thymocytes (Hayakawa et al., 1990, Mercolino et al., 1986, Mercolino et al., 1988), pathogenic/parasitic antigens containing phosphorylcholine (Masmoudi et al., 1990, Wilson et al., 2003), and organic compounds such as phorbol ester (Rothstein and Kolber 1988). In addition to their role in B1a
Human B1 Cells
Recently, human B1 cells were identified as CD20+CD27+CD43+CD70− in cord blood and adult peripheral blood in normal healthy subjects (Griffin et al. 2011). Of these human B1 cells, a minority subset expressing CD11b (10%) expands and strongly stimulates T cells in a lupus environment. In contrast, the majority of CD11b− B1 cells with less capacity to stimulate T cells do not change their population in lupus patients (Griffin and Rothstein 2011).
Conclusions
B1a cells are atheroprotective in murine models. It is clear that B1a-produced natural IgM antibodies provide an efficient clearance of modified LDL, apoptotic cells, and necrotic cells. The role of B1a cells in downregulating production of proinflammatory cytokines from activated macrophages and T cells in atherosclerotic lesions requires further investigation (Figure 1). The possible mechanisms by which IL-10 produced by B1a cells may directly act in downregulating proinflammatory cytokine
Acknowledgments
This study was supported by a grant from the National Health and Medical Research Council, Australia, and in part by Victorian government's Operational Infrastructure Support program.
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