Humoral Immunity in Atherosclerosis

The role of B cells in atherosclerosis has received less attention than that of T cells and macrophages. Overall, the experimental evidence suggests that B cells may be protective. LDLR-deficient mice have normal number of B cells, but bone marrow transplantation from B cell-deficient mice into LDLR-deficient recipients results in complete lack of B cells and antibodies, as well as increased atherosclerotic lesion size (Major et al., 2002). Splenectomy in apoE-/- mice further promotes atherosclerosis, but this progression can be prevented by the transfer of B cells from apoE-deficient mice (Caligiuri et al., 2002). These data suggest that B cells may prevent disease progression in atherosclerosis possibly via antibody production and immune regulation via antigen presentation.

The oxidation process creates multiple chemical modifications on both the protein and the lipid components of the LDL particles (Palinski et al., 1990, 1995b, 1996), resulting in the formation of neo-self-antigens that can elicit the production of anti-oxLDL antibodies. The presence of anti-oxLDL antibodies has been documented in humans and in mouse or rabbit strains prone to atherosclerosis (Palinski and Witztum, 2000; Vaarala, 2000; Thiagarajan, 2001). Although the role of these antibodies in atherosclerosis is still controversial, the correlation of anti-oxLDL titer and disease progression suggests that anti-oxLDL antibody titers are a marker of atherosclerosis progression (Palinski et al., 1990, 1995b; Romero et al., 2000; Thiagarajan, 2001).

Patients with systemic lupus erythematosus (SLE) or antiphospholipid antibody syndrome (APS) are prone to develop arterial complications including arterial thrombosis and atherosclerosis (Roubey, 1996; Haviv, 2000; Hughes, 2000; Urowitz and Gladman, 2000). This fact has attracted attention on the possible role of the autoimmune process in atherosclerosis development. Antibodies to oxLDLs are frequently detected in SLE patients, and several reports have suggested that they also cross-react with phospholipids, suggesting the existence of a significant over lap between anti-oxLDL and antiphospholipid autoantibody populations (Romero et al., 2000; Vaarala, 2000; Thiagarajan, 2001; Nicolo and Monestier, 2004).

The specificities of anti-oxLDL antibodies are quite diverse. Some of them bind to oxidized lipid moieties in the LDL particles, whereas others may recognize the oxidative modifications of apoB (Thiagarajan, 2001). Cross-reactivities toward oxLDLs have been suggested for various autoantibody populations associated with systemic autoimmunity. APS patients have autoantibodies to a phos-pholipid-binding protein, 62-glycoprotein I, which can in turn bind to LDL (Horkko et al., 1997; Reddel et al., 2000). Overall, antibody specificities such as anticardiolipin, anti-62 glycoprotein I, or anti-62 glycoprotein I-cardiolipin complexes have been reported to cross-react with various epitopes of oxLDL (Mizutani et al., 1995; Horkko et al., 2001; Matsuura et al., 2002). It has also been suggested that the clinical associations of these antibodies may be different. For instance, anti-62-glycoprotein I-cardiolipin-complex antibodies are associated with both arterial and venous thrombosis in SLE, whereas anti-oxLDL antibodies are only associated with arterial thrombosis in APS patients (Vaarala, 2000).

With respect to atherosclerosis, an important group of anti-oxLDL antibodies are naturally occurring autoantibodies directed against oxidized phospho-lipids. In the atherosclerosis-prone apoE-deficient mouse strain, oxLDL-specific B cells produce IgM antibodies that recognize oxidized phospholipids (Shaw et al., 2000) and share structural and functional properties with naturally occurring T15 idiotype-positive antiphosphatidylcholine antibodies (Rose and Afanasyeva, 2003; Shaw et al., 2000, 2003). These T15 antibodies are of B-1 cell origin, can be protective against certain microbial infections, and can cross-react with apoptotic cells and mediate their clearance (Shaw et al., 2000, 2003; Cocca et al., 2001; Rose and Afanasyeva, 2003). Some anti-oxLDL antibodies indeed recognize epitopes common to both oxLDL and apoptotic cells (Chang et al., 1999).

The possible role of these autoantibodies in atherosclerosis remains unclear. The initial assumption was that they were probably pathogenic, possibly via the formation of immune complexes. For instance, in vitro studies showed that the presence of LDL-immune complexes promotes macrophage uptake via FcyRI and formation of foam cells (Lopes-Virella et al., 1997). In contrast, more recent studies have suggested a potential protective role for autoantibodies in atherosclerosis. For example, some antiphospholipid antibodies including anti-oxLDL antibodies could interrupt oxLDL uptake of macrophage by blocking their binding to scavenger receptors (Chang et al., 1999; Shaw et al., 2000).

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