Splenic immunity and atherosclerosis: a glimpse into a novel paradigm? (original) (raw)

T cells, which mediate adaptive immunity, are an early and important component of lesions, and macro-phages, which play a key role in both lesion development and in mediating plaque disruption, serve to bridge innate and adaptive immune processes. Immuno-globulins are abundant in the plaque, in part complexed to lesion epitopes, such as “oxidation-specific” epitopes of oxidized LDL (OxLDL). However, B cells themselves are noticeable for their absence, though they have been reported in the adventitia surrounding diseased vessels. Specific humoral, as well as cellular immunity has been demonstrated to a number of antigens in the atherosclerotic lesion, including viral and bacterial antigens, heat-shock proteins, modified arterial wall elements, and especially OxLDL. Indeed, autoantibodies to a variety of oxidation-specific epitopes of OxLDL, such as that modeled by malondialdehyde-modified LDL (MDA-LDL), have generally been shown to correlate with the extent of lesion formation in mice and humans (3, 4).

Evidence that immune responses are important in the natural history of lesion progression comes from many studies now, demonstrating that modulation of specific immune components affects both the rate of atherogenesis as well as the composition of the lesion itself. For example, _ApoE_–/– and LDLR–/– mice have been crossed into a _Rag(1or2)_–/– background, generating hypercholesterolemic mice with a deficiency of both T and B cells. If these mice are fed a high fat diet to produce exceptionally high plasma cholesterol levels (> 1,300 mg/dl), after a sufficient period of time (16–22 weeks), the extent of atherogenesis is not affected (5–7). However, at earlier time points (4–8 weeks), or even at more extended periods of time in the presence of more moderate cholesterol levels (600–800 mg/dl), the combined immunodeficiency does alter the course of atherogenesis, resulting in a 40–80% decreased rate of lesion formation (5, 7, 8).

These studies teach us that if the atherogenic pressure is exceedingly high, immune function is not obligatory for the initiation or progression of lesion formation, but under conditions of more moderate atherogenic pressure, the immune responses play a pro-atherogenic role. Indeed, most studies of immune modulation to date have indicated a proatherogenic influence of the immune system on atherogenesis. For example, neutralizing CD40L interactions, either genetically or by infusion of blocking antibodies, reduces lesion formation (9), as does blocking of the activity of the Th1 cytokine INF-γ (10). This subject has been covered in depth in several recent reviews (4, 11, 12).

During evolution, an increasing number of genes have been devoted to the expansion of what can be collectively called immune function. Surely, the genetic selection of such a complex system must have some important survival advantage. Atherosclerosis is only manifested beyond the reproductive period, and thus is not likely to exert any evolutionary pressure itself. However, it is now apparent that there are generalized responses to inflammatory components of the atherogenic process that are shared with those seen in infectious and acute and chronic diseases. It is likely that such responses exert selective positive pressure on immune components that could also exercise protective mechanisms with regard to atherogenesis. For example, hyper-immunization of hypercholesterolemic rabbit and murine models with OxLDL epitopes, so as to achieve very high plasma titers of antibodies to OxLDL, ameliorates atherogenesis (12), as does the intravenous administration of polyspecific IgG isolated from pooled donors (13).

_ApoE_–/– mice develop very high titers of IgM autoantibodies to a variety of oxidation-specific neoepitopes on OxLDL (14). Furthermore, it has recently been demonstrated that IgM monoclonal autoantibodies to OxLDL, cloned from the spleens of such cholesterol-fed _ApoE_–/– mice, specifically bind to oxidized phospholipid epitopes and block the uptake of OxLDL by macrophage scavenger receptors, a key step in the formation of the atherosclerotic plaque. Presumably, such inhibition of OxLDL uptake serves an anti-atherogenic function, as genetic deletion of scavenger receptors protects against atherogenesis in some genetic backgrounds. These antibodies also bind to apoptotic cells, which display similar oxidized phospholipid epitopes. Interestingly, these antibodies, which are secreted by the spleen, have been shown to be identical to the T15 clonospecific anti-phosphorylcholine (anti-PC) antibodies, which arise without prior immunization and do not require germline recombination to achieve specificity for their target epitopes (15–17). These so-called “natural” antibodies confer optimal protection to mice against lethal infection with encapsulated organisms, such as Streptococcus pneumoniae. Because these germline antibodies are found by day 7 in mice maintained in germ-free environments, it has been postulated that they are actually positively selected for their ability to clear oxidized membranes found on apoptotic cells. Subsequent exposure to microbial PC serves to exert further positive selection pressure. These antibodies are greatly expanded in the cholesterol-fed _ApoE_–/– mice, presumably because of the presence of excess OxLDL (18). Thus, while much evidence supports a pathogenic role for many immune mediated mechanisms, there is, not surprisingly, also precedent for the observation that some aspects of immunity serve to decrease the progression of atherosclerosis as well.