Is atherosclerosis an allergic disease?

A new report in the Journal of Clinical Investigation adds to the ever-increasing evidence that immunological mechanisms play an important role in atherogenesis. These new observations suggest involvement of IgE and its Fc R1 receptor in the promotion of atherosclerosis, and specifically in plaque instability and clinical events. Evidence continues to accumulate supporting an important role for immunological mechanisms in all phases of atherosclerosis.1-3 Previous studies have supported an important modulating role for disease-specific IgG and IgM and for Fc receptors in modulating atherogenesis.4-9 In a recent report, Wang et al contribute to this growing body of literature by presenting novel observations supporting a proatherogenic role for IgE and its high-affinity receptor Fc R1 .10 The authors compared the extent of atherosclerosis in wild-type apoE mice fed a Western diet with apoE/ Fc R1 –/– mice and observed a profound reduction in lesion formation. Although nearly all the cell types known to be involved in atherogenesis express Fc R1 receptors in vivo, the authors focused primarily on the potential role of this receptor in macrophage biology and demonstrated that IgE mediates a variety of proinflammatory effects in macrophages, such as release of interleukin-6 and monocyte chemoattractant protein-1, as well as proteases such as cathepsins. In addition, it promotes apoptosis. In large part, these effects (particularly the induction of apoptosis) were mediated by aggregated IgE, as would occur when cross-linked by antigen, and also by an obligatory interaction of Fc R1 with Toll-like receptor 4. In particular, these observations suggest the possibility that IgE and its Fc R1 receptor on macrophages may be involved in late phases of atherosclerosis, promoting plaque instability and clinical events. The potential relevance of these findings to human disease was supported by the finding of elevated IgE levels in patients with various manifestations of cardiovascular disease (CVD), in particular in those with unstable angina and acute coronary events. A potential role for IgE in CVD has been previously suggested by studies strongly linking mast cells to atherogenesis and aneurysm formation.11-14 By demonstrating the potential for IgE to participate in macrophage activation and promotion of apoptosis, these studies suggest yet another cell type that might become atherogenic by interaction with IgE, particularly IgE cross-linked by antigen. The demonstration that Fc R1 receptors must interact with Toll-like receptor 4 to produce such effects adds to the growing evidence that individual innate immune receptors effect many of their biological actions by combinatorial activity with other innate receptors, as also exemplified by the interactions of CD36 and Toll-like receptor 2 to mediate macrophage apoptosis.15 Such combinatorial groupings undoubtedly increase the specificity of response of a given innate receptor, perhaps providing individualized responses in different cell types or under different conditions. Likely, the proatherogenic activity of IgE in humans is more complex. In contrast to the data described by Wang et al,10 IgE binding to Fc R1 was previously reported to actually promote the survival of human monocytes,16 and in another report, it was reported to induce proinflammatory effects through the low affinity IgE receptor (CD23), including the release of interleukin-6 and thromboxane B2 in human B lymphocytes.17 Nevertheless, these studies suggest novel ways by which IgE may contribute to inflammation and destabilization of the advanced plaque and thus could be relevant to clinical disease. In the article by Wang et al, the authors describe epidemiological studies in which IgE levels were found to be higher in subjects with CVD and, in particular, subjects experiencing unstable angina and acute coronary events.10 It is not clear at what time in relation to acute events these levels were measured, nor were control patients with other acute illness sampled. Because the prevalence of known CVD risk factors was very high in the CVD patients studied, it is not possible to determine whether the elevated IgE levels are disease associated or possibly disease causing. Furthermore, the levels of IgE measured in the patients were 150to 300-fold lower than the concentrations of IgE used in the experimental studies in vitro, raising important questions as to the relevance to human disease of the effects studied in cell culture. Aside from the usual arguments that the localized concentrations at the surface of a macrophage in vivo may be quite different than levels in plasma, it is also possible that simultaneous activation of Toll-like receptor 4 might lead to synergistic effects. For example, one could imagine that in a setting of “metabolic endotoxemia” (in which low but eleThe opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association. Commentaries serve as a forum in which experts highlight and discuss articles (published elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine. Commentaries are edited by Aruni Bhatnagar and Ali J. Marian. From the Center for Molecular Medicine of the Austrian Academy of Sciences (C.J.B.), Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria (C.J.B.); Department of Medicine, University of California, San Diego, La Jolla, CA (C.J.B., J.L.W.). Correspondence to Joseph L. Witztum, MD, Department of MedicineM0682, 9500 Gilman Drive, La Jolla, CA 92093. E-mail [email protected] (Circ Res. 2011;109:1103-1104.) © 2011 American Heart Association, Inc.