Novel immunologic cellular mechanisms in atherosclerosis and potential therapeutic implications

Atherosclerosis, an arterial ailment, is a major cause of cardiovascular diseases (CVD), which cause more than 17 million deaths each year and the number is expected to rise. In recent years atherosclerosis has been shown to be an inflammatory condition involving activated immunocompetent cells, including T-cells, macrophages and dendritic cells (DC), but the mechanism by which these cells are activated remains to be elucidated in detail. Treatment of atherosclerosis is still not satisfactory, primarily due to the complex underlying mechanisms, especially with respect to inflammation and immunity. An additional characteristic of atherosclerosis is the accumulation of dead cells in a necrotic core in the plaques, as well as of oxidized forms of low density lipoprotein (Ox-LDL). Interestingly, the prevalence of atherosclerotic plaques and CVD are elevated among individuals with systemic inflammatory diseases, such as systemic lupus erythematosus (SLE).

These studies focused on the responses of major immunocompetent cells, such as T-cells, DC and macrophages to potential antigens, including heat shock protein (HSP) 60 and 90, phosphorylcholine (PC) and malondialdehyde (MDA), of which the latter two are components of Ox-LDL. Such investigations are related to potential links between the prototypical autoimmune disease SLE and CVD, as well as the development of novel therapies against atherosclerosis. For these purposes, we examined peripheral blood cells from healthy donors and patients with SLE, as well as cells obtained from human atherosclerotic plaques in connection with operations for CVD. We also studied a well-characterized cohort of SLE-patients, SLEVIC. Overall, we found that antibodies against phosphorylcholine (PC) and MDA were correlated with a lower prevalence of atherosclerosis among patients with SLE. Potential mechanisms involve enhanced uptake of apoptotic cells and a reduction in oxidative stress. Furthermore, anti-PC antibodies promoted polarization of T-reg cells, which may protect against both SLE and atherosclerosis. Surprisingly, production of these antibodies was dependent on T-cells.

HSP60 and HSP90 exerted pro-inflammatory effects on DCs and DCs stimulated in this manner induced pro-inflammatory activation of T-cells obtained from human peripheral blood and atherosclerotic plaques. Expression of HSP60 was induced by OxLDL. A conjugate of MDA with human serum albumin (MDA-HSA) promoted pro-inflammatory activation of DCs and, subsequently, of T-cells obtained from human peripheral blood and atherosclerotic plaques via these DCs. Importantly, MDA-HSA also activated such T-cells directly. Both MDA-HSA itself and T-cells exposed to MDA-HSA promoted polarization of pro-inflammatory M1 macrophages. Annexin A5 inhibited the pro-inflammatory effects of HSP60 (in line with our previous identification of this substance as potentially protective against atherosclerosis) and anti-MDA antibodies or an inhibitor of mitochondrial production of reactive oxygen species (ROS) attenuated the activation of T-cells by MDA-HSA.

Taken together, immunity plays an important role in connection with atherosclerosis and atherosclerotic plaques. Potential links between autoimmunity and atherosclerosis were identified. In particular, HSP60 and MDA may be important activators of immune cells in connection with atherosclerosis and, importantly, antibodies against PC and MDA, Annexin A5 and inhibitors of ROS could prove to be of value for prevention of and/or therapy against atherosclerosis.

List of scientific papers

I. Rahman M, Sing S, Golabkesh Z, Fiskesund R, Gustafsson T, Jogestrand T, Frostegård AG, Hafström I, Liu A, Frostegård J. IgM antibodies against malondialdehyde and phosphorylcholine are together strong protection markers for atherosclerosis in systemic lupus erythematosus: Regulation and underlying mechanisms. Clin Immunol. 2016 May;166-167:27-37.
https://doi.org/10.1016/j.clim.2016.04.007

II. Mizanur Rahman, Johnny Steuer, Peter Gillgren, Assim Hayderi, Anquan Liu, and Johan Frostegård. Induction of Dendritic Cell–Mediated Activation of T Cells from Atherosclerotic Plaques by Human Heat Shock Protein 60. J Am Heart Assoc. 2017 Nov; 6(11).
https://doi.org/10.1161/JAHA.117.006778

III. Sun J, Lundström SL, Zhang B, Zubarev RA, Steuer J, Gillgren P, Rahman M, Ajeganova S, Liu A, Frostegård J. IgM antibodies against phosphorylcholine promote polarization of T regulatory cells from patients with atherosclerotic plaques, systemic lupus erythematosus and healthy donors. Atherosclerosis. 2018 Jan;268:36-48.
https://doi.org/10.1016/j.atherosclerosis.2017.11.010

IV. Mizanur Rahman, Johnny Steuer, Peter Gillgren, Ákos Végvári, Anquan Liu and Johan Frostegård. Malondialdehyde-conjugated with albumin induces a pro-inflammatory activation of T cells from human atherosclerotic plaques through both a direct and a dendritic cell-mediated mechanism. [Manuscript]