Atherosclerosisis the main underlying cause of heart attack and stroke, and is expected to be the leading cause of death in the world from a long time to come. Approximately a third of patients do not respond to statin treatment. The disease is characterized by the narrowing of the arterial walls resulting from the accumulation of lipids and cells – the so-called atherosclerotic plaque. When the plaque ruptures, blood clots can form that restrict the blood flow to vital organs, such as the heart and brain. Atherosclerosis progression is modulated by interactions with the adaptive immune system. Humoral immunity can help protect against atherosclerosis formation, however the existence, origin and function of putative atherogenic antibodies is controversial. How such atherosclerosis-promoting antibodies could affect the specific composition and stability of plaques, as well as the vasculature generally, remains unknown.
Researchers at Karolinska Institutet in Sweden have found that type IgG antibodie play an unexpected role in atherosclerosis. A study on mice shows that the antibodies stabilize the plaque that accumulates on the artery walls, which reduces the risk of it rupturing and causing a blood clot. It is hoped that the results will eventually lead to improved therapies.To reduce the number of deaths from atherosclerosis, researchers are therefore trying to find ways to prevent this from happening. Immune system B lymphocytesproduce antibodies that are involved in fighting infection. But the antibodies can also help to clean up damaged tissue, for instance in the form of atherosclerotic plaques. Scientists also know that the immune system has a bearing on the development of plaque, but exactly how this happens remains largely unresearched. The team behind the present study has studied how atherosclerotic plaquedevelops in mice that lack antibodies.
They found that plaque formed in an antibody-free environment was unusually small. But on closer inspection, we discovered that the plaque looked different and contained more lipid and fewer muscle cells than normal. This suggested that the plaque is unstable and more prone to rupturing, which also turned out to be the case. The researchers found that the necessary ingredient for plaque stability was so-called IgG antibodies, the most common class of antibody in the blood. Further analyses showed that the smooth muscle cellsof the aorta need these antibodies to divide correctly; when the cells cannot divide correctly, the plaque seems to become smaller and more unstable.These IgG antibodies were shown to be derived from germinal centers and mice genetically deficient for germinal centerformation had strongly reduced plaque formation. They were required for both the sufficient expression of multiple signal induced and growth promoting transcription factors to allow aortas undergo large-scale metabolic reprograming in their absence.
Stephen Malin, senior researcher at Karolinska Institutet’s Department of Medicine in Solna, commented: “We propose that germinal center derived IgG antibodies promote the size and stability of atherosclerosis plaques, through promoting arterial smooth muscle cell proliferation and maintaining the molecular identity of the aorta. These results could have implications for therapies that target B cells or B-T cell interactions for immunosuppressive therapies. They could actually explain some adverse effects that appear in patients using therapeutic antibodies (biologicals). It came as a huge surprise to us that antibodies can play such an important role in the formation of arterial plaque. We now want to find out if it is some special type of IgG antibody that recognizes plaque components. If so, this could be a new way of mitigatin atherosclerosis and hopefully reducing the number of deaths from cardiovascular disease”.
Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Centa M et al., Malin SG. Circulation. 2019 Mar 21.
Yao G et al. Int J Rheum Dis 2019 Mar; 22(3):488-496.
Wang F, Zhang Z et al. Front Immunol 2019 Jan; 9:3127.