What is the function of B cells in experimental atherosclerosis?

Sammanfattning: Cardiovascular disease is one of the leading causes of death worldwide. A major cause is atherosclerosis, which is a chronic inflammatory disease of medium and large size arteries characterized by the accumulation of cholesterol rich low-density lipoprotein (LDL) particles in the sub-endothelium layer of the vessel. Retention and modification of LDL triggers a systemic inflammatory response sustained by the humoral and cellular branches of the immune system. Early atherosclerosis initiation is often in the form of fatty streaks whilst necrotic core formation, inflammation, fibrosis and stenosis are characteristics of advanced atherosclerotic plaques. A protective humoral immune response is induced upon vaccination against oxidized LDL in experimental models of atherosclerosis, whilst studies on follicular B cells report an opposite pathogenic function of this subset. Furthermore, association studies on cardiovascular disease risk and antibody titers against oxidized LDL provide inconsistent results. Given these seemingly contradictory observations, the role of B cells and antibodies in atherosclerosis is still poorly understood. Atherosclerosis can develop as a silent disease over decades, and asymptomatic plaques usually have a robust fibrotic cap consisting of collagen and extracellular matrix deposited by smooth muscle cells. However, sudden clinical symptoms can occur in terms of myocardial infarction and stroke when the stability of the cap is impaired and the content of the plaque is released into the bloodstream. In this thesis we identify a potential mechanism involved in regulating the growth and the stability of atherosclerotic lesions. We first demonstrate that a germinal center response occurs promptly upon acute hypercholesterolemia, and is associated with an autoimmune-like deposition of immune complexes and systemic autoantibody production. Secondly, we characterize the effects of B cells in late stage atherosclerosis and we show that antibodies promote increased lesion size. Furthermore, we illustrate how these effects are depending on germinal center-derived antibodies. Thirdly, we observe that antibodies originating from the germinal center reaction induce a stable atherosclerotic plaque phenotype, in part through promoting smooth muscle cell proliferation. Finally, we report that antibodies regulate transcriptional pathways involved in maintaining the integrity, function and stability of the aorta. Collectively, the findings presented in this thesis identify germinal center B cells as an important factor affecting the composition, size and stability of the atherosclerotic plaque.