In this thesis, single-cell approaches were applied to characterize the impact of aging on the immunological B cell landscape in different models of atherosclerotic cardiovascular disease, with the goal to identify and study new B cell-associated biomarkers and therapeutic targets to halt atherosclerosis progression.
In chapter 2 we provide an overview of the aged B cell in health and disease. We describe how aging affects the proliferation and function of distinct B cell subsets, and their possible effect in atherosclerosis development. In chapter 3, we characterized the impact of aging on atherosclerosis progression in Ldlr-/- mice and illustrated that aging promotes more advanced atherosclerotic lesions, enriched in collagen, cholesterol crystals, and calcification. In addition, we identified age-associated immune cells, such as age-associated B cells (ABCs), and revealed increased immunosenescence in the aged...
Show moreIn this thesis, single-cell approaches were applied to characterize the impact of aging on the immunological B cell landscape in different models of atherosclerotic cardiovascular disease, with the goal to identify and study new B cell-associated biomarkers and therapeutic targets to halt atherosclerosis progression.
In chapter 2 we provide an overview of the aged B cell in health and disease. We describe how aging affects the proliferation and function of distinct B cell subsets, and their possible effect in atherosclerosis development. In chapter 3, we characterized the impact of aging on atherosclerosis progression in Ldlr-/- mice and illustrated that aging promotes more advanced atherosclerotic lesions, enriched in collagen, cholesterol crystals, and calcification. In addition, we identified age-associated immune cells, such as age-associated B cells (ABCs), and revealed increased immunosenescence in the aged atherosclerotic environment, using single-cell RNA sequencing and flow cytometry. We compared the morphology and immune landscape of atherosclerotic lesions between aged female and aged male aged Ldlr-/- mice in chapter 4, and show that age-associated B cells are more pronounced in females and that B cells exhibit a more activated phenotype. In chapter 5, we induced atherosclerosis in non-atherosclerotic aged C57Bl/6 mice, providing insight into how immunosenescence influences disease development. We demonstrate that the immune system of aged mice show immunosenescent features, including the emergence of ABCs and increased antibody production, which was accompanied with aggravated atherosclerosis development in aged mice compared to young mice. To investigate the role of age-associated B cells in atherosclerosis development, we further characterized these cells in chapter 6. We show that ABCs predict coronary events in humans and are clonally expanded in aged atherosclerotic mice. Upon adoptive transfer, we reveal that ABCs differentiate into plasma cells, thereby exacerbating lesion development. In chapter 7, we identified a new anti-atherosclerotic strategy with IFN-γ-stimulated B cells by significant upregulation of the inhibitory ligand PD-L1. We demonstrated that these cells inhibit follicular T helper cell responses and halt atherosclerosis progression. To further explore anti-atherogenic therapies in the aged CVD patient, we aimed to reduce advanced atherosclerosis with rapamycin treatment in chapter 8. We show that rapamycin was able to restrict inflammation in the aged atherosclerotic lesion and reduced the frequency of ABCs, which might stabilize the atherosclerotic lesion and reduce the risk for a cardiovascular event. Chapter 9 provides a summary and discussion of all the data presented in this thesis, along with concluding remarks and future perspectives.
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