- Author
-
L.A. Bosmans
- Title
- Immune checkpoints in atherosclerosis
- Subtitle
- The atlas is in the palm of your hand
- Supervisors
-
E. Lutgens
M.P.J. de Winther - Co-supervisors
-
A. Shami
- Award date
- 25 February 2022
- Number of pages
- 245
- ISBN
- 9789464169805
- Document type
- PhD thesis
- Faculty
- Faculty of Medicine (AMC-UvA)
- Abstract
-
Atherosclerosis, the underlying cause for most cardiovascular diseases (CVD), is a multifactorial, immunoinflammatory disease of medium sized and larger arteries driven by lipids. Although lipid lowering strategies reduced the incidence of atherosclerotic cardiovascular events, a residual inflammatory risk remains. Immune checkpoint proteins (ICP), regulators of the continuous immune response propelling atherosclerosis, are promising targets to combat CVD. Here, we determine the expression of ICP in various stages of atherosclerosis and evaluate the effect of ICP deficiency on the development of atherosclerosis.
We identified, using mass cytometry by time of flight, the expression of ICP on various immune cell populations in the atherosclerotic aorta, blood leukocytes, lymph nodes and spleen. Overall, the expression of ICP are upregulated specifically during initial and advanced plaque development.
Next, we investigate the role of glucocorticoid induced TNF receptor related protein (GITR) in human and murine atherosclerosis. CVD patients revealed a higher concentration of soluble GITR in plasma samples compared to healthy controls. Furthermore, plaques of stroke or TIA patients showed an increased immunoreactivity of GITR, which correlated with markers of plaque vulnerability. GITR deficient Apolipoprotein E knock out mice (Gitr-/- ApoE-/-) exhibited reduced atherosclerosis, due to decreased myeloid recruitment and activation.
Lastly, we examined CD40, a known potent ICP in atherogenesis, which is expressed on various immune and non immune cells. Myeloid-CD40 deficient ApoE-/- mice exhibited reduced atherosclerosis, as sequencing data of myeloid CD40 deficient aortae revealed reduced inflammation and a shift towards alternatively activated macrophages. Interestingly, T cell CD40 deficiency did not alter plaque size, however plaque progression is decreased. - Persistent Identifier
- https://hdl.handle.net/11245.1/cc5a3123-4301-4db0-8372-ec8f96ee42ab
- Downloads
-
Thesis (complete)
Front matter
Chapter 1: General introduction
Chapter 2: The landscape of co-stimulatory and co-inhibitory immune checkpoint proteins in atherosclerosis
Chapter 3: Glucocorticoid induced TNR receptor family-related protein (GITR): A novel driver of atherosclerosis
Chapter 4: Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans
Chapter 5: The CD40-CD40L dyad as immunotherapeutic target in cardiovascular disease
Chapter 6: CD40 in atherosclerosis: The macrophage side of the story
Chapter 7: CD40 deficiency on T cells in atherosclerosis: An exploratory study
Chapter 8: General discussion
Summary; Nederlandse samenvatting; Author contributions; Portfolio; Publications; Curriculum vitae; Dankwoord
- Supplementary materials
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