Abstract
Cardiovascular disease (CVD), including atherosclerosis, is a leading global cause of death. Atherosclerosis, characterized by plaque accumulation in arteries, can lead to myocardial infarctions (MI) or strokes. Imaging techniques like computed tomography angiography (CTA) are crucial for diagnosing and assessing the disease. The coronary artery calcification (CAC) score calculated from CTA images is a prognostic tool for atherosclerosis, with high scores correlating with increased risks of major adverse cardiovascular events (MACE) and all-cause mortality. Despite the emerging efforts and existing therapies, the residual risk and the onset of coronary events remains high.
Immune cells, including T cells and B cells, play complex roles in atherosclerosis and their precise function is dependent on the cell subtype. T cells in plaques can promote or inhibit disease progression, while B cells produce antibodies affecting lipid uptake and foam cell formation. Loss of TET2 in immune cells is linked to higher risk of CVD and hematological malignancies.
Precision medicine sought to better stratify patients and identify biomarkers that can help design therapies suitable for patients’ individual profiles. Given the complex nature of the immune system and its role in the progression of atherosclerosis, the motivation for this work is to demonstrate how multi-omics can enhance our understanding of CVD and underlying genetic conditions, guiding the development of more precise and effective treatments
Here, I present a study, where we investigated TET2's role in regulating B1 cell numbers and functions. TET2 loss increased B cell subtypes in the peritoneal cavity, bone marrow, and spleen. B1a cells from TET2-KO mice showed fewer unique CDR3 sequences, indicating reduced antigen diversity. The TRUST4 algorithm enabled accurate detection of BCR and TCR repertoires from bulk RNASeq data, providing insights into immune cell receptor diversity.
In a pilot study, I analyzed phosphorylation states of effector molecules in IL-1β and IL-6 signaling pathways in patients with no CAC and high CAC. T cells were the primary immune cells activated by both cytokines. T regulatory cells showed lower phosphorylation of STAT5 in patients with high coronary calcification. Additionally, Subjects with high CAC showed a lower response to IL-1β and IL-6 stimulation, a phenomenon, to our knowledge, never reported before. The study provides interesting findings but is limited by sample size. Identifying specific T cell subpopulations responsive to IL-1β and IL-6 presents new research opportunities and potential therapeutic targets.
Understanding immune cell dynamics in atherosclerosis could improve disease prognosis and treatment response, aligning with precision medicine's goals. Further studies are needed to elucidate the biological significance of these findings and their clinical applications in managing cardiovascular disease.
