The Immunological Biography of the Carotid Plaque: From Trained Immunity and Clonal Lymphocytes to Spatial Immune Niches and Plaque Vulnerability

Atherosclerotic carotid plaques are shaped by years of interaction between systemic risk factors, hematopoietic conditioning, vascular injury, and local immune responses, yet conventional assessment captures only a limited snapshot of this biological history. This review introduces the concept of the “immunological biography” of the carotid plaque and examines how trained innate immunity, macrophage state and defective resolution, adaptive immune memory, T- and B-cell clonal selection, and spatially organized immune niches contribute to plaque heterogeneity and vulnerability. The literature was identified through a structured PubMed search complemented by reference screening, with emphasis on human carotid tissue, paired blood–plaque studies, immune-repertoire analyses, and single-cell and spatial technologies. Current evidence indicates that immune-cell abundance alone incompletely characterizes plaque biology: functional state, antigen experience, clonality, tissue localization, and interactions with vascular and stromal cells provide additional levels of biological information. We propose the Carotid Plaque Immune Phenotype (CPIP) as an integrative framework linking systemic immune history with cellular state, clonal architecture, spatial organization, and clinically relevant plaque features. Combining circulating biomarkers with tissue-resolved immune profiling may ultimately improve biological phenotyping of carotid atherosclerosis and provide a framework for prospective studies linking plaque immune architecture with cerebrovascular events.