Immunomodulatory roles of the HLA family and B2M in atherosclerosis

Atherosclerosis (AS), a chronic inflammatory disease driven by lipid accumulation and immune dysregulation, predisposes to acute cardiovascular events via plaque rupture and thrombosis. The molecular mechanisms linking immune microenvironment imbalance to plaque instability remain incompletely defined. Utilizing the GSE100927 dataset (69 AS patients vs 35 controls), we identified differentially expressed genes (DEGs) and constructed co-expression networks via weighted gene co-expression network analysis. Hub genes were intersected with DEGs to determine core genes. Immune cell infiltration was quantified using Cell-type Identification By Estimating Relative Subsets Of RNA Transcripts, and correlations between core genes and immune subsets were assessed. Diagnostic potential was evaluated by receiver operating characteristic (ROC) analysis. We identified 2596 DEGs (1575 up-/1021 downregulated) in AS tissues. Weighted gene co-expression network analysis revealed 3 disease-associated modules, yielding 54 hub genes. Intersection with DEGs identified 12 core genes, including HLA-G, HLA-A, HLA-C, and beta-2-microglobulin (B2M). These genes were enriched in “major histocompatibility complex class Ib-mediated antigen presentation” and significantly upregulated in AS ( P < .001). Immune profiling showed elevated M0 macrophages and reduced resting CD4 + memory T cells in AS ( P < .0001). Expression of HLA-G, HLA-A, HLA-C, and B2M positively correlated with M0 macrophages and negatively with CD4 + T cells ( P < .001). ROC analysis within the GSE100927 dataset demonstrated high diagnostic accuracy for distinguishing AS samples from controls (HLA-G/A/C area under the ROC curve = 0.94; B2M area under the ROC curve = 0.87). HLA-G, HLA-A, HLA-C, and B2M modulate macrophage and T cell functions, driving immune dysregulation in AS. This immune imbalance is associated with plaque instability and may contribute to thrombosis risk, highlighting the potential of these molecules as diagnostic biomarkers and therapeutic targets.