Correlation of CD19+CD24hiCD38hi B Cells in Coronary Artery Disease with Severity of Atherosclerosis
Atherosclerosis is a chronic inflammatory disease that involves multiple types of immune cells, including both innate and adaptive immune cells. The adaptive immune system, particularly T cells, has been extensively studied in the context of atherosclerosis. Regulatory T cells (Tregs) with anti-inflammatory properties have been identified in atherosclerotic plaques, where they suppress the activity of pro-inflammatory effector T cells, dendritic cells, and macrophages. However, the role of B cells in atherosclerosis has only recently begun to gain attention. Among the various subsets of B cells, a particular subset known as regulatory B cells (Bregs) has emerged as a critical player in immune regulation. These Bregs, characterized by the CD19+CD24hiCD38hi phenotype, have been shown to exert anti-inflammatory effects by producing cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). This study aims to investigate the correlation between CD19+CD24hiCD38hi B cells and the severity of atherosclerosis in patients with coronary artery disease (CAD).
The study enrolled 73 patients with CAD who required coronary artery bypass graft (CABG) surgery. A control group of 36 healthy blood donors was also included. The severity of coronary atherosclerosis in CAD patients was assessed using the modified Gensini stenosis scoring system, which quantifies the extent and severity of coronary artery lesions based on angiographic findings. Peripheral blood mononuclear cells (PBMCs) were isolated from both CAD patients and healthy controls within two hours of blood collection. The PBMCs were then stained with a panel of antibodies to identify CD19+CD24hiCD38hi B cells. The antibodies used included CD19-APC, CD19-APC-Cy7, CD20-PerCP-Cy7, CD24-PE-Cy7, CD27-V450, CD38-APC, and CD38-FITC. Intracellular cytokine production was analyzed by stimulating the PBMCs with phorbol myristate acetate, ionomycin, and Brefeldin A for five hours, followed by staining with IL-10-BV605 and TGF-β-BV421 antibodies.
The results revealed that CD19+CD24hiCD38hi B cells were present in both CAD patients and healthy controls, but the percentage of these cells was significantly lower in CAD patients compared to healthy individuals. Specifically, the percentage of CD19+CD24hiCD38hi B cells in CAD patients was 1.5% ± 0.6%, whereas in healthy controls, it was 2.3% ± 0.8% (P = 0.006). Furthermore, upon stimulation with cytosine-phosphate-guanine (CpG), all B cell subsets, including CD19+CD24hiCD38hi B cells, were capable of producing IL-10 and TGF-β. However, the levels of IL-10 and TGF-β produced by CD19+CD24hiCD38hi B cells were significantly lower in CAD patients compared to healthy controls. The mean IL-10 production in CAD patients was 15.2% ± 4.3%, compared to 22.7% ± 5.1% in healthy controls (P < 0.001). Similarly, the mean TGF-β production in CAD patients was 12.8% ± 3.7%, compared to 18.4% ± 4.6% in healthy controls (P = 0.001).
The severity of atherosclerosis in CAD patients was quantified using the Gensini score, which had an average value of 66 ± 28. A Spearman correlation analysis was performed to assess the relationship between the frequency of CD19+CD24hiCD38hi B cells and the Gensini score. The analysis revealed a significant moderate inverse correlation between the two variables, with a correlation coefficient of r = -0.283 (P = 0.015). This indicates that as the severity of atherosclerosis increases, the frequency of CD19+CD24hiCD38hi B cells decreases.
The findings of this study suggest that CD19+CD24hiCD38hi B cells are numerically and functionally deficient in CAD patients. The reduced frequency of these Bregs and their diminished production of anti-inflammatory cytokines such as IL-10 and TGF-β may contribute to the progression of atherosclerosis. IL-10 is known to have atheroprotective effects by inhibiting T-cell activation and reducing inflammation. In animal models, overexpression of IL-10 has been shown to inhibit atherosclerosis, whereas IL-10 deficiency exacerbates the disease. Similarly, TGF-β plays a crucial role in maintaining vascular homeostasis and preventing the development of unstable atherosclerotic lesions. Disruption of TGF-β signaling in animal models has been associated with the rapid progression of atherosclerosis.
The role of B cells in atherosclerosis has been a subject of increasing interest. Early studies suggested that B cells have atheroprotective effects, particularly B1 cells, which produce natural IgM antibodies that bind to oxidized low-density lipoprotein (oxLDL) and apoptotic cells, thereby preventing their uptake by macrophages and the formation of foam cells. However, the role of B2 cells, including Bregs, in atherosclerosis is less well understood. Bregs share functional and phenotypic similarities with B1a cells and are thought to exert their anti-inflammatory effects through the production of IL-10 and TGF-β. In this study, the observed numerical and functional deficit of CD19+CD24hiCD38hi B cells in CAD patients suggests that these cells may play a protective role in atherosclerosis. The inverse correlation between the frequency of Bregs and the severity of atherosclerosis further supports this hypothesis.
In conclusion, this study provides evidence that CD19+CD24hiCD38hi B cells are numerically and functionally deficient in CAD patients. The reduced frequency of these Bregs and their diminished production of anti-inflammatory cytokines such as IL-10 and TGF-β may contribute to the progression of atherosclerosis. These findings suggest that CD19+CD24hiCD38hi B cells could serve as a biomarker for the severity of atherosclerosis and may represent a potential therapeutic target for the treatment of CAD. Further research is needed to explore the mechanisms underlying the protective effects of Bregs in atherosclerosis and to investigate the potential of Breg-based therapies for the prevention and treatment of CAD.
doi.org/10.1097/CM9.0000000000000765
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