Aim: T and B lymphocytes, the main cellular effectors of adaptive immunity, are deeply involved in the chronic inflammatory process that drives atherosclerosis. As the main source of antibodies, B cells were originally thought to be anti-atherogenic via production of neutralising antibodies against oxidised low density lipoprotein (LDL). Recent studies that depleted B lymphocytes in animal models of atherosclerosis have unravelled pro-atherogenic effects of conventional mature B2 B cells and protective roles for the innate B1a B-cell subset. Recently, B cells with regulatory function (Bregs) have also been identified in both animals and humans, but their role in atherosclerosis is currently unknown. Impairment of Bregs has been implicated in the pathogenesis of autoimmune disorders, but whether the same is true in atherosclerosis is yet to be determined. Our aim was to examine Bregs in patients with coronary atherosclerosis.
Methods: Bregs were defined as CD19+CD24hiCD38hi B cells. The percentage and absolute number of Bregs was quantified in the circulation of patients with myocardial infarction (MI, n=60) and stable angina (SA, n=40), as well as in healthy subjects (n=30) using flow cytometry. The production of interleukin-10 (IL-10) by mature, memory and Breg cells was quantified by intracellular staining and flow cytometry.
Results: We found a marked reduction in the percentage and absolute number of Bregs in patients with coronary atherosclerosis (MI and SA) compared to healthy subjects. No differences were noted in the percentage and absolute number of total B cells, mature and memory B cells in the study groups, suggesting a specific numerical deficit in Bregs in patients with coronary atherosclerosis. Furthermore, Bregs from patients with coronary atherosclerosis produced significantly less IL-10 in response to CpG and CD40L compared to Bregs from healthy subjects, while the production of IL-10 from mature and memory B cells was not impaired. We are now characterising the molecular mechanisms that underlie the defects in Bregs in patients with coronary atherosclerosis.
Conclusion: Our data show for the first time that patients with coronary atherosclerosis harbour marked numerical and functional deficits in Breg cells that may tip the balance in favour of pro-inflammatory B and T lymphocytes. A better understanding of these defects may reveal novel targets for future therapies to quench the inflammatory process that drives atherosclerosis.