**Preface to "Current Challenges and Advances in Atherosclerosis"**

Atherosclerosis is a systemic disorder which is of major interest in both basic science and clinical medicine in order to achieve healthy longevity worldwide. Atherosclerosis generally develops without any signs and symptoms, eventually resulting in various kinds of catastrophic cardiovascular events, such as ischemic heart disease, ischemic stroke, and rupture of major vessel aneurysms. Scientists working on the biological facets of atherosclerosis have recently focused on the persistent inflammation in vessel walls from intimal to adventitial tissues. Although inflammation is indeed a dominant pathological phenomenon in atherosclerosis, it has been recognized that there is no simple answer to the question of whether inflammation promotes or delays atherosclerosis. Atherosclerosis is a complex disease that involves several different cell types, such as lymphocytes, macrophages, monocytes, dendric cells, and their molecular products. Chronic inflammation in atherosclerosis can be accompanied by immunological changes, including auto-immune disorders. For example, our recent studies have shown that multiple auto-antibodies are found in the sera of subjects with atherosclerosis via inventory high-throughput auto-antibody screening techniques using cell-free technologies. Nevertheless, the immune system is even more complicated, with many cell types, hundreds of cytokines, and literally millions of different antigens, making research into atherosclerosis more complicated. Macrophages, which are differentiated from monocytes, one of the components of blood cells, phagocytize denatured LDL cholesterol on the vascular wall, become foamy cells, accumulate under the vascular endothelium, and cause atherosclerotic plaque formation. This forms the primary lesion, the fatty streak. Some of the aggregated foam cells undergo cell death over time, release denatured lipids in the cytoplasm, and increase in volume while forming a lipid core (necrotic core). The lipid core is surrounded by immune response cells, such as T cells, monocytes, macrophages, dendritic cells, and fibroblasts, to form atherosclerotic plaques. Enlarged lipid cores are at risk of rupture due to stresses on the vascular endothelium, such as blood pressure and shear stress from blood flow. The vulnerability of atherosclerotic plaques is thought to be determined by the formation of a fibrous cap around the plaque and the antagonism of degradation of fibrous components by protease, peptidase, etc., secreted by cells.

Fatal and non-fatal myocardial infarctions and cerebral infarctions, collectively referred to as cardiovascular events, result from accidental plaque rupture. As a result of plaque rupture, plaque components leak into the vascular lumen, causing local thrombus formation and subsequent activation of the fibrinolytic system. When the force of thrombus formation brought about by the qualitative and quantitative abnormalities of denatured lipids leaking from the lipid core exceeds the force of the endogenous fibrinolytic system, the thrombus occupies the finite space of the vascular lumen. As a result, blood flow with the thrombus is interrupted, and infarction of important organs occurs. Plaque rupture is accidental and unpredictable, and medical treatment starting from plaque rupture is a post-event response. Regarding the occurrence of cardiovascular events, there is only a therapeutic strategy that controls the risk and lowers the probability of atherosclerotic accidents, and a fundamental, radical therapeutic approach is required.

Among the immune cells and inflammatory cells involved in atherosclerosis, B cells have not necessarily been recognized to play a central role so far. Looking back at the history of atherosclerosis research, we can see that research on B cells is progressing. Arteries have a three-layered structure consisting of the intima, media, and adventitia. In 1915, at the very early stage of atherosclerosis research, Sir Clifford Allbutt investigated the relationship between atherosclerosis and B cells infiltrating the tunica adventitia, which can be traced back to the description of "round cell growth in the adventitia in atherosclerosis is correlated with absorption of depraved matter from the diseased intima." ([Diseases of the Artery]). The "round cells" infiltrating the adventitia described in this article were also reported in 1956 and 1962, and were found to be mainly B cells. Recent studies have shown that the activation of B cells in the adventitia is important in controlling atherosclerosis. Hamze et al. used microdissection techniques to analyze individual lymphocytes in coronary arteries. (J Immunol. 2013;191:3006-16.) They found that the majority of B cells reside in the adventitia of coronary arteries. In human and rodent models of atherosclerosis, B cells are present in the adventitia and form the tertiary lymph node tissue (ATLO, Artery Tertiary Lymphoid Organ). PVAT (perivascular adipose tissue), which is adjacent to the adventitia of arteries, contains complex and diverse cellular components, such as macrophages, T cells, and B cells, named FALCs (Fat-Associated Lymphoid Clusters). FALCs are in close proximity to the adventitial ATLO and may play a role in the establishment of atherosclerosis. Inflammation in atherosclerosis is not a transient inflammation. We reported that as a result of the activation and conditioning of B2 cells in the spleen, they infiltrate PVAT, and become the starting point of the pathology related to the onset of atherosclerosis. (Chen L, Ishigami T, et al. eBioMedicine, 2016) A high-fat, high-calorie diet causes changes in intestinal bacteria, dysbiosis, a decrease in intestinal barrier function, and activation of splenic B2 cells. Activated B2 cells can serve as a hypothetical biological model of atherosclerosis, in which they infiltrate the aortic adipose tissue and secrete IgG/IgG3 antibodies to promote atherosclerosis.

B cells infiltrate the PVAT from the very early stage of atherosclerosis, form FALCs, and form ATLO, a tertiary lymphoid tissue, in the adventitia. This may be the origin of immune response in atherosclerotic plaques in the endothelium/intima. The humoral immune response mediated by atherosclerotic B cells derives from antibody production and specific activation of B cell subtypes in the spleen. If this reaction, which can be said to be the biological starting point of atherosclerosis, can be controlled, it may become an option for the treatment of atherosclerosis.

This Special Issue, entitled "Current Challenges and Advances in Atherosclerosis", will focus on recent challenges and advances in the field of atherosclerosis by global expert scientists and clinicians to elucidate the complicated features of atherosclerosis and translational attempts for both medical and scientifical frontiers.

> **Tomoaki Ishigami** *Editor*
