Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice

Abstract

Atherosclerosis is characterized by vascular inflammation and associated with systemic and local immune responses to oxidized LDL (oxLDL) and other antigens. Since immunization with oxLDL reduces atherosclerosis, we hypothesized that the disease might be associated with development of protective immunity. Here we show that spleen-associated immune activity protects against atherosclerosis. Splenectomy dramatically aggravated atherosclerosis in hypercholesterolemic apoE knockout (apoE°) mice. Transfer of spleen cells from atherosclerotic apoE°mice significantly reduced disease development in young apoE°mice. To identify the protective subset, donor spleen cells were divided into B and T cells by immunomagnetic separation before transfer. Protection was conferred by B cells, which reduced disease in splenectomized apoE°mice to one-fourth of that in splenectomized apoE°controls. Protection could also be demonstrated in intact, nonsplenectomized mice and was associated with an increase in antibody titers to oxLDL. Fewer CD4 + T cells were found in lesions of protected mice, suggesting a role for T-B cell cooperation. These results demonstrate that B cell-associated protective immunity develops during atherosclerosis and reduces disease progression.

Adaptive Response of T and B Cells in Atherosclerosis

“…76 In line with these data, reconstitution of irradiated Ldlr −/− with B cell-deficient bone marrow has been shown to worsen atherosclerosis. 77 Another study suggested that the lack of B1a cells and the consequent lowering of IgM was responsible for the deleterious effects of B-cell deficiency.…”

Control of the T Follicular Helper–Germinal Center B-Cell Axis by CD8 + Regulatory T Cells Limits Atherosclerosis and Tertiary Lymphoid Organ Development

“…[25][26][27][28] Initial studies 1,29,30 indicated the atheroprotective potential of the B-cell compartment that relies on B1a cells and germ-line-encoded immunoglobulins. In contrast, recent studies have identified T-dependent B cells (B2 cells) as potent proatherogenic mediators in the ApoE° and low-density lipoprotein receptor-knockout mouse models.…”

High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

“…In addition, hypertensive patients with high percentages of CD40 + B cells were at lower risk for stroke,22 whereas high numbers of CD86 + B cells showed higher risk for stroke 22. A larger body of evidence is derived from elaborate mouse studies, which identified a subset‐specific role for B lymphocytes in atherosclerosis 23, 24, 25. To date, it is generally accepted that (auto)antibody‐producing B1 B cells are atheroprotective26, 27 and this protective effect depends on IgM secretion,28 whereas conventional B2 B cells are generally considered proatherogenic 29.…”