Role of the adaptive immune system in atherosclerosis

Abstract

Atherosclerosis, the pathology underlying heart attacks, strokes and peripheral artery disease, is a chronic inflammatory disease of the artery wall initiated by elevated low-density lipoprotein (LDL) cholesterol levels. LDL accumulates in the artery wall, where it can become oxidized to oxLDL. T cell responses to ApoB, a core protein found in LDL and other lipoproteins, are detectable in healthy mice and people. Most of the ApoB-specific CD4T cells are FoxP3+ regulatory T cells (Treg). In the course of atherosclerosis development, the number of ApoB-reactive T cells expands. At the same time, their phenotype changes, showing cell surface markers, transcription factors and transcriptomes resembling other T-helper lineages like Th17, Th1 and follicular helper (TFH) cells. TFH cells enter germinal centers and provide T cell help to B cells, enabling antibody isotype switch from IgM to IgG and supporting affinity maturation. In people and mice with atherosclerosis, IgG and IgM antibodies to oxLDL are detectable. Higher IgM antibody titers to oxLDL are associated with less, IgG antibodies with more atherosclerosis. Thus, both T and B cells play critical roles in atherosclerosis. Modifying the adaptive immune response to ApoB holds promise for preventing atherosclerosis and reducing disease burden.

Keywords: atherosclerosis; autoimmunity; immunology.

Figure. Adaptive Immunity in Atherosclerosis.

Mature T cells (naive CD4: light blue, CD8: dark blue, Tregs: green) leave the thymus and migrate to lymph nodes, spleen and the artery wall (blue arrows). B cell precursors leave the bone marrow and seed lymph nodes, spleen and the artery wall (thin red arrows) with B cells (red). Naive T and B cells are mostly in the adventitia of the artery. In the plaque, T cells interact with macrophages (blue and brown to indicate subsets) and dendritic cells (DCs, peach) in a recall response. They differentiate to Th1 and Th17 (pink). T cells from the artery wall leave and home to lymph nodes (orange arrow). There, naive T cells differentiate into Th1, Th17, Treg and TFH (purple). In germinal centers of the spleen and lymph nodes, TFH provide critical help to B cells (red), allowing them to isotype switch and home to the bone marrow (green arrows). In the bone marrow, they differentiate to plasma cells (large red cells) and secrete IgG and IgM specific for atherosclerosis antigens. The small dark red arrow in the capsule of the lymph node indicates where soluble antigens and antigen-loaded dendritic cells from tissue enter. I wish to acknowledge Andreas Schober, LMU Munich, Germany for the histological image of a human carotid artery with severe atherosclerosis and Servier http://smart.servier.com/ for digital artwork I used for the immune cells.