Artery Tertiary Lymphoid Organs: Powerhouses of Atherosclerosis Immunity

Abstract

Artery tertiary lymphoid organs (ATLOs) are atherosclerosis-associated lymphoid aggregates with varying degrees of complexity ranging from small T/B-cell clusters to well-structured lymph node-like though unencapsulated lymphoid tissues. ATLOs arise in the connective tissue that surrounds diseased arteries, i.e., the adventitia. ATLOs have been identified in aged atherosclerosis-prone hyperlipidemic apolipoprotein E-deficient (ApoE−/−) mice: they are organized into distinct immune cell compartments, including separate T-cell areas, activated B-cell follicles, and plasma cell niches. Analyses of ATLO immune cell subsets indicate antigen-specific T- and B-cell immune reactions within the atherosclerotic arterial wall adventitia. Moreover, ATLOs harbor innate immune cells, including a large component of inflammatory macrophages, B-1 cells, and an aberrant set of antigen-presenting cells. There is marked neoangiogenesis, irregular lymphangiogenesis, neoformation of high endothelial venules, and de novo synthesis of lymph node-like conduits. Molecular mechanisms of ATLO formation remain to be identified though media vascular smooth muscle cells may adopt features of lymphoid tissue organizer-like cells by expressing lymphorganogenic chemokines, i.e., CXCL13 and CCL21. Although these data are consistent with the view that ATLOs participate in primary T- and B-cell responses against elusive atherosclerosis-specific autoantigens, their specific protective or disease-promoting roles remain to be identified. In this review, we discuss what is currently known about ATLOs and their potential impact on atherosclerosis and make attempts to define challenges ahead.

Recent Developments in Vascular Adventitial Pathobiology

“…93 ATLOs contain large numbers of T-regulatory cells, including naïve T cells that are recruited to ATLOs, where they are converted to T-regulatory cells. 94 Moreover, genes involved in somatic hypermutation of the B-cell receptor and B-cell memory generation have been discovered to be expressed at significant levels in ATLOs. 94 This suggests that ATLOs are involved in both the innate and adaptive immune responses observed in atherosclerosis.…”

“…94 Moreover, genes involved in somatic hypermutation of the B-cell receptor and B-cell memory generation have been discovered to be expressed at significant levels in ATLOs. 94 This suggests that ATLOs are involved in both the innate and adaptive immune responses observed in atherosclerosis. 95 However, the cause and effect mechanisms are not currently understood.…”

Chronic Inflammation: A Common Promoter in Tertiary Lymphoid Organ Neogenesis

“…Under chronic inflammatory conditions, resident stromal mesenchymal cells (62), such as fibroblasts, endothelial cells, VSMCs, and pericytes, are activated by proinflammatory molecules, including TNFα, LTα 1 β 2 , IL-17, IL-23, and chemokines, including CCL2, CCL3, CXCL9, CXCL10, and CXCL11 (1,6,63,64). After activation, these cells are transformed into lymphoid tissue organizer (TLo)-like cells to release lymphorganogenic chemokines, such as CXCL13 and CCL21, to initiate the formation of TLOs (43, 62).…”

Antigen-Presenting Cells and Antigen Presentation in Tertiary Lymphoid Organs

“…These so-called tertiary lymphoid organs (TLOs) are thought to function as a local site for perpetuation of adaptive immune responses providing a local source of antibody, generated as the result of local antigen presentation, and lymphocyte activation and maturation in the newly formed structure. In some settings, development of these lymphoid structures may be advantageous, as in bacterial and viral infections (2–4), atherosclerosis (5, 6), and cancer (7, 8), while in a number of diseases, particularly autoimmune disorders, the development of TLOs may be associated with non-resolving inflammation, with a vigorous and sustained response to self-antigen amplifying severe and chronic pathology [reviewed in Ref. (9); see also Ref.…”