The Discovery of Cellular Immunity in the Atherosclerotic Plaque

Abstract

Abstract-It is now generally accepted that atherosclerosis is an inflammatory/immune disease triggered by LDL accumulation in the artery wall. When discovering T cells and the molecular components of a cellular immune response, we proposed that atherosclerosis is an inflammatory process with an autoimmune component. This notion was met with general skepticism but has gained support from experimental and clinical studies. Here we describe some of the early studies that helped developing this concept. Key Words: athersclerosis Ⅲ immunity Ⅲ inflammation Ⅲ cytokines Ⅲ T cells Ⅲ macrophages T hirty years ago the pathogenesis of atherosclerosis was still poorly understood. Although it was evident that hypercholesterolemia is a major risk factor and that cholesterol accumulates in atherosclerotic lesions, the cell biology of atherosclerosis remained a puzzle. It was speculated that the arterial lesions formed as a reaction to mechanical or chemical injury, developed from mural thrombi, or alternatively represented a hyperplastic or neoplastic process involving altered smooth muscle cells (SMCs). According to a prevailing theory, a proliferative expansion of SMCs from the media to the intima was driven by growth factors released from platelets. The subsequent deposition of both lipid and collagen would then result in the formation of local fibrous plaques.Lipid-laden foam cells were commonly detected in both experimental and human plaques. Some of these foam cells showed ultrastructural characteristics of SMCs, but in the early 1980s it became obvious that many of them shared histochemical and morphological features of macrophages suggesting a monocytic origin. Because monocyte-derived macrophages play major roles in the immune system, it would seem obvious that the presence of such cells would point to an immune component of atherosclerosis. The idea of an involvement of immune cells in the pathogenesis of atherosclerosis had in fact been raised already by Virchow in 1856. However, more than 125 years after his report, the presence of lymphocyte-like infiltrates were still reported only incidentally in the literature and until the late 1980s immunologic events in atherosclerosis were ignored by most investigators.A major reason for this ignorance was the difficulty to identify immunocompetent cells. Morphological changes that occur during differentiation or activation are not specific to any one of the major lymphocyte subsets, namely T cells, B cells, and natural killer cells. The contribution of blood-borne cells in atherosclerosis therefore remained unclear until the advent of the monoclonal antibody technology. The development of monoclonal antibodies against cell type-specific molecules on leukocytes, so-called cluster of differentiation (CD) antigens, thus opened up new and unique opportunities for identifying immune cells and determine their distribution in the atherosclerotic plaque.In the early 1980s, when we worked in the Departments of Histology and Clinical Chemistry at Goteborg University, we designed a ne...

Mechanisms of Plaque Formation and Rupture

“…[33][34][35][36] The adaptive immune system recognizes modified LDL and other autoantigens related to the atherosclerotic process, and immune cells participate in the development of lesions. 27 T helper 1 cells appear in the human intima coincident with foam cells and secrete proinflammatory cytokines (interferon-γ and tumor necrosis factor-α) that accentuate vascular inflammation in mouse models, 37 but other immune cell types, such as regulatory T cells and possibly B cells, ameliorate it. 38 Both macrophages and dendritic cells serve as deposits of lipids from the insudating lipoproteins and become foam cells by mechanisms that remain incompletely understood in vivo.…”

CD8 + T Cells Regulate Monopoiesis and Circulating Ly6C high Monocyte Levels in Atherosclerosis in Mice

“…1 However, it is now well recognized that also local and systemic adaptive immune responses play a critical role in atherogenesis. 2 Since the first description of a localization of CD4 + and CD8 + T cells in human atherosclerotic plaques, 3 pro-and antiatherogenic CD4 + T-helper cell subsets have been defined. 4 In particular, CD4 + T-helper cells 1 (Th1) and their major cytokine interferon (IFN)-γ promote atherosclerosis, whereas Foxp3 + CD25…”

Fecal transplant: A safe and sustainable clinical therapy for restoring intestinal microbial balance in human disease?

“…In line, atherosclerosis is nowadays regarded an autoimmune disease [57] and increased intestinal permeability in subjects with atherosclerosis was suggested in the Bruneck study showing that plasma endotoxin levels above the 90th percentile were associated with a threefold increase in cardiovascular event risk [58]. Also, intestinal bacterial DNA (eg Porphyromonas gingivalis) has been isolated from human carotid plaque material [59,60].…”