CD40-CD40L Interactions in Atherosclerosis

Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.
Trends in Cardiovascular Medicine (Impact Factor: 2.91). 02/2002; 12(1):27-32. DOI: 10.1016/S1050-1738(01)00142-6
Source: PubMed


Increasing evidence supports a central role for CD40-CD40L interactions in the pathogenesis of atherosclerosis. Recently, we have shown that CD40L deficiency as well as pharmacological inhibition of CD40L in ApoE(-/-) mice results in the development of a stable atherosclerotic plaque phenotype. This phenotype is rich in smooth muscle cells and collagen, and contains only a small amount of macrophages and T-lymphocytes. CD40 and CD40L protein are present in almost all cell types in human atherosclerotic lesions. Expression was observed in early plaques, but was more predominant in advanced, rupture-prone, and ruptured plaques. Because most of the acute complications of atherosclerosis are the result of plaque rupture, CD40L inhibition might be a novel therapeutic approach to prevent atherosclerotic plaque destabilization and plaque rupture.

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    • "Since CD40 and CD40L have been detected in atheromatous plaques,78 it is conceivable that, in addition to plaque smooth muscle cells, activated CD40L-expressing platelets recruited at the site of endothelial damage, would tether monocytes and induce TF synthesis, thus increasing the thrombogenicity of the plaque during the inflammatory responses of atherogenesis and arterial injury. "
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    ABSTRACT: The aim of this review is to summarize the contribution of platelets and leukocytes and their interactions in inflammation and blood coagulation and its possible relevance in the pathogenesis of thrombosis. There is some evidence of an association between infection/inflammation and thrombosis. This is likely a bidirectional relationship. The presence of a thrombus may serve as a nidus of infection. Vascular injury indeed promotes platelet and leukocyte activation and thrombus formation and the thrombus and its components facilitate adherence of bacteria to the vessel wall. Alternatively, an infection and the associated inflammation can trigger platelet and leukocyte activation and thrombus formation. In either case platelets and leukocytes co-localize and interact in the area of vascular injury, at sites of inflammation and/or at sites of thrombosis. Following vascular injury, the subendothelial tissue, a thrombogenic surface, becomes available for interaction with these blood cells. Tissue factor, found not only in media and adventitia of the vascular wall, but also on activated platelets and leukocytes, triggers blood coagulation. Vascular-blood cell interactions, mediated by the release of preformed components of the endothelium, is modulated by both cell adhesion and production of soluble stimulatory or inhibitory molecules that alter cell function: adhesion molecules regulate cell-cell contact and facilitate the modulation of biochemical pathways relevant to inflammatory and/or thrombotic processes.
    Mediterranean Journal of Hematology and Infectious Diseases 08/2010; 2(3):e2010023. DOI:10.4084/MJHID.2010.023
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    • "This suggests that CD154 may have cytokine functions. Expression of CD154 occurs on activated T cells but has been demonstrated on platelets and macrophages as well as other cell types (Lutgens and Daemen, 2002; Sprague et al., 2007; Toubi and Shoenfeld, 2004). Over-expression of CD154 is associated with many autoimmune conditions (Datta, 1998; Jinchuan et al., 2004; Toubi and Shoenfeld, 2004) and this can lead to persistent CD40-stimulation with expansion of effector T cells thus establishing and perpetuating the disease state (Vaitaitis and Wagner, 2008; Vaitaitis et al., 2010; Wagner, 2009). "
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    ABSTRACT: The CD40-CD154 dyad is an intensely studied field as is glycosylation status and both impact immunological functions and autoimmune conditions. CD40 has several isoforms, is modified by glycosylation, and trimerizes to form the functional receptor. We described a CD4(+)CD40(+) T cell (Th40) subset which is expanded in autoimmunity and is necessary and sufficient in transferring type 1 diabetes. Glycosylation impacts immunological events and T cells from autoimmune mouse strains express 30-40% less GlcNAc-branched N-glycans than T cells from non-autoimmune strains, a decrease known to activate T cells. Here we demonstrate that several CD40 receptor constellations exist on CD4 T cells. However, rather than containing different isoforms of CD40 they contain different glycoforms of isoform I. The glycoform profile is dependent on availability of CD154 and autoimmune NOD mice express a high level of a less glycosylated form. Interestingly, CD40 stimulation induces some CD40 receptor constellations that contain TNF-receptors 1 and 2 and targeting of those alters CD40 signaling outcomes in NOD Th40 cells. CD40-stimulation in vivo of non-autoimmune BALB/c mice expands the Th40 population and alters the CD40 glycoform profile of those cells to appear more like that of autoimmune prone NOD mice. Further understanding the dynamics and composition of the different CD40 receptor constellations will provide important insights into treatment options in autoimmunity.
    Molecular Immunology 08/2010; 47(14):2303-13. DOI:10.1016/j.molimm.2010.05.288 · 2.97 Impact Factor
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    • "For example, in one study using athero sclerosis-prone apolipoprotein E–null (ApoE –/– ) mice, chronic oral exposure to BaP enhanced athero genesis, producing larger lipid core plaques with higher levels of T lymphocytes than plaques formed in control animals without BaP exposure (Curfs et al. 2004). Because studies have shown that CD40 (a receptor present on macrophage and antigen-presenting cells) and its ligand CD40L (found on T lymphocytes) are associated with rupture-prone athero sclerotic plaques, an increase in lymphocyte numbers is of particular significance (Lutgens and Daemen 2002). CS contains numerous chemical oxidants that contribute to inflammation and atheroclerotic plaque initiation and progression in exposed individuals (Link et al. 2007). "
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    ABSTRACT: Cardiovascular disease (CVD) affects 71 million American adults and remains the leading cause of death in the United States and Europe. Despite studies that suggest that the development of CVD may be linked to intrauterine growth or early events in childhood, little direct experimental evidence supports the notion. We investigated whether exposure to cigarette smoke in utero alters the risk of developing CVD later in life. We exposed B(6)C(3)F(1) mice (via whole-body inhalation) to either filtered air or mainstream cigarette smoke (MCS, at a particle concentration of 15 mg/m(3)) from gestational day 4 to parturition. Adult offspring were fed a normal chow diet or switched to a high-fat diet 2 weeks before sacrifice. We measured dam and offspring body weight, plasma lipid parameters, lipoprotein subclass particle numbers and sizes, and total antioxidant capacities. Adult female mice prenatally exposed to MCS demonstrated significantly higher body weight and levels of plasma high-density lipoprotein (HDL) and low-density lipoprotein than did their air-exposed counterparts. When fed a high-fat diet for 2 weeks, males, but not females, exposed prenatally to MCS gained substantially more weight and exhibited dramatic alterations in total cholesterol and HDL levels compared with their air-exposed counterparts. These data provide, for the first time, direct experimental evidence supporting the notion that prenatal exposure to cigarette smoke affects offspring weight gain and induces a lipid profile that could alter the offspring's risk of developing CVD later in life.
    Environmental Health Perspectives 08/2009; 117(7):1042-8. DOI:10.1289/ehp.0800193 · 7.98 Impact Factor
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