CD40-CD40L interactions in atherosclerosis. Trends Cardiovasc Med

Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands.
Trends in Cardiovascular Medicine (Impact Factor: 2.07). 02/2002; 12(1):27-32. DOI: 10.1016/S1050-1738(01)00142-6
Source: PubMed

ABSTRACT 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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    • "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 · 3.00 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 · 7.03 Impact Factor
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    • "The other component of the dyad, CD40, is a phosphorylated membrane glycoprotein receptor of the TNF gene superfamily. The biological functions of CD40–CD154 interaction are diverse, with enhanced CD154 expression described on atheromaassociated cells including monocytes, macrophages, vascular endothelial cells (ECs) and vascular smooth muscles cells (SMCs), and also on circulating leukocytes and platelets [7] [10]. Ligation of EC, SMC, macrophage and Tlymphocyte CD40 by membrane CD154 upregulates adhesion molecule expression, interstitial collagenases (matrix metalloproteinases-1, -8, -13), pro-tissue factor expression and enhances the release of cytokines and chemokines in these key atheroma-associated cells [6] [11] [12]. "
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    ABSTRACT: The expression and potential role of platelet membrane CD154 and sCD154 in atherosclerosis was investigated in patients with peripheral arterial disease. This prospective observational study measured the expression of platelet-bound CD154 and soluble CD154 (sCD154) in 39 patients with critical limb ischaemia (CLI, n=15), stable intermittent claudication (SIC, n=12) and age-matched controls (AMC, n=12). Basal and agonist-stimulated CD154, P-selectin expression and fibrinogen binding was measured by whole blood flow cytometry, while sCD154 was measured in paired plasma samples by ELISA. Basal expression of CD154 on the platelet surface was enhanced in both groups of patients with peripheral arterial disease. However, the critical limb ischaemics showed the highest level of basal expression 0.7+/-0.3 [median+/-IQR] and was significantly increased compared to both stable intermittent claudicants and age-matched controls (P<0.001). On agonist stimulation with either ADP or thrombin critical limb ischaemics demonstrated greater platelet reactivity and propensity to express CD154 compared to age-matched controls (P<0.05). Confirmation of the cellular expression of CD154 results was obtained by measuring sCD154 concentrations in autologous plasma samples. Here plasma levels of sCD154 in critical limb ischaemics were significantly greater than both stable intermittent claudicants and age-matched controls (P<0.005). Enhanced basal platelet expression and increased propensity to express CD154 and sCD154 in critical limb ischaemics compared to both controls and patients with stable intermittent claudication support evidence for the role of CD154 in atherogenesis and suggest a novel function in progressive and acute peripheral arterial disease.
    Atherosclerosis 02/2007; 190(2):452-8. DOI:10.1016/j.atherosclerosis.2006.02.038 · 3.97 Impact Factor
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