Atherosclerosis, autoimmunity, and vascular‐associated lymphoid tissue

Wick, Georg; Romen, Maria; Amberger, Albert; Metzler, Bernhard; Mayr, Manuel; Falkensammer, Gerda; Xu, Qingbo

doi:10.1096/fasebj.11.13.9367355

Cited by 183 publications

(159 citation statements)

References 46 publications

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“…12 Thus, hsps expressed in the vessel wall may serve as (auto)antigens, resulting in immune reactions. 5 Our previous study 13 demonstrated that serum antibodies to mycobacterial hsp65 were significantly increased in subjects with carotid atherosclerosis, which has subsequently been confirmed by several laboratories. 14 -17 This increased antibody level was independent of other established risk factors, such as hyperlipidemia, smoking, hypertension, diabetes mellitus, and obesity.…”

Section: See P 1148mentioning

confidence: 65%

“…26a,35 Preexisting antibodies could react with these surfaceexposed or released hsp60 components, causing further endothelial and macrophage injury and perpetuating the progress of atherosclerotic lesions. 5 Thus, immune reactions mediated by anti-hsp antibodies could play an important role in the pathogenesis of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

“…5,7 The discovery of activated T lymphocytes, dendritic cells, mast cells, and macrophages in atherosclerotic lesions, the detection of HLA class II antigen expression, and the finding of lytic complement complexes support the concept that immune and inflammatory responses play an important role in the pathogenesis of atherosclerosis. [5][6][7] What are the pathogens or (auto)antigens that evoke such responses? A large number of studies have reported on the association of atherosclerosis and certain persistent bacterial and viral infections, including Chlamydia pneumoniae and herpesviruses.…”

Section: See P 1148mentioning

confidence: 99%

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Association of Serum Antibodies to Heat-Shock Protein 65 With Carotid Atherosclerosis

et al. 1999

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Background-Previous work has proved that increased titers of antibodies against heat-shock protein (hsp) 65 are associated with atherosclerotic lesions independently of other established risk factors. The present follow-up study was designed to further scrutinize the association of hsp antibodies and atherosclerosis and evaluate the possible predictive value of these antibodies for the development and/or progression of lesions in the same population. Methods and Results-A total of 750 subjects 45 to 74 years old were recruited, and the rate of participation was 93.6%; 58 subjects died between 1990 and 1995. All participants were subjected to determination of serum antibodies against hsp65 and sonography to assess carotid atherosclerotic lesions and evaluate other risk factors, ie, age, sex, body mass index, blood cholesterol, apolipoprotein B, apolipoprotein A, triglycerides, lipoprotein(a), fibrinogen, leukocyte number, antithrombin III, ESR, ferritin, hypertension, smoking, and diabetes mellitus. Our data show that hsp65 antibody titers in the population emerged as highly consistent over a 5-year observation period (rϭ0.78, PϽ0.0001). Titers were significantly elevated in subjects with progressive carotid atherosclerosis and correlated with intima/media thickness. Multiple linear regression analysis documented these associations to be independent of age, sex, and other risk factors. Subanalyses revealed a preferential association of hsp65 antibody titers with advanced lesions (odds ratio, 1.42; 95% CI, 1.02 to 1.98; Pϭ0.039). Other risk factors neither confounded nor modified this association. Finally, hsp65 antibody titers significantly predicted the 5-year mortality (hazard ratio, 1.52; 95% CI, 1.14 to 2.03; PϽ0.001). Conclusions-These findings indicate a sustained existence of anti-hsp65 antibodies in subjects with severe atherosclerosis, which is predictive for mortality. (Circulation. 1999;100:1169-1174.)

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Section: See P 1148mentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: See P 1148mentioning

confidence: 99%

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Association of Serum Antibodies to Heat-Shock Protein 65 With Carotid Atherosclerosis

et al. 1999

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“…Moreover, macrophages in atherosclerotic lesions constitutively express tissue factor leading to local generation of thrombin (1,4). Therefore, thrombin could recruit DC to the vascular-associated lymphoid tissue (11,43) in atherosclerotic lesions. Indeed, stimulation of the matured DC either with thrombin, PAR1-AP, or PAR3-AP elicited a concentration-dependent chemotaxis.…”

Section: Discussionmentioning

confidence: 99%

Mature Dendritic Cells Express Functional Thrombin Receptors Triggering Chemotaxis and CCL18/Pulmonary and Activation-Regulated Chemokine Induction

Syrovets

Paskaš

et al. 2008

The Journal of Immunology

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Protease-activated receptors (PARs) are a family of G protein-coupled receptors that are activated by serine protease-mediated proteolytic cleavage of their extracellular domain. We have previously characterized the expression and function of PARs in human monocytes and macrophages, yet information about PARs in dendritic cells (DC) is scarce. Monocyte-derived immature DC do not express PARs. Upon maturation with LPS, but not with TNF-α or CD40 ligand, DC express PAR1 and PAR3, but not PAR2 or PAR4. Stimulation of DC with the serine protease thrombin or PAR1-activating peptide elicits actin polymerization and concentration-dependent chemotactic responses in LPS-, but not in TNF-α-matured DC. The thrombin-induced migration is a true chemotaxis with only negligible chemokinesis. Stimulation of PARs with thrombin or the respective receptor-activating peptides activates ERK1/2 and Rho kinase as well as subsequent phosphorylation of the regulatory myosin L chain 2. The ERK1/2- and Rho kinase 1-mediated phosphorylation of myosin L chain 2 was indispensable for the PAR-mediated chemotaxis as shown by pharmacological inhibitors. Additionally, thrombin stimulated the Rho-dependent release of the CC chemokine CCL18/pulmonary and activation-regulated chemokine, which induces chemotaxis of lymphocytes and immature DC as well as fibroblast proliferation. The colocalization of CD83+ DC with CCL18 in human atherosclerotic plaques revealed by immunofluorescence microscopy combined with the presence of functionally active thrombin receptors on mature DC point to a previously unrecognized functional role of thrombin in DC biology. The thrombin-induced stimulation of mature DC may be of particular relevance in atherosclerotic lesions, which harbor all components of this novel mechanism.

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“…Recently, substantial evidence has accumulated indicating that proinflammatory and immunologic factors play an important role in atherogenesis (Hajjar and Pomerantz 1992;Hansson et al, 1989;Nilsson, 1993;Wick et al, 1995Wick et al, , 1997. It was found that acute phase markedly influences the structure of lipoproteins (Malle et al, 1993;Pruzanski et al, 1998Pruzanski et al, , 2000 and their functions (Kisilevsky and Subrahmanyan, 1992;Shephard et al, 1987;Van Lenten et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Mitogenic Effect of Lipoproteins on Human Vascular Smooth Muscle Cells: The Impact of Hydrolysis by gr II A Phospholipase A2

Pruzanski

Stefanski

Kopilov

et al. 2001

Laboratory Investigation

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SUMMARY:Multifactorial interaction among lipoproteins, vascular wall cells, and inflammatory mediators has been recognized as the basis of atherogenesis. In the arterial wall high-density lipoprotein (HDL) and human secretory phospholipase A 2 (sPLA 2 ) colocalize with vascular smooth muscle cells and concentrate in the atherosclerotic lesions. It has been shown that gr IIA sPLA 2 hydrolyzes lipoproteins, altering their structure and releasing active agents such as lyso-phosphatidylcholine (PtdCho) and free fatty acids. We investigated the impact of normal HDL 3 (NHDL 3 ), acute phase HDL 3 (APHDL 3 ), and low-density lipoprotein (LDL), both unhydrolyzed and sPLA 2 -hydrolyzed, and some products of hydrolysis, such as lyso-PtdCho, oleic and linoleic acid, on [ 3 H] thymidine incorporation by DNA of cultured human vascular smooth muscle cells (VSMC). NHDL 3 markedly enhanced mitogenic activity of VSMC in a dose-and time-dependent manner. Doubling of thymidine incorporation was usually achieved by 40 g/ml of NHDL 3 after 4 hours of incubation. APHDL 3 had invariably a stronger inducing effect on the mitogenic activity than NHDL 3 ; 40 g/ml more than tripled [ 3 H] thymidine incorporation after 4 hours of incubation. NHDL 3 preincubated with human apo serum amyloid A apolipoprotein-induced higher mitogenic activity in VSMC than NHDL 3 alone. Hydrolysis of NHDL 3 , APHDL 3 , or LDL by gr IIA sPLA 2 markedly enhanced mitogenic activity of VSMC as compared with unhydrolyzed lipoproteins. sPLA 2 concentrations that can be found in atherosclerotic vascular walls markedly enhanced lipoprotein-induced mitogenic activity of VSMC. sPLA 2 per se did not affect thymidine incorporation and VSMC did not release sPLA 2 into the medium. There was no evidence for hydrolysis of the wall of VSMC by gr IIA sPLA 2 . The presence of the products of hydrolysis of lipoproteins such as oleic and linoleic acids and lyso-PtdCho or their combinations with NHDL 3 explains in part markedly enhanced mitogenic activity of VSMC. It is conceivable that sPLA 2, which is known to colocalize with lipoproteins in the vascular wall in the domain of VSMC, is capable of induction of the mitogenic activity in these cells in vivo and should be considered as a proatherogenic enzyme. (Lab Invest 2001, 81:757-765).A therosclerosis is the end stage of a complex interaction of several types of vascular wall resident and infiltrating cells, lipoproteins, and a variety of inflammatory mediators (Daugherty, 1997;Libby et al, 1997;Steinberg and Witztum, 1990). Recently, substantial evidence has accumulated indicating that proinflammatory and immunologic factors play an important role in atherogenesis (Hajjar and Pomerantz 1992;Hansson et al, 1989;Nilsson, 1993;Wick et al, 1995Wick et al, , 1997. It was found that acute phase markedly influences the structure of lipoproteins (Malle et al, 1993;Pruzanski et al, 1998Pruzanski et al, , 2000 and their functions (Kisilevsky and Subrahmanyan, 1992;Shephard et al, 1987;Van Lenten et al, 1995). In acute phase (Baumann and ...

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Atherosclerosis, autoimmunity, and vascular‐associated lymphoid tissue

Cited by 183 publications

References 46 publications

Association of Serum Antibodies to Heat-Shock Protein 65 With Carotid Atherosclerosis

Association of Serum Antibodies to Heat-Shock Protein 65 With Carotid Atherosclerosis

Mature Dendritic Cells Express Functional Thrombin Receptors Triggering Chemotaxis and CCL18/Pulmonary and Activation-Regulated Chemokine Induction

Mitogenic Effect of Lipoproteins on Human Vascular Smooth Muscle Cells: The Impact of Hydrolysis by gr II A Phospholipase A2

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