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Cardiovascular Research 2002 55(4):708-709; doi:10.1016/S0008-6363(02)00507-2
© 2002 by European Society of Cardiology
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Copyright © 2002, European Society of Cardiology

Potential role of dendritic cells in atherogenesis

Andreas Link* and Michael Böhm

Innere Medizin III; Universitätskliniken des Saarlandes, Kirrberger Straße, D-66424 Homburg/Saar, Germany

andreas.link{at}telemed.de

* Corresponding author. Tel.: +49-6841-1623-372; fax: +49-6841-1623-369

Received 10 June 2002; accepted 11 June 2002

See article by Alderman et al. [13] (pages 806–819) in this issue.

Dendritic cells (DCs), originally described by Steinmann and Cohn in 1973, play a crucial role in initiation of an immune response: they are the key antigen presenting cells (APCs) [1]. They originate from hematopoietic stem cells in bone marrow, migrate as immature precursors within the monocyte cell population in the blood stream, and emigrate into different tissues. Within these tissues, DCs differentiate (Fig. 1) and become active in taking up (pinocytosis; phagocytosis) and processing antigens bound to molecules of the major histocompatibility complex (MHC-I or MHC-II). In response to antigen-processing DCs mature, migrate to the T-cell areas of secondary lymphoid organs and activate naïve T and B-lymphocytes. DCs with antigen-peptides bound to MHC-I molecules stimulate and activate cytotoxic T-lymphocytes [2]. Re-expression of antigens to MHC-II molecules results in stimulation of T helper cells with profound immune regulatory effects.


Figure 1
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  		Fig. 1 Antigen presentation by dendritic cells and lymphocyte responses. Antigens: modified low density lipoproteins, e.g. oxidised LDL (ox-LDL); neoantigens, e.g. heat-shock-protein (HSP), bacteria, virus. Pinocytosis and phagocytosis by dendritic cells. Antigen presentation: Antigen-major-histocompatibility-complex (MHC)-II. Interaction with T-cell-receptor (TCR). T-lymphocyte-stimulation: T-helper-cells (Th1; Th2); cytotoxic T-cells. B-lymphocyte-stimualtion. Interferon-{gamma} (IFN-{gamma}). Interleucin (IL).

 

   1. Dendritic cells and atherogenesis
Top
 1. Dendritic cells and...
2. Perspectives
 References
 
The main theories of atherogenesis are the ‘response to injury’ [3], the ‘response to altered lipoprotein’ [4] and during the last years the ‘immunological’ hypotheses [5]. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY)-study, published previously, documents by using immunhistochemical methods, that inflammatory activity represents the first step towards atherosclerosis development in young adults. An accumulation of activated T-lymphocytes, dendritic cells, macrophages and aberrant MHC class II expression on cells can be noticed in the intima predisposed to the development of atherosclerotic lesions later in life particularly if classical risk factors are present [6]. Also in animal models of experimental atherogenesis dendritic cells are found clustered around arterial branch-points where they localise with T-lymphocytes and macrophages. Furthermore, the presence of dendritic cells in normal arterial intima suggests T-cell sensitisation [7,8]. And finally, analogous to the mucosa-associated lymphoid tissue (MALT), Wick et al. established the description vascular-associated lymphoid tissue (VALT) for accumulations of mononuclear cells in the arterial intima which provides a local defense mechanism.

The following candidate-antigens that may lead to cellular immune reactions in atherogenesis are discussed: (a) modified lipoproteins (e.g. oxidized-LDL); (b) denatured macromolecules from plaque-material; (c) neoantigens: heat shock proteins (HSPs) or endothelial surface antigens; (d) antigens of infectious organisms such as herpes virus, cytomegalovirus or Chlamydia pneumoniae.

Modified lipoproteins (e.g. ox-LDL) are one of the endogenous activators of immune response. In vitro studies show that elevated levels of ox-LDL would favor a rapid generation of mature dendritic cells from monocytes [10]. Autoantibodies to ox-LDL are considered to have a protective role in atherogenesis. In an experimental model with ox-LDL immunized animals induction of atherosclerosis was not possible [11]. Furthermore it could be demonstrated that activated dendritic cells that overexpress heat shock proteins (HSP60/65) might be responsible for T-cell activation within the arterial wall [9]. In early intimal lesions HSP70 is overexpressed exclusively by DCs [12].

In the present issue of Cardiovascular Research Alderman and coworkers [13] demonstrate that ox-LDL induces a balanced immunogenic cascade. They show that DCs are activated and mature, under the influence of mildly oxidized LDL, and with continuous stimulation T-cell activation and proliferation occurs, representing a chronic inflammatory response. Surprisingly, in the presence of more highly oxidised LDL finally apoptosis of DCs is observed. Thus, highly-oxidized LDL would serve to limit T-cell activation due to DC elimination by apoptosis.


   2. Perspectives
Top
 1. Dendritic cells and...
 2. Perspectives
References
 
The immunological hypothesis for the development of atherosclerosis postulates an immune/autoimmune reaction against candidate-antigens as a main initiating factor. This first inflammatory step of atherogenesis has been shown to be reversible, but continuous presence of classical risk factors for atherosclerosis will lead to irreversible severe lesions. Therefore, it is necessary to treat the vascular-associated lymphoid tissue (VALT) in the early step of atherogenesis. Due to their special immunostimulating properties DCs appear to be predestined for the induction of an immunomodulation. Similar to first experiences in the fields of immunotherapy of malignancies and autoimmune diseases, a genetic modification of autologous dendritic cells may induce an efficient cytotoxic or protective immune response. In the field of cell therapy in vitro treatment of DCs with candidate-antigen (i.e. ox-LDL, HSP) or alternatively genetic modification of these cells could provide new strategies in therapy of atherogenesis.


   References
Top
 1. Dendritic cells and...
 2. Perspectives
 References
 

  1. Steinman R., Cohn Z. Identification of a novel cell type in peripheral lymphoid organs of mice. J Exp Med (1973) 137:1142–1162.[Abstract]
  2. Banchereau J., Steinman R.M. Dendritic cells and the control of immunity. Nature (1998) 392:245–252.[CrossRef][Medline]
  3. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature (1993) 362:801–809.[CrossRef][Medline]
  4. Steinberg D., Witztum J.L. Lipoproteins and atherogenesis: current concepts. J Am Med Assoc (1990) 264:3047–3052.[Abstract/Free Full Text]
  5. Wick G., Schett G., Amberger A., Kleindienst R., Xu Q. Is atherosclerosis an immunologically mediated disease? Immunol Today (1995) 16:27–33.[CrossRef][Web of Science][Medline]
  6. Millong G., Malcom G.T., Wick G. Early inflammatory-immunological lesions in juvenile atherosclerosis from The Pathobiological Determinants of Atherosclerosis in Youth (PDAY)-study. Atherosclerosis (2002) 160:441–448.[CrossRef][Web of Science][Medline]
  7. Bobryshev Y.V., Taksir T., Lord R.S., Freeman M.W. Evidence that dendritic cells infiltrate atherosclerotic lesions in apolipoprotein E-deficient mice. Histol Histopathol (2001) 16(3):801–808.[Web of Science][Medline]
  8. Ozem J., Bobryshev Y.V., Lord R.S., Ashwell K.W. Identification of dendritic cells in aortic atherosclerosic lesions in rats with diet-induced hypercholesteraemia. Histol Histopathol (2002) 17(1):223–237.[Web of Science][Medline]
  9. Wick G., Romen M., Amberger A., Metzler B., Mayr M., Falkensammer G., Xu Q. Atherosclerosis, autoimmunity, and vascular-associated lymphoid tissue. FASEB (1997) 11:1199–1207.[Web of Science][Medline]
  10. Perrin-Cocon L., Coutant F., Agaugué S., Deforges S., André P., Lotteau V. Oxidized low-density lipoprotein promotes mature dendritic cell transition from differentiating monocyte. J Immunol (2001) 167:3785–3791.[Abstract/Free Full Text]
  11. Witztum J.L. The oxidation hypothesis of atherosclerosis. Lancet (1994) 344:793–795.[CrossRef][Web of Science][Medline]
  12. Bobryshev Y.V., Lord R.S. Expression of heat shock protein-70 by dendritic cells in the arterial intima and its potential significance in atherogenesis. J Vasc Surg (2002) 35(2):368–375.[CrossRef][Web of Science][Medline]
  13. Alderman C.J.J., Bunyarad R., Chain B.M., Foreman J.C., Leake D.S., Katz D.R. Effects of oxidised low density lipoprotein on dendritic cells: a possible immunoregulatory component of the atherogenic microenvironment? Cardiovasc Res (2002) 55:806–819.[Abstract/Free Full Text]

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