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  1. 1. From LDL Cholesterol To Fibrin Clot, Travel With CD40 Airline! Editorial Slides VP Watch – December 4, 2002 - Volume 2, Issue 48
  2. 2.  During the last decade, atherosclerosis has found a new face. 1, 2  A snapshot of atherosclerosis in 2002 views it as an immune-mediated disease that is mixed with an abnormal metabolic background such as hyperlipidemia.
  3. 3.  CD40, a cell surface molecule member of the tumor necrosis factor receptor family, was first identified and functionally characterized on B lymphocytes . 12  CD40 ligand (CD154) is a 33 kDa type II glycoprotein which is transiently expressed on the surface of T cells following activation. 13
  4. 4.  In recent years it has become clear that CD40 expression is much broader, as it is found on monocytes, dendritic cells, hematopoietic progenitors, endothelial cells, and epithelial cells.  They are also abundantly found on platelets. 3,4  Disruption of CD40 and its ligand leads to immunodeficiency as in the case of hyper- IgM syndrome. 12
  5. 5.  Early studies focused on CD40 in B cell biology, but recent work demonstrates a broader role for CD40 in the immune system contributing to cell- mediated as well as humoral immune responses. 12  The major role of CD40L in the immune response involves binding to its receptor on B cells; CD40, to induce B-cell proliferation, generate memory B cells, block B-cell apoptosis, and mediate antibody class switching. 4,5
  6. 6.  Latest studies show that CD40/CD40L system plays an important role in the pathogenesis of atherosclerotic plaque. 6,7  CD40/CD40L interaction triggers a predominantly Th1 cytokine–driven inflammation which establishes the immune reaction characteristic for atherogenesis. 6, 7
  7. 7.  CD40 and CD40L protein are present in almost all cell types in human atherosclerotic lesions. 9  Libby et al shown that lipid lowering limits the expression of CD40L in experimental atheroma. 7  Libby, Schönbeck, and colleagues showed co-localization of both CD40 and CD40L on atheroma-associated endothelial cells, SMCs, and macrophages in vitro. 8
  8. 8.  CD40L is released from platelet-rich thrombi and contributes to various steps in atherosclerotic lesion progression: 10  Thrombosis - CD40L stabilizes platelet-rich thrombi.  Inflammation - CD40L induces cytokines production and release.  Restenosis - CD40L inhibits the re- endothelialization of the injured vessel, potentially leading to the activation and proliferation of smooth muscle cells.
  9. 9.  As reported in VP Watch of this week, Schönbeck and colleagues studied the effect oxidized LDL on CD40/CD40L expression on cells implicated in atherogenesis. 11  They showed that oxLDL increases basal expression of CD40 and CD40L mRNA and protein in endothelial cells, SMCs, and macrophages. 11
  10. 10.  They found that statins reduces the expression of CD40 and CD40L on human vascular endothelial and smooth muscle cells and macrophages in vitro. 11  Platelet-enriched plasma of CD40L- deficient mice showed delayed fibrin clot formation. 11
  11. 11. 0 3 6 9 12 15 - + - + West { IL1/TNF 0 10 0 10 Cerivastatin (nM) sCD40L(ng/ml) Supernatants of endothelial cell cultures were harvested after incubation with medium alone ( - ) or IL-1ß/TNF-alpha ( + ; 10/50 ng/mL, 1 hour) in the absence or presence of cerivastatin (10 nmol/L) and were analyzed by ELISA for sCD40L using recombinant CD40L as standard. Cells obtained from 4 different donors yielded comparable data. 11 Statin Reduces the Release of Soluble CD40L From Endothelial Cells.
  12. 12. Conclusion:  CD40L plays multiple roles in atherosclerotic disease, from inflammatory aspects of plaque progression, to thrombosis and restenosis.  Oxidized LDL is a potential inducer of the CD40/CD40L on cell types implicated in atherogenesis.
  13. 13.  Statins limit the expression of the CD40 receptor/ligand in two ways, directly as well as through reduced lipoprotein levels. Conclusion:
  14. 14. Questions:  What is the mechanism of inhibitory effect of statins on CD40/CD40L system?  Is the effect of statins on CD40 specific or they have similar effects on other members of TNF receptor family?
  15. 15. Questions:  Why in CD40 -/-, Apo E -/- mice the initial stage of plaque development is not affected?  Whereas advanced plaques in CD154-/- ApoE-/- mice are very much affected and show a less-lipid-containing, collagen-rich stable plaque phenotype?
  16. 16. Questions:  Is it correct to say that CD40 may be a critical marker of plaque inflammation and vulnerability but does not play an important role in plaque formation and early stage of atherosclerosis?  Why host CD40 ligand deficiency induces long- term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis?
  17. 17. 1) Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med 1999;340:115-126. 2) Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844-2850. 3) Cheng G, Schoenberger SP. CD40 signaling and autoimmunity. Curr Dir Autoimmun. 2002;5:51-61. 4) Van Kooten C, Banchereau J. CD40-CD40 ligand: a multifunctional receptor-ligand pair. Adv Immunol. 1996; 61: 1–77. 5) Clark LB, Foy TM, Noelle RJ. CD40 and its ligand. Adv Immunol. 1996; 63: 43–78. 6) Phipps RP. Atherosclerosis: the emerging role of inflammation and the CD40-CD40 ligand system. Proc Natl Acad Sci U S A. 2000; 97: 6930–6932. 7) Schönbeck U, Mach F, Libby P. CD154 (CD40 ligand). Int J Biochem Cell Biol. 2000; 32: 687–693. 8) Aikawa M, Voglic SJ, Sugiyama S, Rabkin E, Taubman MB, Fallon JT, Libby P. Dietary lipid lowering reduces tissue factor expression in rabbit atheroma. Circulation. 1999; 100: 1215–1222. 9) Lutgens E, Daemen MJ. ; CD40-CD40L interactions in atherosclerosis. Trends Cardiovasc Med. 2002 Jan;12(1):27-32. Review. 10) Patrick André, Lisa Nannizzi-Alaimo, Srinivasa K. Prasad, and David R. Phillips ; Platelet-Derived CD40L: The Switch- Hitting Player of Cardiovascular Disease . Circulation 2002 106: 896 11) Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells. Circulation. 2002 Dec 3;106(23):2888-93 12) Vogel LA, Noelle RJ. CD40 and its crucial role as a member of the TNFR family. Semin Immunol. 1998 Dec;10(6):435- 42. 13) Fanslow WC, Srinivasan S, Paxton R, Gibson MG, Spriggs MK, Armitage RJ.Structural characteristics of CD40 ligand that determine biological function. Semin Immunol. 1994 Oct;6(5):267-78. Review. 14) Shimizu K, Schonbeck U, Mach F, Libby P, Mitchell RN.Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis. J Immunol. 2000 Sep 15;165(6):3506-18. References