SHAPE Society

1. From LDL Cholesterol To Fibrin Clot,
Travel With CD40 Airline!
Editorial Slides
VP Watch – December 4, 2002 - Volume 2, Issue 48

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.  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.  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.  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.  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.  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.  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.  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.  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. 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. 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.  Statins limit the expression of the
CD40 receptor/ligand in two ways,
directly as well as through reduced
lipoprotein levels.
Conclusion:

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. 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. 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. 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