From LDL Cholesterol To Fibrin Clot,
Travel With CD40 Airline!
VP Watch – December 4, 2002 - Volume 2, Issue 48
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.
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
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
Disruption of CD40 and its ligand leads to
immunodeficiency as in the case of hyper-
IgM syndrome. 12
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
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
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
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
CD40L is released from platelet-rich thrombi
and contributes to various steps in
atherosclerotic lesion progression: 10
Thrombosis - CD40L stabilizes platelet-rich
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.
As reported in VP Watch of this week,
Schönbeck and colleagues studied the
effect oxidized LDL on CD40/CD40L
expression on cells implicated in
They showed that oxLDL increases basal
expression of CD40 and CD40L mRNA and
protein in endothelial cells, SMCs, and
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
- + - +
0 10 0 10
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.
CD40L plays multiple roles in
atherosclerotic disease, from
inflammatory aspects of plaque
progression, to thrombosis and
Oxidized LDL is a potential inducer of
the CD40/CD40L on cell types
implicated in atherogenesis.
Statins limit the expression of the
CD40 receptor/ligand in two ways,
directly as well as through reduced
What is the mechanism of inhibitory
effect of statins on CD40/CD40L
Is the effect of statins on CD40 specific
or they have similar effects on other
members of TNF receptor family?
Why in CD40 -/-, Apo E -/- mice the initial
stage of plaque development is not
Whereas advanced plaques in CD154-/-
ApoE-/- mice are very much affected and
show a less-lipid-containing, collagen-rich
stable plaque phenotype?
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?
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.
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-
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.