Editorial Slides VP Watch December 4, 2002 Volume 2, Issue 48

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

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 cytokinedriven
• 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
Statin Reduces the Release of Soluble CD40L From
Endothelial Cells.
sCD40L (ng/ml)
IL1/TNF
0 10 0 10
Cerivastatin (nM)
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
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
Conclusion

• Statins limit the expression of the CD40
  receptor/ligand in two ways, directly as well as
  through reduced lipoprotein levels.

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
References

• Ross R. Atherosclerosis-an inflammatory disease.
  N Engl J Med 1999340115-126.
• Libby P. Molecular bases of the acute coronary
  syndromes. Circulation 1995912844-2850.
• Cheng G, Schoenberger SP. CD40 signaling and
  autoimmunity. Curr Dir Autoimmun. 2002551-61.
• Van Kooten C, Banchereau J. CD40-CD40 ligand a
  multifunctional receptor-ligand pair. Adv
  Immunol. 1996 61 177.
• Clark LB, Foy TM, Noelle RJ. CD40 and its ligand.
  Adv Immunol. 1996 63 4378.
• Phipps RP. Atherosclerosis the emerging role of
  inflammation and the CD40-CD40 ligand system.
  Proc Natl Acad Sci U S A. 2000 97 69306932.
• Schönbeck U, Mach F, Libby P. CD154 (CD40
  ligand). Int J Biochem Cell Biol. 2000 32
  687693.
• 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
  12151222.
• Lutgens E, Daemen MJ. CD40-CD40L interactions
  in atherosclerosis. Trends Cardiovasc Med. 2002
  Jan12(1)27-32. Review.