Interaction of antibodies against cytomegalovirus with heat-shock protein 60 in pathogenesis of atherosclerosis.
BACKGROUND
Infections and autoimmunity have been implicated in the pathogenesis of atherosclerosis. Cytomegalovirus has been shown to contribute to the disease. Autoantibodies against human heat-shock protein (HSP) 60 are present in most atherosclerotic patients, and their titre correlates with disease severity, suggesting that anti-HSP60 might be implicated in disease pathogenesis. We postulated that cytomegalovirus infection might induce antibodies able to bind human HSP60 and to cause endothelial-cell damage.


METHODS
We studied 180 patients with coronary-artery disease, raised high sensitivity C-reactive protein concentrations, and presence or absence of traditional risk factors; 90 patients with coronary-artery disease, normal values for high sensitivity C-reactive protein, and no traditional risk factors; and 98 controls. Individual sera were used to define the relevant epitope of HSP60 by ELISA. Affinity purified IgGs were used to identify endothelial cell-surface ligands by western blot and to induce apoptotic cell death.


RESULTS
We identified an 11 aminoacid sequence of HSP60 that was recognised by most patients with coronary-artery disease. This peptide shares homology with cytomegalovirus-derived proteins UL122 and US28. The same patients' sera recognised UL122-derived and US28-derived peptides. Purified IgGs against HSP60 and the viral peptides bound non-stressed human endothelial cells and induced endothelial-cell apoptosis by interaction with cell-surface molecules.


CONCLUSIONS
During cytomegalovirus infection, antibodies against the virus can arise that are able to crossreact with human HSP60 and cause apoptosis of non-stressed endothelial cells, which is judged a primary event in the pathogenesis of atherosclerosis.
Bason
Caterina
C
Department of Experimental Medicine, University of Genova, Genova, Italy.
Corrocher
Roberto
R
Lunardi
Claudio
C
Puccetti
Patrizia
P
Olivieri
Oliviero
O
Girelli
Domenico
D
Navone
Riccardo
R
Beri
Ruggero
R
Millo
Enrico
E
Margonato
Alberto
A
Martinelli
Nicola
N
Puccetti
Antonio
A
D000914:Antibodies, Viral / Q000276:immunology*; D000918:Antibody Specificity / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D018834:Chaperonin 60 / Q000276:immunology* / Q000378:metabolism; D003324:Coronary Artery Disease / Q000276:immunology* / Q000378:metabolism; D003429:Cross Reactions / Q000276:immunology; D003587:Cytomegalovirus / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020539:Sequence Analysis, Protein; D017385:Sequence Homology
D000914:Antibodies, Viral; D018834:Chaperonin 60