Human 60-kDa heat shock protein is a target autoantigen of T cells derived from atherosclerotic plaques.
Epidemiological studies suggest the potential importance of an inflammatory component in atherosclerosis and support the hypothesis that immune responses to Ags of pathogens cross-react with homologous host proteins due to molecular mimicry. Protein candidates involved may be the stress-induced proteins known as heat shock proteins (HSP). In this study, we report that atherosclerotic plaques harbor in vivo-activated CD4(+) T cells that recognize the human 60-kDa HSP. Such in vivo-activated 60-kDa HSP-specific T cells are not detectable in the peripheral blood. In patients with positive serology and PCR for Chlamydia pneumoniae DNA, but not in patients negative for both, most of plaque-derived T cells specific for human 60-kDa HSP also recognized the C. pneumoniae 60-kDa HSP. We characterized the submolecular specificity of such 60-kDa HSP-specific plaque-derived T cells and identified both the self- and cross-reactive epitopes of that autoantigen. On challenge with human 60-kDa HSP, most of the plaque-derived T cells expressed Th type 1 functions, including cytotoxicity and help for monocyte tissue factor production. We suggest that arterial endothelial cells, undergoing classical atherosclerosis risk factors and conditioned by Th type 1 cytokines, express self 60-kDa HSP, which becomes target for both autoreactive T cells and cross-reactive T cells to microbial 60-kDa HSP via a mechanism of molecular mimicry. This hypothesis is in agreement with the notion that immunization with HSP exacerbates atherosclerosis, whereas immunosuppression and T cell depletion prevent the formation of arteriosclerotic lesions in experimental animals.
Benagiano
Marisa
M
Department of Internal Medicine, University of Florence, Florence, Italy.
D'Elios
Mario M
MM
Amedei
Amedeo
A
Azzurri
Annalisa
A
van der Zee
Ruurd
R
Ciervo
Alessandra
A
Rombolà
Gianni
G
Romagnani
Sergio
S
Cassone
Antonio
A
Del Prete
Gianfranco
G
D000368:Aged; D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D001161:Arteriosclerosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D002465:Cell Movement / Q000276:immunology; D018834:Chaperonin 60 / Q000276:immunology* / Q000378:metabolism; D016993:Chlamydophila pneumoniae / Q000276:immunology; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018716:Molecular Mimicry / Q000276:immunology; D008969:Molecular Sequence Data; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D013925:Thromboplastin / Q000096:biosynthesis
D001324:Autoantigens; D018834:Chaperonin 60; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D013925:Thromboplastin