Autoreactive HSP60 epitope-specific T-cells in early human atherosclerotic lesions.
Atherosclerosis is a multifactorial chronic inflammatory disease characterized by the presence of T-cells, macrophages, and dendritic cells in the arterial intima. Classical risk factors lead to over-expression of stress proteins, especially heat shock protein 60 (HSP60). HSP60 on the surface of arterial endothelial cells (ECs) then becomes a target for pre-existing adaptive anti-HSP60 immunity resulting in infiltration of the intima by mononuclear cells. In the present study, T-cells derived from early, clinically still inapparent human atherosclerotic lesions were analyzed phenotypically and for their reactivity against HSP60 and HSP60-derived peptides. HSP60 was detected in ECs and CD40- and HLA Class II-positive cells within the intima. Effector memory CD4(+) T-cells producing high amounts of interferon-γ and low levels of interleukin-4 were the dominant subpopulation. T-cells derived from late lesions displayed a more restricted T-cell receptor repertoire to HSP60-derived peptides than those isolated from early lesions. Increased levels of soluble HSP60 and circulating anti-human HSP60 autoantibodies were found in donors with late but not early lesions. This is the first functional study of T-cells derived from early human atherosclerotic lesions that supports the previously proposed concept that HSP60-reactive T-cells initiate atherosclerosis by recognition of atherogenic HSP60 epitopes.
Laboratory of Autoimmunity, Section of Experimental Pathophysiology and Immunology, Biocenter, Innsbruck Medical University, Fritz-Pregl-Strasse 3, Schöpfstraße 41/1, A-6020 Innsbruck, Austria.
Giovanni
G
Almanzar
Robert
R
Öllinger
Julianna
J
Leuenberger
Elisabeth
E
Onestingel
Barbara
B
Rantner
Sarah
S
Zehm
Benno
B
Cardini
Ruurd
R
van der Zee
Cecilia
C
Grundtman
Georg
G
Wick
D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood / Q000235:genetics / Q000276:immunology*; D001344:Autopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D018834:Chaperonin 60 / Q000097:blood / Q000235:genetics / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013997:Time Factors; D017539:Tunica Intima / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D001323:Autoantibodies; D019013:CD40 Antigens; D018834:Chaperonin 60; D000949:Histocompatibility Antigens Class II; C508598:IL4 protein, human; D010455:Peptides; D015847:Interleukin-4; D007371:Interferon-gamma