3 years ago

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.

Highlights

► First analysis of T-cells derived from early human atherosclerotic lesions. ► Proof that HSP60 reactive T-cells precede anti-HSP60 antibodies in atherogenesis. ► Identification of potentially atherogenic HSP60 peptides in human atherosclerosis. ► Interesting future diagnostic and therapeutic potential. ► Support of the “Autoimmune Concept of Atherogenesis”.

Publisher URL: www.sciencedirect.com/science

DOI: S0896841112001023

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