Autoreactive HSP60 epitope-specific T-cells in early human atherosclerotic lesions

Abstract

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.

Tolerization against atherosclerosis using heat shock protein 60

“…Similarly, also T cells derived from late complicated human atherosclerotic plaques harbored specific hHSP60 epitope reaction, which confirms earlier data where also cross-reactive epitopes were found between cHSP60 and hHSP60 (Almanzar et al 2012;Benagiano et al 2005). Interestingly, some potentially atherogenic hHSP60 epitopes were only found in early lesions vs. late plaques while others were shared (Almanzar et al 2012). T cells from atherosclerotic lesions from rabbits do also give strong proliferative response to mbHSP65 (Xu et al 1993a, b).…”

“…Soluble HSP60 (sHSP60) and/or anti-hHSP60 antibody concentrations may be used as prognostic biomarkers for the risk of develop cardiovascular disease (CVD) as several studies have demonstrated a correlation between high antihHSP60 antibody titers and/or elevated sHSP60 levels in individuals suffering from CVD (Willeit and Kiechl 1993;Xu et al 1993a, b;Hoppichler et al 2000;Pockley et al 2000;Zhang et al 2008;Almanzar et al 2012). Also, common carotid artery intima media thickness (IMT; the combined thickness of both the tunica intima and tunica media) correlates with elevated sHSP60 levels in individuals with prevalent carotid atherosclerosis Xiao et al 2005).…”

“…Lesion-derived T cells display an oligoclonally restricted repertoire in contrast to the polyclonal pattern of peripheral blood mononuclear cells (PBMCs), indicating that oligoclonal T cell expansion can take place in human atherosclerotic lesions (Rossmann et al 2008). We have recently shown that these early autoreactive intralesional T cells, derived from early, clinically still inapparent human atherosclerotic lesions, can specifically react to certain hHPS60 epitopes (Almanzar et al 2012). Similarly, also T cells derived from late complicated human atherosclerotic plaques harbored specific hHSP60 epitope reaction, which confirms earlier data where also cross-reactive epitopes were found between cHSP60 and hHSP60 (Almanzar et al 2012;Benagiano et al 2005).…”

“…We have recently shown that these early autoreactive intralesional T cells, derived from early, clinically still inapparent human atherosclerotic lesions, can specifically react to certain hHPS60 epitopes (Almanzar et al 2012). Similarly, also T cells derived from late complicated human atherosclerotic plaques harbored specific hHSP60 epitope reaction, which confirms earlier data where also cross-reactive epitopes were found between cHSP60 and hHSP60 (Almanzar et al 2012;Benagiano et al 2005). Interestingly, some potentially atherogenic hHSP60 epitopes were only found in early lesions vs. late plaques while others were shared (Almanzar et al 2012).…”

Hsp60 chaperonopathies and chaperonotherapy: targets and agents

“…The actions of Hsp60 could lead to the modification of those proteins, and in this manner it could have a role in many diseases, including carcinogenesis. Heart Heart failure; Coronary vascular disease [137][138][139][140] Kidney Glomerulonephritis [141] Large bowel Inflammatory bowel diseases [19,142,143] Lung Chonic obstructive pulmonary disease [20] Oral cavity Periodontitis [144,145] Pancreas Type 1 diabetes [146][147][148][149][150][151] Skin Scleroderma, pemphigoid; Psoriasis; Dermatomyositis [152,153] Synovial joints Rheumatoid arthritis; Juvenile idiopathic arthritis [154][155][156][157] Vessels Vasculitis; Atherosclerosis [158][159][160][161][162][163][164][165][166][167] Adapted from [2]. Hsp60 seems to contribute to tumor cell survival, but this is controversial.…”