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.
PurposeThe epithelial lining of the anorectum still raises discussions concerning the levels of transition between the various zones and leads to an incomplete understanding of the immmunoprofile of rectal carcinoma. Since the expression of cytokeratins depends on the epithelial cell-type and the parahox-gene CDX2 is important for the development of the colorectal epithelium, we investigated different cytokeratins and CDX2 in the anorectum of human prenatal stages and in adult normal and neoplastic anorecta.Materials and MethodsThe differentiation and spatiotemporal distribution of the epithelial zones were examined in 33 human embryos and fetuses, in a 2-year-old child and four adults. In comparison, 17 specimens of ultralow rectal adenocarcinoma and 4 specimens of anal carcinoma were investigated. Monoclonal antibodies were directed against cytokeratin (CK) 18, 20, 7 and 14 and CDX2.ResultsDue to the cytokeratin profile and to CDX2 expression, the different anorectal zones could already be differentiated in human prenatal life. We showed that anorectal epithelial differentiation including the squamous epithelia ran in a craniocaudal direction, and that the anorectal zone was a transitional zone between rectal zone and anal transitional zone where CK 7, 18, 20 and CDX2 are simultaneously expressed. All cases of rectal adenocarcinoma showed positivity for CK 18, 20 and CDX2, and three also labelled for CK 7, whereas CK 14 was only expressed in the cases of anal carcinoma.ConclusionsOur results elucidate the connection between the prenatal pattern and the origin of the different types of anorectal carcinoma.
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