Lymphocyte gene expression signatures from patients and mouse models of hereditary hemochromatosis reveal a function of HFE as a negative regulator of CD8+ T-lymphocyte activation and differentiation in vivo

Abnormally low CD8+ T-lymphocyte numbers is characteristic of some patients with hereditary hemochromatosis (HH), a MHC-linked disorder of iron overload. Both environmental and genetic components are known to influence CD8+ T-lymphocyte homeostasis but the role of the HH associated protein HFE is still insufficiently understood. Genome-wide expression profiling was performed in peripheral blood CD8+ T lymphocytes from HH patients selected according to CD8+ T-lymphocyte numbers and from Hfe-/- mice maintained either under normal or high iron diet conditions. In addition, T-lymphocyte apoptosis and cell cycle progression were analyzed by flow cytometry in HH patients. HH patients with low CD8+ T-lymphocyte numbers show a differential expression of genes related to lymphocyte differentiation and maturation namely CCR7, LEF1, ACTN1, NAA50, P2RY8 and FOSL2, whose expression correlates with the relative proportions of naïve, central and effector memory subsets. In addition, expression levels of LEF1 and P2RY8 in memory cells as well as the proportions of CD8+ T cells in G2/M cell cycle phase are significantly different in HH patients compared to controls. Hfe-/- mice do not show alterations in CD8+ T-lymphocyte numbers but differential gene response patterns. We found an increased expression of S100a8 and S100a9 that is most pronounced in high iron diet conditions. Similarly, CD8+ T lymphocytes from HH patients display higher S100a9 expression both at the mRNA and protein level. Altogether, our results support a role for HFE as a negative regulator of CD8+ T-lymphocyte activation. While the activation markers S100a8 and S100a9 are strongly increased in CD8+ T cells from both, Hfe-/- mice and HH patients, a differential profile of genes related to differentiation/maturation of CD8+ T memory cells is evident in HH patients only. This supports the notion that HFE contributes, at least in part, to the generation of low peripheral blood CD8+ T lymphocytes in HH

Joint and several liability of the investor and general contractor for consideration due to the subcontractors after the changes introduced by the Act of 7 April 2017

Publikacja recenzowana / Peer-reviewed publicationPublikacja dotyczy niezmiernie istotnego z punktu widzenia praktyki budowlanej zagadnienia odpowiedzialności solidarnej inwestora i generalnego wykonawcy za zapłatę wynagrodzenia należnego podwykonawcy. Analizą objęte zostały nowe rozwiązania prawne, które wprowadzono ustawą z dnia 7 kwietnia 2017 r. o zmianie niektórych ustaw w celu ułatwienia dochodzenia wierzytelności. Na pierwszy rzut oka wydaje się, że rozstrzygają one wszelkie wątpliwości, jakie pojawiały się na gruncie wykładni art. 6471 k.c. Wnikliwa lektura rzeczonego przepisu prawnego pozwala stwierdzić, że jest to mylne odczucie.Th is article considers the problem of joint and several liability of the investor and general contractor for consideration due to the subcontractors what is an extremely principal issue from the point of view of construction industry. Th e analysis includes the new legal solutions which were introduced by the Act of 7 April 2017 about the changes of some acts to facilitate debt recovery. It seems at fi rst sight that the mentioned changes solve any kind of doubt which existed on basis of the interpretation of the Article 6471 of the Civil Code. A thorough reading of the said legal provision leads to a conclusion that it might be a confusing impression