Biliary epithelium and liver B cells exposed to bacteria activate intrahepatic MAIT cells through MR1

Background & AimsMucosal-Associated Invariant T (MAIT) cells are innate-like T cells characterised by the invariant TCR-chain, Vα7.2-Jα33, and are restricted by MR1, which presents bacterial vitamin B metabolites. They are important for antibacterial immunity at mucosal sites; however, detailed characteristics of liver-infiltrating MAIT (LI-MAIT) and their role in biliary immune surveillance remain unexplored.MethodsThe phenotype and intrahepatic localisation of human LI-MAIT cells was examined in diseased and normal livers. MAIT cell activation in response to E. coli-exposed macrophages, biliary epithelial cells (BEC) and liver B cells was assessed with/without anti-MR1.ResultsIntrahepatic MAIT cells predominantly localised to bile ducts in the portal tracts. Consistent with this distribution, they expressed biliary tropic chemokine receptors CCR6, CXCR6, and integrin αEβ7. LI-MAIT cells were also present in the hepatic sinusoids and possessed tissue-homing chemokine receptor CXCR3 and integrins LFA-1 and VLA-4, suggesting their recruitment via hepatic sinusoids. LI-MAIT cells were enriched in the parenchyma of acute liver failure livers compared to chronic diseased livers. LI-MAIT cells had an activated, effector memory phenotype, expressed α4β7 and receptors for IL-12, IL-18, and IL-23. Importantly, in response to E. coli-exposed macrophages, liver B cells and BEC, MAIT cells upregulated IFN-γ and CD40 Ligand and degranulated in an MR1-dependent, cytokine-independent manner. In addition, diseased liver MAIT cells expressed T-bet and RORγt and the cytokines IFN-γ, TNF-α, and IL-17.ConclusionsOur findings provide the first evidence of an immune surveillance effector response for MAIT cells towards BEC in human liver; thus they could be manipulated for treatment of biliary disease in the future

A role for cyclooxygenase in aging-related changes of beta-adrenoceptor-mediated relaxation in rat aortas

beta-Adrenoceptor-mediated vasorelaxation decreases with age in various vascular beds. The present study investigated the roles of cyclooxygenase (COX) on beta-adrenoceptor vasorelaxation by isoprenaline in 8- and 54-week-old rat aortas. The vasorelaxation responses by isoprenaline (0.03-3 mu M) were significantly reduced in 54-week-old aortas compared to 8-week. Addition of the non-selective COX inhibitors indomethacin (10 mu M) or aspirin (10 mu M) restored isoprenaline vasorelaxation of 54-week-old aortas to levels found in 8-week-old aortas. This suggests the involvement of COX prostanoids in the age-related reduction of beta-adrenoceptor vasorelaxation. Immunohistochemistry revealed greater levels of COX-1 and COX-2 staining in 54-week-old aortas compared to 8-week with expression located mainly in medial smooth muscle. An age-linked increase in COX-1 and COX-2 protein was found in cremaster arterioles of 54-week-old rats (compared to 8-week) mainly in the endothelial layer. The age-related increase in COX-1 and COX-2 protein led to elevation of prostacyclin (measured as 6-keto prostagladin F-1 alpha) and thromboxane A(2) (measured as thromboxane B-2) in 54-week compared to 8-week-old aortas. Endothelium removal in 54-week aortas markedly reduced the 6-keto prostaglandin F-1 alpha level, thus suggesting an endothelial source for elevated prostacyclin. These findings in combination with the effects of COX inhibitors suggest that the age-related decrease in beta-adrenoceptor vasorelaxation by isoprenaline is due to an age-linked increase in COX expression, which elevates production of COX-derived vasoactive prostanoids

Novel conventional and modular LSF wall panels with improved fire performance

Fire performance of Light-gauge Steel Frame (LSF) constructions is being extensively investigated recently, due to the critical behaviour of cold-formed steel structures at elevated temperatures. Among the many design parameters involved with LSF constructions, the effect of cavity insulation inside LSF walls at different ratios on the Fire Resistance Level (FRL) has not been addressed yet. Hence, Finite Element Models (FEMs) were developed for the LSF walls to simulate the full-scale fire tests conducted applying the standard fire temperatures, where the Finite Element Analyses (FEA) results were very well agreeing with the experimental results. Thereafter, the validated FEMs were extended to study the fire performance of the conventional and modular LSF wall systems with different cavity insulation ratios, where 0.4 cavity insulation ratio was found to be most efficient when structural FRL is of concern while producing satisfactory energy performance at reduced material costs. To calculate the structural FRLs of conventional and modular, single and double plasterboard layers sheathed LSF walls, 4 empirical models have been proposed where more than 97% accuracy was achieved. Moreover, incorporating back blocking panels and discontinuous insulation options, several novel conventional and modular LSF walls have been proposed with up-to 70% improvement in structural FRL