Irradiation-Induced Up-Regulation of HLA-E on Macrovascular Endothelial Cells Confers Protection against Killing by Activated Natural Killer Cells

BACKGROUND: Apart from the platelet/endothelial cell adhesion molecule 1 (PECAM-1, CD31), endoglin (CD105) and a positive factor VIII-related antigen staining, human primary and immortalized macro- and microvascular endothelial cells (ECs) differ in their cell surface expression of activating and inhibitory ligands for natural killer (NK) cells. Here we comparatively study the effects of irradiation on the phenotype of ECs and their interaction with resting and activated NK cells. METHODOLOGY/PRINCIPAL FINDINGS: Primary macrovascular human umbilical vein endothelial cells (HUVECs) only express UL16 binding protein 2 (ULBP2) and the major histocompatibility complex (MHC) class I chain-related protein MIC-A (MIC-A) as activating signals for NK cells, whereas the corresponding immortalized EA.hy926 EC cell line additionally present ULBP3, membrane heat shock protein 70 (Hsp70), intercellular adhesion molecule ICAM-1 (CD54) and HLA-E. Apart from MIC-B, the immortalized human microvascular endothelial cell line HMEC, resembles the phenotype of EA.hy926. Surprisingly, primary HUVECs are more sensitive to Hsp70 peptide (TKD) plus IL-2 (TKD/IL-2)-activated NK cells than their immortalized EC counterpatrs. This finding is most likely due to the absence of the inhibitory ligand HLA-E, since the activating ligands are shared among the ECs. The co-culture of HUVECs with activated NK cells induces ICAM-1 (CD54) and HLA-E expression on the former which drops to the initial low levels (below 5%) when NK cells are removed. Sublethal irradiation of HUVECs induces similar but less pronounced effects on HUVECs. Along with these findings, irradiation also induces HLA-E expression on macrovascular ECs and this correlates with an increased resistance to killing by activated NK cells. Irradiation had no effect on HLA-E expression on microvascular ECs and the sensitivity of these cells to NK cells remained unaffected. CONCLUSION/SIGNIFICANCE: These data emphasize that an irradiation-induced, transient up-regulation of HLA-E on macrovascular ECs might confer protection against NK cell-mediated vascular injury

Broadened Population-Level Frequency Tuning in Human Auditory Cortex of Portable Music Player Users

Nowadays, many people use portable players to enrich their daily life with enjoyable music. However, in noisy environments, the player volume is often set to extremely high levels in order to drown out the intense ambient noise and satisfy the appetite for music. Extensive and inappropriate usage of portable music players might cause subtle damages in the auditory system, which are not behaviorally detectable in an early stage of the hearing impairment progress. Here, by means of magnetoencephalography, we objectively examined detrimental effects of portable music player misusage on the population-level frequency tuning in the human auditory cortex. We compared two groups of young people: one group had listened to music with portable music players intensively for a long period of time, while the other group had not. Both groups performed equally and normally in standard audiological examinations (pure tone audiogram, speech test, and hearing-in-noise test). However, the objective magnetoencephalographic data demonstrated that the population-level frequency tuning in the auditory cortex of the portable music player users was significantly broadened compared to the non-users, when attention was distracted from the auditory modality; this group difference vanished when attention was directed to the auditory modality. Our conclusion is that extensive and inadequate usage of portable music players could cause subtle damages, which standard behavioral audiometric measures fail to detect in an early stage. However, these damages could lead to future irreversible hearing disorders, which would have a huge negative impact on the quality of life of those affected, and the society as a whole

Measurements of charged current lepton universality and |Vus| using tau lepton decays to e- (e) ( ), - ( ) ( ), - ( ), and K- ( ).

9 pages, 12 encapsulated postscript figures, submitted to Physical Review LettersInternational audienceUsing 467 $fb^{-1}$ of $e^+e^-$ annihilation data collected with the BaBar detector, we measure $\frac{{\cal{B}}(\tau^- \to \mu^- \bar{\nu}_\mu \nu_\tau)}{{\cal{B}}(\tau^- \to e^- \bar{\nu}_e \nu_\tau)} = (0.9796 \pm 0.0016 \pm 0.0036)$, $\frac{{\cal{B}}(\tau^- \to \pi^- \nu_\tau)}{{\cal{B}}(\tau^- \to e^- \bar{\nu}_e \nu_\tau)} = (0.5945 \pm 0.0014 \pm 0.0061)$, and \frac{{\cal{B}}(\tau^- \to \K^- \nu_\tau)}{{\cal{B}}(\tau^- \to e^- \bar{\nu}_e \nu_\tau)} = (0.03882 \pm 0.00032 \pm 0.00057), where the uncertainties are statistical and systematic, respectively. From these precision measurements we test the Standard Model assumption of $\mu$-$e$ and $\tau$-$\mu$ charged current lepton universality and also obtain a value for $|V_{us}| = 0.2255 \pm 0.0024$, which is consistent with the prediction from the unitarity of the Cabibbo-Kobayashi-Maskawa matrix

Differential lung NK cell responses in avian influenza virus infected chickens correlate with pathogenicity

Infection of chickens with low pathogenicity avian influenza (LPAI) virus results in mild clinical signs while infection with highly pathogenic avian influenza (HPAI) viruses causes death of the birds within 36–48 hours. Since natural killer (NK) cells have been shown to play an important role in influenza-specific immunity, we hypothesise that NK cells are involved in this difference in pathogenicity. To investigate this, the role of chicken NK-cells in LPAI virus infection was studied. Next activation of lung NK cells upon HPAI virus infection was analysed. Infection with a H9N2 LPAI virus resulted in the presence of viral RNA in the lungs which coincided with enhanced activation of lung NK cells. The presence of H5N1 viruses, measured by detection of viral RNA, did not induce activation of lung NK cells. This suggests that decreased NK-cell activation may be one of the mechanisms associated with the enhanced pathogenicity of H5N1 viruses

The interstitium in cardiac repair: role of the immune-stromal cell interplay

Cardiac regeneration, that is, restoration of the original structure and function in a damaged heart, differs from tissue repair, in which collagen deposition and scar formation often lead to functional impairment. In both scenarios, the early-onset inflammatory response is essential to clear damaged cardiac cells and initiate organ repair, but the quality and extent of the immune response vary. Immune cells embedded in the damaged heart tissue sense and modulate inflammation through a dynamic interplay with stromal cells in the cardiac interstitium, which either leads to recapitulation of cardiac morphology by rebuilding functional scaffolds to support muscle regrowth in regenerative organisms or fails to resolve the inflammatory response and produces fibrotic scar tissue in adult mammals. Current investigation into the mechanistic basis of homeostasis and restoration of cardiac function has increasingly shifted focus away from stem cell-mediated cardiac repair towards a dynamic interplay of cells composing the less-studied interstitial compartment of the heart, offering unexpected insights into the immunoregulatory functions of cardiac interstitial components and the complex network of cell interactions that must be considered for clinical intervention in heart diseases

Minimizing the risk of allo-sensitization to optimize the benefit of allogeneic cardiac-derived stem/progenitor cells

Allogeneic human cardiac-derived stem/progenitor cells (hCPC) are currently under clinical investigation for cardiac repair. While cellular immune response against allogeneic hCPC could be part of their beneficial-paracrine effects, their humoral immune response remains largely unexplored. Donor-specific HLA antibodies (DSA-HLA-I/DSA-HLA-II), primary elements of antibody-mediated allograft injury, might present an unidentified risk to allogeneic hCPC therapy. Here we established that the binding strength of anti-HLA monoclonal antibodies delineates hCPC proneness to antibody-mediated injury. In vitro modeling of clinical setting demonstrated that specific DSA-HLA-I of high/intermediate binding strength are harmful for hCPC whereas DSA-HLA-II are benign. Furthermore, the Luminex-based solid-phase assays are suitable to predict the DSA-HLA risk to therapeutic hCPC. Our data indicate that screening patient sera for the presence of HLA antibodies is important to provide an immune-educated choice of allogeneic therapeutic cells, minimize the risk of precipitous elimination and promote the allogeneic reparative effects