283 research outputs found
Myocardial Ischemia and Reperfusion Leads to Transient CD8 Immune Deficiency and Accelerated Immunosenescence in CMV-Seropositive Patients
No full textRationale: There is mounting evidence of a higher incidence of coronary heart disease (CHD) in cytomegalovirus (CMV) seropositive individuals.
Objective: The aim of this study was to investigate whether acute MI triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in CMV-seropositive patients.
Methods and Results: Thirty-four patients with acute MI undergoing primary PCI (PPCI) were longitudinally studied within 3 months following reperfusion (Cohort A). In addition, 54 patients with acute and chronic MI were analyzed in a cross-sectional study (Cohort B). CMV-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 min of reperfusion compared with CMV-seronegative patients (-192 vs. -63 cells/µl; p=0.008), correlating with the expression of programmed cell death-1 (PD-1) before PPCI (r=0.8; p=0.0002). A significant proportion of TEMRA cells remained depleted for at least 3 months in CMV-seropositive patients. Using high-throughput 13-parameter flow cytometry and HLA class I CMV-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and CMV-specific CD8+ cells in CMV-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic CMV-seropositive post-MI patients was associated with signs of terminal differentiation including an increase in KLRG1 and shorter telomere length in CD8+ T cells (2225 bp vs. 3397 bp; p<0.001).
Conclusions: Myocardial ischemia and reperfusion in CMV-seropositive patients undergoing PPCI leads to acute loss of antigen-specific, terminally differentiated CD8 T-cells, possibly through PD-1-dependent programmed cell death. Our results suggest that acute MI and reperfusion accelerate immunosenescence in CMV-seropositive patients
Rezension: "Besuch in der Hölle. Dantes Göttliche Komödie. Biographie eines Jahrtausendbuchs" von Franziska Meier
No full textFranziska Meiers vorliegende Studie stellt einen wichtigen Beitrag zur aktuellen wissenschaftlichen Erforschung von Dantes Divina Commedia dar. In ihrer Untersuchung erläutert sie nicht nur die grundlegenden Kontexte der Entstehungsgeschichte und die Biografie des schon zu Lebzeiten umstrittenen Verfassers. Vielmehr gelingt es Meier, auch linguistische Aspekte, Fragen der Übersetzung und der Rezeption außerhalb Europas schlüssig darzustellen. Die Autorin und Übersetzerin Lorena Pircher, selbst auch Romanistin, hat diese Studie für die Medienimpulse rezensiert.Franziska Meier\u27s study represents an important contribution to current scholarly research on Dante\u27s Divina Commedia. In her new book, she not only explains the fundamental contexts of the genesis of the Commedia and biography of the author, who was already controversial during his lifetime. Rather, Meier also succeeds in coherently presenting linguistic aspects, questions of translation and reception outside Europe. The author and translator Lorena Pircher, herself also a Romance scholar, reviewed this study for Medienimpulse
Regulation of RAG‐1 and CD69 expression in the thymus during positive and negative selection
No full textSuccessful interaction of the T cell receptor (TCR) with major histocompatibility complex (MHC) molecules during thymic selection down-regulates the expression of the recombination activating genes (RAG)-1 and -2 in cortical thymocytes and thereby prevents further endogenous TCR alpha-chain gene rearrangements (Borgulya, P., Kishi, H., Uematsu, Y. and von Boehmer, H., Cell. 1992. 69: 529-537; Brändle, D., Müller, C., Rülicke, T., Hengartner, H. and Pircher, H., Proc. Natl. Acad. Sci. USA 1992. 89: 9529-9533). To address the question whether down-regulation of RAG-1 activity represents an irreversible process we have blocked TCR-MHC interactions of thymocytes with thymic stromal cells. Firstly, transgenic (Tg) mice expressing a virus-specific MHC class I (H-2Db)-restricted TCR were injected with anti-Db or anti-CD8 monoclonal antibodies and RAG-1 expression was examined by in situ hybridization on thymus sections. The results show that cortical thymocytes up-regulated RAG-1 expression within 24 h after antibody administration. Secondly, immature thymocytes from TCR Tg mice were released from the thymic microenvironment and cultured in vitro for 14 h in single-cell suspension. The amount of RAG-1 mRNA was increased sixfold in cultured cells when compared to freshly isolated thymocytes. In addition, we show that immature thymocytes from TCR transgenic mice bearing non-selective MHC molecules (H-2d) down-regulated RAG-1 expression after antigen-induced TCR engagement. Cytofluorometric analysis further revealed that surface expression of CD69 on immature thymocytes inversely correlated with RAG-1 expression during positive and negative selection processes
Abrogation of CCL21 chemokine function by transgenic over-expression impairs T cell immunity to local infections
No full textThe CC chemokine receptor 7 (CCR7) and its two ligands, CCL21 and CCL19, play an important role in migration of immune cells to lymphoid tissue. To analyze the function of CCR7 in T cell immunity to infectious agents in vivo, transgenic (tg) mice expressing CCL21 in an ubiquitous fashion were generated. These mice contained high amounts of CCL21 in the serum (similar to 0.3 mu g/ml that resulted in CCR7 down-regulation and in a strongly impaired migration of T cells toward CCL21 in vitro. Lymph nodes in CCL21-tg mice were reduced in size but with intact microanatomy and normal distribution of T and B cells. CCL21-tg mice showed a significantly decreased CD8 T cell response to lymphocytic choriomeningitis virus after footpad infection, whereas the response after systemic infection was not altered. Likewise, the CD4 T cell response to footpad infection with Leishmania major was considerably lowered and CCL21-tg mice failed to clear parasites from infected skin. Taken together, these data demonstrate the importance of CCR7 in mediating T cell immunity to viral and parasitic pathogens after local infection
Comprehensive analysis of HBV-specific CD8+ T cell responses and characterization of viral immune escape in chronic HBV infection
No full textAnalysis of the CD4+ T cell immune response in vivo using CD4 up-regulation as an activation marker: normal versus autoimmune peripheral CD4+ T cell response development
No full textAdaptive immunity in murine Bartonella infection
No full textBartonella is a genus of facultative-intracellular bacteria causing a long-lasting intra-erythrocytic bacteremia
in their mammalian reservoir hosts. Clearance of the bacteremia has been described to be mediated by antibodies. The exact clearance mechanism, however, has not been investigated so far. In this work, several
aspects related to the immune response against Bartonella have been studied in more detail, with an emphasis on the host’s protective antibody response.
For the manuscript "Neutralizing antibodies protect against murine Bartonella infection by interfering with
erythrocyte adhesion", infection of mice with B. taylorii served as a model for the infection of the natural
reservoir host by Bartonella. Bacteremia clearance kinetics and antibody responses were investigated in
different murine knock-out models. The clearance was observed to be independent of the presence of the
complement or Fc-receptors. An in-vitro erythrocyte adhesion inhibition assay was established, which correlated with protection by an immune serum or antibody in vivo and lead to the conclusion that neutralizing
antibodies protect by interfering with the red blood cell attachment of the bacteria. We identified a so far
understudied virulence factor, a predicted autotransporter on the bacterial surface, as a target of the murine
antibody response and suggest that it plays a role in erythrocyte adhesion.
Further experiments investigating the role of T-cells in clearing the bacteremia showed that although the
cytolytic response is negligible, T-help is essential for mounting a protective antibody response and thus
clearance.
Some experiments concerning both, the antibody and the T-cell response upon infection, were additionally
performed using B. birtlesii as a mouse model for Bartonella infection and indicate that the observations
made with B. taylorii are not species specific but seem to be common for lineage 4, if not for all Bartonella
species.
In addition, the vertical transmission of B. taylorii was investigated. The bacterium could be transmitted
from mother to embryo before birth, however, only if the mother had a deficiency in the adaptive immune
system. Immunocompetent offspring cleared the bacteremia after birth, indicating that there is no state of
immunological tolerance induced by transplacental transmission of Bartonella
Identification and characterisation of differentially expressed genes in naive and activated CD8⁺ T cells
No full textAntibody control and immunopathogenesis of viral infection
No full textAcross the animal kingdom, multivalency discriminates antibodies from all other immunoglobulin superfamily members. The evolutionary forces conserving multivalency above any other structural hallmark of antibodies remain, however, ill-defined. Here we have used antibody engineering techniques to investigate mechanisms of protection of neutralizing and non-neutralizing antibodies (nAbs, nnAbs) in a viral infection model in mice.
Antibody bivalency enabled the tethering of virions to the infected cell surface, thereby inhibiting the release of infectious virions in cell culture and suppressing viral loads in vivo independently of Fc. Conversely, virion release inhibition and in vivo control of infection by monovalent antibody formats were strictly Fc-dependent. Comparable amounts of nAb and nnAb were required for in vivo protection and correlated with similar virion release-inhibiting activity.
These observations provide a mechanistic understanding of the evolutionary conservation of antibody bivalency and may help establishing better correlates on nnAb protection for vaccine development.
Arenaviruses such as Lassa virus cause hemorrhagic fever. Terminal shock is associated with a systemic cytokine storm but remains mechanistically ill-defined.
In a mouse model of arenavirus hemorrhagic fever (AHF) disease manifested in pleural effusions, edematous skin swelling and serum albumin loss. It culminated in hypovolemic shock despite a compensatory increase in cardiac ejection fraction. A characteristic cytokine storm included numerous pro-inflammatory cytokines and NO metabolites. Intriguingly, edema formation and terminal shock were abrogated in mice lacking inducible nitric oxide synthase (iNOS), while the cytokine storm persisted. iNOS was upregulated in the liver in a T cell- and IFN-gamma dependent fashion. Accordingly, blockade of IFN-gamma or depletion of T cells repressed hepatic iNOS and prevented disease despite unchecked high-level viremia.
We identify the IFN-gamma– iNOS axis as an essential and druggable molecular pathway to AHF-induced shock, demonstrating that a virus-induced cytokine storm can be mechanistically dissected to devise novel therapeutic approaches
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