Robert S. Jack
University of Cologne
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Featured researches published by Robert S. Jack.
Nature | 1997
Robert S. Jack; Xiaolong Fan; Martin Bernheiden; Gabriele Rune; Monika Ehlers; Albert Weber; Gerhard Kirsch; Renate Mentel; Birgit Fürll; Marina A. Freudenberg; Gerd Schmitz; Felix Stelter; Christine Schütt
An invading pathogen must be held in check by the innate immune system until a specific immune response can be mounted. In the case of Gram-negative bacteria, the principal stimulator of the innate immune system is lipopolysaccharide (LPS), a component of the bacterial outer membrane. In vitro, LPS is bound by lipopolysaccharide-binding protein (LBP) and transferred to CD14—the LPS receptor on the macrophage surface,—or to high-density lipoprotein (HDL) particles,. Transfer to CD14 triggers an inflammatory response which is crucial for keeping an infection under control. Here we investigate how LBP functions in vivo by using LBP-deficient mice. Surprisingly, we find that LBP is not required in vivo for the clearance of LPS from thecirculation, but is essential for the rapid induction of an inflammatory response by small amounts of LPS or Gram-negative bacteria and for survival of an intraperitoneal Salmonella infection.
Infection and Immunity | 2001
Bernd Echtenacher; Marina A. Freudenberg; Robert S. Jack; Daniela N. Männel
ABSTRACT Loss, reduction, or enhancement of the ability to respond to bacterial lipopolysaccharide (LPS) has no influence on survival of mice in a model of postoperative polymicrobial septic peritonitis induced by cecal ligation and puncture (CLP). This was demonstrated by using either mice with a defective Tlr4 gene, which encodes the critical receptor molecule for LPS responses, or mice deficient for LPS binding protein (LBP) or mice sensitized to LPS byPropionibacterium acnes. Though interleukin-12 (IL-12) and gamma interferon (IFN-γ) play an important role in the sensitivity to LPS as well as in the resistance to several infections, loss of these cytokine pathways does not affect survival after CLP. Thus, neutralization of neither endogenous IL-12 nor IFN-γ altered mortality. In addition, IFN-γ receptor-deficient mice demonstrated the same sensitivity to CLP as mice with a functional IFN-γ receptor. However, administration of IFN-γ at the time of operation or pretreatment of both IFN-γ-sensitive and IFN-γ-resistant mice with IL-12 significantly enhanced mortality. This indicates that in the present infection model activation of innate defense mechanisms is not dependent on LPS recognition and does not require endogenous IL-12 or IFN-γ function. Indeed, exogenous application of these two mediators had deleterious effects.
Journal of Immunology | 2001
Jan-Michael Heinrich; Martin Bernheiden; Gabriela Minigo; Kang Kang Yang; Christine Schütt; Daniela N. Männel; Robert S. Jack
Acute and chronic hyperinflammation are of major clinical concern, and many treatment strategies are therefore directed to inactivating parts of the inflammatory system. However, survival depends on responding quickly to pathogen attack, and since the adaptive immune system requires several days to adequately react, we rely initially on a range of innate defenses, many of which operate by activating parts of the inflammatory network. For example, LPS-binding protein (LBP) can transfer the LPS of Gram-negative bacteria to CD14 on the surface of macrophages, and this initiates an inflammatory reaction. However, the importance of this chain of events in infection is unclear. First, the innate system is redundant, and bacteria have many components that may serve as targets for it. Second, LBP can transfer LPS to other acceptors that do not induce inflammation. In this study, we show that innate defense against a lethal peritoneal infection with Salmonella requires a direct proinflammatory involvement of LBP, and that this is a major nonredundant function of LBP in this infection model. This emphasizes that blocking the LBP-initiated inflammatory cascade disables an essential defense pathway. Any anti-inflammatory protection that may be achieved must be balanced against the risks inherent in blinding the innate system to the presence of Gram-negative pathogens.
Gut | 2008
Mandy Busse; Tobias Traeger; Christian Pötschke; Anja Billing; Annegret Dummer; Erika Friebe; Cornelia Kiank; Uwe Grunwald; Robert S. Jack; Christine Schütt; Claus-Dieter Heidecke; Stefan Maier; Barbara M. Bröker
Background: Abdominal sepsis due to intestinal leakage of endogenous gut bacteria is a life-threatening condition. In healthy individuals, T lymphocytes have essential functions in balancing the immune response to the commensal gut flora. Aim: To determine how T lymphocytes shape the process of diffuse faecal peritonitis. Methods: In colon ascendens stent peritonitis (CASP), a clinically relevant mouse model of diffuse peritonitis, the kinetics of systemic T cell activation were investigated by assessment of activation markers. CD4+ T cells were then depleted with monoclonal antibodies, and survival, bacterial dissemination and cytokine concentrations were measured. T cell receptor signalling was blocked with tacrolimus. Results: In diffuse peritonitis, CD4+ T cells, both Foxp3− and Foxp3+, became systemically involved within hours and upregulated CTLA-4 and other activation markers. Depletion of the CD4+ T cells enhanced local bacterial clearance from the peritoneal cavity, reduced bacterial dissemination and improved survival. This was accompanied by increased immigration of granulocytes and macrophages into the peritoneum, indicating that CD4+ T cells inhibit the local innate immune response. Blockade of T cell receptor (TCR) signalling by tacrolimus did not influence the survival in this peritonitis model, showing that the inhibitory effects of the CD4+ T lymphocytes were independent of TCR-mediated antigen recognition. Conclusion: In diffuse peritonitis caused by commensal gut bacteria the CD4+ T lymphocytes exert a net negative effect on the local anti-bacterial defence, and thereby contribute to bacterial dissemination and poor outcome.
Biochemical and Biophysical Research Communications | 1990
Robert S. Jack
A sequence specific DNA binding protein has been demonstrated in extracts of Drosophila melanogaster third instar larval nuclei which binds close to a chromosome-scaffold associated region. This protein has proven difficult to work with because of its strong tendency to aggregate. Here I show that the protein can be readily maintained in solution in the presence of high concentrations of urea. Surprisingly, the protein turns out to be remarkably resistant to denaturation by urea. It is capable of mediating sequence specific DNA binding in the presence of urea at concentrations up to 8M. When incubated in 4M urea the binding activity appears to slowly degrade, but in 1.3M urea the protein is active, soluble and stable over extended periods of time at room temperature. The molecular basis of this unexpected finding must await the purification of the protein. The ability to keep the protein both soluble and active should now permit its isolation.
European Journal of Immunology | 1977
Robert S. Jack; Thereza Imanishi-Kari; Klaus Rajewsky
FEBS Journal | 1997
Felix Stelter; Martin Bernheiden; René Menzel; Robert S. Jack; Sabine Witt; Xiaolong Fan; Martin Pfister; Christine Schütt
European Journal of Immunology | 1977
Ulrich Krawinkel; Matthias Cramer; Thereza Imanishi-Kari; Robert S. Jack; K. Rajewsky; O. Mäkelä
FEBS Journal | 1992
Robert S. Jack; Harald Eggert
European Journal of Immunology | 1995
Robert S. Jack; Uwe Grunwald; Felix Stelter; Grefachew Workalemahu; Christine Schütt