The adaptive immune system based on T and B lymphocytes provides us with a marvellously variable and sophisticated defense against pathogens. However there is a price to be paid for the specificity and sophistication of the system and the price is - time. A system based on clonal selection and clonal expansion takes several days to get up and running and we cannot simply sit around doing nothing over this initial period. This temporal gap in our defences is covered by the so-called innate immune system. Innate immunity does not have access to the zillions of receptors available to the adaptive system but, being hard-wired, it is able to respond immediately to an infection. There is an impressive array of options open to the innate immune system ranging from the Toll Like Receptors which permit macrophages to rapidly detect invading pathogens, or the complement proteins which may intercept invading bacteria and viruses, to the deamination enzymes which provide an initial defense against retroviruses. These innate defense systems are essential to our ability to survive and if they are lost or impeded life tends to be short and unpleasant. However the protection afforded by these mechanisms is mediated by effector systems which, once activated may be hard to control. Thus, inadvertant activation of innate immunity can result in disease states which are no less serious than the autoimmune syndromes caused by inadvertant activation of the adaptive system. Indeed, just as the concept of innate and adaptive immunity as two separate stand-alone systems blurs, so it is becoming clear that in many disease situations elements of both systems contribute to the pathogenesis. In short, dysregulated activation of one system may in some cases spill over into a dysregulated activation of the other. This is almost certainly the case in the acute life threatening dysregulation associated with the systemic inflammatory syndrome variously referred to as septic or toxic shock. It is these dysregulative phenomena which form the core interest in the department.
Reaching an understanding of the complex phenomena lying at the root of the aetiology of acute immune dysfunction requires that we maintain a broad perspective. A forum has been established to meet this challenge. The DFG Graduierten Kolleg Host-Pathogen Interactions in Bacterial Infection" (Speaker: Professor B. Bröker) which is centred in the Immunology department, provides for constant intellectual cross fertilisation between the various groups in the University interested in infection biology.
Clinical research has by long tradition been bedevilled by a tendency for clinicians and scientist to talk past each other.
Building effective bridges between them has for years been a much vaunted goal in bio-medical research, but it is one which has seldom managed to advance beyond worthy resolutions by establishing itself in external reality. The "Sepsis" group provides this essential bridge and has rapidly become a central element in coordinating research into systemic inflammation within the University.
The Department consists of three small research groups whose interests all lie in trying to understand how the host´s response to bacterial challenge may under certain circumstances be counterproductive and lead to an acute immunological crisis.
Research group – Professor B. M. Bröker
- Superantigens of Staphylococcus aureus
S. aureus is frequently found as a persisting commensal bacterium in humans. Neverthless, it can also cause severe infections which may lead to sepsis and death, and this is especially worrisome since antibiotic resistant strains of S.aureus are becominig increasingly common. For these reasons it will be important to understand in detail the interactions of S.aureus with its human host.
Amongst the virulence factors produced by S.aureus are a set of exotoxins known as superantigens which are able to potently stimulate T-cells. This activation can itself lead to the syndrome of toxic shock and it is thought that it may also potentiate the induction of septic shock resulting from the activation of macrophages/monocytes with LPS and other bacterial products.In this study we wish to answer the following questions: How does the immune system of healthy individuals react to superantigens produced by commensal S.aureus?. Is there a difference in the immune response once the bacterium invades and causes disease?
Do superantigens in conjunction with LPS contribute to the symptoms of sepsis in vivo?
Cooperation: Dr. Susanne Engelmann, Prof. Michael Hecker (Department of Microbiology and Molecular Biology), Dr. Brigitte Panzig (Medizinische Mikrobiologie), and Dr. Kathleen Selleng and Prof. Andreas Greinacher (Department of Transfusion Medicine).
- Function of staphylococcal exotoxin-like proteins (Set)
Complete genome sequencing of S. aureus has revealed a large cluster of genes - the staphylococcal exotoxin-like genes (set) – which show homology to superantigen genes present on the staphylococcal pathogenicity island 2. The Set proteins encoded by these genes do not have superantigen activity and their function is as yet unknown. Nevertheless, since they are present in every S.aureus isolate so far tested, they would seem to have some important non-redundant function(s) . This project aims to define and characterise Set protein function. The Sets will be expressed in an LPS-free system and their effects on blood cells will be analysed using transcription profiling.
Cooperation: Dr. Susanne Engelmann, Prof. Michael Hecker (Department of Microbiology and Molecular Biology), Dr. Brigitte Panzig (Medizinische Mikrobiologie), and Prof. Uwe Völker (Department of Functional Genome Research).
- T cell function in murine peritonitis
T cells are centrally important both as regulators and as effectors of the adaptive immune response. They are generally thought of as being rather slow to respond and indeed in many situations an effective T cell response may take a week or more to develop. However, this is by no means always the case. Using an animal model of polymicrobial peritoniteal sepsis, we have demonstrated T cell activation within a time frame of just a few hours. In this project we will ask two questions. First, we wish to know what these cells are doing. We plan to address this question by defining their cytokine expression profile both by real time RCR and by intracellular cytokine staining. Second we wish know how the activation of these cells affects the development of the symptoms of sepsis. To this end we plan to manipulate T cell functions in this sepsis model by using appropriate gene deficient mice.
Cooperation: Prof. Claus-Dieter Heidecke, Dr. Stefan Maier, and many others from surgery.
Research group – Dr. R. Jack
- Monocyte activation after major trauma
Blood monocytes are sentinel cells of the innate immune system. To follow their activation during the development of systemic inflammation we have, in collaboration with Dr. M. Gründing (Department of Anesthesiology), established cDNA libraries from isolated blood monocytes of trauma patients. Many of these patients experience a transient systemic inflammation (SIRS) and around 15% suffer from severe sepsis or septic shock. We are using cDNA microarrays to define genes in the libraries which are upregulated in these patient groups and are assessing the relationship of the changing gene expression profile to the development of the inflammatory syndrome.
- Granulocyte activation after major trauma
Work on the analysis of monocyte activation after major trauma has demonstrated that while monocytes do rapidly respond to trauma they do not appear to contribute significantly to the pro-inflammatory mediators which are thought to sustain a systemic inflammatory response. For this reason we wish now to examine changes in the activation state of the second major inflammatory cell type in the blood – the granulocytes. In analogy to the work on monocytes outlined above, we intend to screen gene expression profiles of these cells from SIRS and from shock patients to identify syndrome associated activation states.
- T cell activation status in patients after major operations.
The T-cells of patients with an uneventful recovery after major operations are known to have a reduced capacity to respond to stmulation with mitogens in vitro. Together with the group of Professor Heidecke in the Department of Surgery, we are interested in defining what is happening in the T-cell compartment in such patients. To this end we are constructing cDNA banks from patients T cells and will carry out a microarray analysis of their gene expression profiles to define broad changes in their gene expression profiles and permit a molecular analysis of the nature of this transient T-cell inactivation.
- Conditional IL-10 receptor ko mouse.
IL-10 is a regulatory cytokine which plays important roles both in the innate and in the adaptive immune response. To allow for an analysis of the molecular and cellular basis of its regulatory activities, we have used the cre-loxP approach to generate conditional IL-10 receptor ko animals. In collaboration with groups in Paris, Berlin and Braunschweig we are now starting to analyse the mutant line for its role in anergy induction in T-cells, in B cells and in macrophages.
