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FHL / HLH - Pathogenesis and diagnosis of familial hemophagocytic lymphohistiocytosis
Summary
Familial haemophagocytic lymphohistiocytosis (FHL) is a rare primary immunodeficiency which is fatal without treatment. The disease is characterised by a severe disturbance of immune homeostasis. Most cases of FHL are due to genetic defects in Perforin or in other genes involved in cellular cytotoxicity by NK cells or cytotoxic T cells. The hemophagocytic syndrome (HLH) frequently develops in the context of infections. The pathogenesis of this disease remains poorly understood. However, this is an important prerequisite for development of targeted immunological therapies.
We have established the HLH mouse model based on infection of perforin-deficient mice with lymphocytic choriomeningitis virus to adress the following questions:
(i) Which initial triggers are required for the induction of HLH?
(ii) Which pathogens can initiate HLH in mice and through which particular properties?
(iii) What is the relevance of persisting antigen fort he pathogenesis of HLH?
(iv) What is the impact of the frequency of antigen-specific T cells?
(v) How do different genetic defects of cytotoxicity influence the threshhold for induction of HLH?
In the context of a European research initiative (Cure-HLH) we have established a novel diagnostic algroithm for patients with HLH that includes perforin staining and analysis of degranulation and cytotoxicity by NK cells and CTL, that is currently prospectively evaluated. In collaboration with the German HLH registry in Hamburg, we provide the functional immunological analysis for HLH patients from German speaking countries. On the basis of these diagnostic studies, we identify novel biomarkers for HLH activity. We also perform extensive phenotypic and functional analysis and establish cell lines for functional reconstitution experiments for the 20-30% of patients where the genetic defect remains to be identified.
Cooperation Partners
- Gritta Janka-Schaub, Pädiatrische Hämatologie und Onkologie, Uniklinik Hamburg-Eppendorf
- Charlotte Niemeyer, Brigitte Strahm - Pädiatrische Hämatologie und Onkologie, Uniklinik Freiburg
- EU Cure-HLH-Consortium
- Peter Aichele, Immunologie, Institut für Medizinische Mikrobiologie und Hygiene, Uniklinik Freiburg
- Andreas Diefenbach, Mikrobiologie, Institut für Medizinische Mikrobiologie und Hygiene, Uniklinik Freiburg
- Annette Schmitt-Gräff, Pathologisches Institut, Uniklinik Freiburg
Funding
Cure HLH Consortium, European Union, Seventh Research Framework Programme
Thyssen-Stiftung
"Pathogenese und Therapie der hämaphagozytischen Lymphohistiozytose im Mausmodell und beim Menschen"
Publications
For an up-to-date list of publications by Prof. Stephan Ehl please see the PubMed search:
