Centrum für Chronische Immundefizienz - CCI

Summary

Familial hemophagocytic lymphohistiocytosis (FHL) is one of the most dramatic and life-threatening human inflammatory diseases characterized by prolonged fever, cytopenia, splenomegaly, liver dysfunction, and hemophagocytosis. Most cases of FHL are due to genetic defects in perforin or other genes involved in lymphocyte cytotoxicity. In about 10% of patients with FHL, the genetic basis of the disease remains unresolved.  

As a diagnostic reference center, we provide functional immunological evaluation for all HLH patients from German speaking countries. In extension of these diagnostic studies, we characterize the T cell and macrophage response in HLH to better understand the pathophysiological basis of the disease. Patients without a genetic diagnosis are evaluated by whole exome sequencing for novel genetic causes. Patients with HLH offer a unique opportunity to study the molecular regulation of lymphocyte cytotoxicity and intracellular vesicle trafficking. To translate our findings back into clinical application, we have set up an international registry and a clinical study platform for experimental treatment studies on HLH (TREAT-HLH) in collaboration with G. Janka and K. Lehmberg (Hamburg).  

We have also established an HLH mouse model based on infection of perforin- or MUNC13-deficient mice with lymphocytic choriomeningitis virus (LCMV) or murine cytomegalovirus (MCMV) to address the following questions:

• Which initial triggers are required for the induction of HLH?
• What is the relevance of persisting antigen for HLH?
• Which cell types and cytokines drive the disease?

Together with Toni Cathomen (CCI), we are using observations in human patients and in MUNC13 deficient mice to prepare gene therapy for human patients with FHL.  

Methods

• Flow cytometry
• Functional immune cell analysis
• Signalling studies
• Protein studies
• Fluorescence microscopy
• Cell culture
• Interpretation of genome/exome data
• Genetic manipulation of human T cells
• Mouse models  

Cooperations

• Gritta Janka-Schaub, Kai Lehmberg, Udo zur Stadt, Pädiatrische Hämatologie und Onkologie, Uniklinik Hamburg-Eppendorf        
• Peter Aichele, Department für Medizinische Mikrobiologie und Hygiene, Uniklinik Freiburg
• Annette Schmitt-Gräff, Institut für klinische Pathologie, Uniklinik Freiburg
• Toni Cathomen, CCI Freiburg
• Despina Moshous, Institute Imagine, Paris, France
• Bobby Gaspar, Claire Booth, Great Ormond Street Hospital, London, UK
• Gillian Griffiths, University of Cambridge, UK
• Yenan Bryceson, Karolinska Institute, Stockholm, Sweden
• Michael Maschan, Department of hematopoietic stem cell transplantation, Dmitriy Rogachev Federal center for pediatric hematology, oncology and immunology, Moscow, Russia

Funding

• DFG: SFB1160, TP 1 (2015-2019)
• DFG: SFB1160, TP17 (2015-2019)
• BMBF: scientific collaboration programme with Russia (2015-2017)     

Publications

• Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome. Ammann S, Schulz A, Krägeloh-Mann I, Dieckmann NM, Niethammer K, Fuchs S, Eckl KM, Plank R, Werner R, Altmüller J, Thiele H, Nürnberg P, Bank J, Srauss A, von Bernuth H, Zur Stadt U, Grieve S, Griffiths GM, Lehmberg K, Hennies HC, Ehl S. Blood. 2016 Jan 7.
• The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis. Bode SF, Ammann S, Al-Herz W, Bataneant M, Dvorak CC, Gehring S, Gennery A, Gilmour KC, Gonzalez-Granado LI, Groß-Wieltsch U, Ifversen M, Lingman-Framme J, Matthes-Martin S, Mesters R, Meyts I, van Montfrans JM, Pachlopnik Schmid J, Pai SY, Soler-Palacin P, Schuermann U, Schuster V, Seidel MG, Speckmann C, Stepensky P, Sykora KW, Tesi B, Vraetz T, Waruiru C, Bryceson YT, Moshous D, Lehmberg K, Jordan MB, Ehl S; Inborn Errors Working Party of the EBMT. Haematologica. 2015 Jul;100(7):978-88.
• Translating the genomic revolution - targeted genome editing in primates. Cathomen T, Ehl S. N Engl J Med. 2014 Jun 12;370(24):2342-5.
• The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2. Jessen B, Bode SF, Ammann S, Chakravorty S, Davies G, Diestelhorst J, Frei-Jones M, Gahl WA, Gochuico BR, Griese M, Griffiths G, Janka G, Klein C, Kögl T, Kurnik K, Lehmberg K, Maul-Pavicic A, Mumford AD, Pace D, Parvaneh N, Rezaei N, de Saint Basile G, Schmitt-Graeff A, Schwarz K, Karasu GT, Zieger B, Zur Stadt U, Aichele P, Ehl S. Blood. 2013 Apr 11;121(15):2943-51.
• A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Bryceson YT, Pende D, Maul-Pavicic A, Gilmour KC, Ufheil H, Vraetz T, Chiang SC, Marcenaro S, Meazza R, Bondzio I, Walshe D, Janka G, Lehmberg K, Beutel K, zur Stadt U, Binder N, Arico M, Moretta L, Henter JI, Ehl S. Blood. 2012 Mar 22;119(12):2754-63.  
• Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome. Jessen B, Maul-Pavicic A, Ufheil H, Vraetz T, Enders A, Lehmberg K, Längler A, Gross-Wieltsch U, Bay A, Kaya Z, Bryceson YT, Koscielniak E, Badawy S, Davies G, Hufnagel M, Schmitt-Graeff A, Aichele P, Zur Stadt U, Schwarz K, Ehl S. Blood. 2011 Oct 27;118(17):4620-9.
• ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis. Maul-Pavicic A, Chiang SC, Rensing-Ehl A, Jessen B, Fauriat C, Wood SM, Sjöqvist S, Hufnagel M, Schulze I, Bass T, Schamel WW, Fuchs S, Pircher H, McCarl CA, Mikoshiba K, Schwarz K, Feske S, Bryceson YT, Ehl S. Proc Natl Acad Sci U S A. 2011 Feb 22;108(8):3324-9.
• Lethal hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type II. Enders A, Zieger B, Schwarz K, Yoshimi A, Speckmann C, Knoepfle EM, Kontny U, Müller C, Nurden A, Rohr J, Henschen M, Pannicke U, Niemeyer C, Nurden P, Ehl S. Blood. 2006 Jul 1;108(1):81-7.

For an up-to-date list of publications by Prof. Stephan Ehl please see the PubMed search.