Zu den Inhalten springen

Centrum für Chronische Immundefizienz - CCI

Research Group „Human T-cell immunodeficiency“

Prof. Dr. Stephan Ehl

The research group „Human T-cell immunodeficiency“ works at the interface of clinical and basic research with a focus on human T cell immunity. The research projects encompass the whole spectrum of translational research from the identification and characterization of novel gene defects followed by pathophysiological studies in mouse models and human patients to the development of novel diagnostic tools and using this basic knowledge in the design of international treatment trials.

CV

seit 2015Sprecher SFB1160 "IMPATH"
seit 2012Medizinischer Direktor des Centrum für Chronische Immundefizienz
2008-2012Wissenschaftlicher Direktor des Centrum für Chronische Immundefizienz
2003 Habilitation in Pädiatrie
seit 2002 Oberarzt, Universitäts-Kinderklinik Freiburg
1998-2002 Assistenzarzt, Universitäts-Kinderklinik Freiburg
1995-1997Post-Doc, Institut für Experimentelle Immunologie, Universität Zürich
1994-1995Postgraduate Course für Experimentelle Medizin und Biologie, Universität Zürich
1993-1994Assistenzarzt, Universitäts-Kinderklinik Ulm
1985-1991Medizinstudium in Aachen, Erlangen und München

Research Areas

T cell immunity is important for the control of most infections. A successful T cell response involves antigen recognition, cellular activation and differentiation, rapid expansion and exertion of eff ector functions. These potent and highly dynamic processes must be tightly regulated in order to avoid inappropriate or uncontrolled infl ammatory responses. Human genetic diseases provide a fascinating window to understand T cell immunity and its relevance for the control of infectious diseases as well as for diseases of immune dysregulation.  

The research group „Genetic deficiencies of human T cell immunity“ works at the interface between clinical and basic immunology with a particular focus on T cell immunity. The research activities cover a large spectrum from basic research in animal models or the identifi cation of new genetic defects to international diagnostic and clinical studies. The group integrates both physicians and basic scientists.  

We study three immunodeficiency states representing models for different aspects of T cell immunity:

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.

TCR-Spectratyping by P. Fisch

Summary

Combined immunodeficiency (CID) is the phenotypic presentation of a large number of genetic disorders of the immune system. Clinical manifestations include a wide range of infectious diseases including persistent viral and opportunistic infections and manifestations of impaired immune regulation such as autoimmunity, eczema, granulomas or infl ammatory bowel disease. The common immunological abnormality is impaired T cell immunity, but other immune and epithelial cells can also be affected. The study of CID offers a unique opportunity to understand the limiting factors of protective T cell immunity. We approach this problem by the study of individual patients, patient cohorts and mouse models. To transfer this knowledge to patient care, a prospective clinical study has been initiated to better define the threshold when stem cell transplantation should be performed in affected patients.  

In the laboratory, we perform a careful phenotypic and functional immunological analysis. In some cases, we identify mutations in known genes and can then analyze the consequence of specific mutations for protein and cellular immune function. In other cases, we use functional assays in combination with exome sequencing (collaboration with Klaus Schwarz, Ulm) to elucidate novel genetic causes for CID. These findings are related to the particular clinical phenotypes with the goal to better understand infection control and immune regulation in humans. We also use mouse models of “leaky” SCID that show features of infection susceptibility and immune dysregulation similar to human patients. In particular, we study T cell development and differentiation and T cell mediated control of viral infections. The overall goal is to understand how human T cell immunity works under limiting conditions.

Methods

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

Cooperations                         

  • Paul Fisch, Molekulare Pathologie, Pathologisches Instituts, Uniklinik Freiburg
  • Klaus Schwarz, Institut für Transfusionsmedizin, Universität Ulm
  • Wolfgang Schamel, Institute of Biology III, Universität Freiburg           
  • Alessandro Aiuti, Milano, Italy
  • Despina Moshous, Capucine Picard, Institute Imagine, Paris, France                                               

Funding

  • BMBF: CCI Professorship Pediatric Immunology (2013-2018)
  • DFG: Genetic, immunologic and phenotypic variability of combined immunodeficiencies (2014-2017)
  • DFG: Euro-CID – Non-SCID combined immunodeficiencies (2016-2019)  

Publications

  • Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency. Fuchs S, Rensing-Ehl A, Pannicke U, Lorenz MR, Fisch P, Jeelall Y, Rohr J, Speckmann C, Vraetz T, Farmand S, Schmitt-Graeff A, Krüger M, Strahm B, Henneke P, Enders A, Horikawa K, Goodnow C, Schwarz K, Ehl S. Blood. 2015 Oct 1;126(14):1658-69.
  • Deficiency of innate and acquired immunity caused by an IKBKB mutation. Pannicke U, Baumann B, Fuchs S, Henneke P, Rensing-Ehl A, Rizzi M, Janda A, Hese K, Schlesier M, Holzmann K, Borte S, Laux C, Rump EM, Rosenberg A, Zelinski T, Schrezenmeier H, Wirth T, Ehl S*, Schroeder ML*, Schwarz K*. (equal contribution) N Engl J Med. 2013 Dec 26;369(26):2504-14.
  • 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.
  • Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency. Speckmann C, Pannicke U, Wiech E, Schwarz K, Fisch P, Friedrich W, Niehues T, Gilmour K, Buiting K, Schlesier M, Eibel H, Rohr J, Superti-Furga A, Gross-Wieltsch U, Ehl S. Blood. 2008 Nov 15;112(10):4090-7.
  • A variant of SCID with specific immune responses and predominance of gamma delta T cells. Ehl S, Schwarz K, Enders A, Duffner U, Pannicke U, Kühr J, Mascart F, Schmitt-Graeff A, Niemeyer C, Fisch P. J Clin Invest. 2005 Nov;115(11):3140-8.

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

Summary

The phenotype of benign lymphoproliferation and autoimmunity, in particular autoimmune cytopenia, is observed in a number of primary immunodeficiencies. The most prevalent disorder is autoimmune lymphoproliferative syndrome (ALPS), which is mostly associated with germline or somatic mutations in CD95. CD95 is involved in lymphocyte apoptosis, but has also additional non-apoptotic signaling functions. We investigate the pathophysiological basis of impaired T cell homeostasis in human ALPS by a combination of genetic, phenotypic and functional investigations.  

In the last years, new diseases associated with lymphoproliferation and autoimmunity have been discovered. This includes APDS (PIK3CD; PIK3R1), CTLA-4 deficiency or activating mutations in STAT1, STAT3, RAS-pathway associated genes or CARD11 (autosomal-dominant) and LRBA, TPP2, ADA2 or PRKCD deficiency (autosomal-recessive). A number of these conditions affect signalling pathways and metabolic programming of T cells, offering interesting insights into human T cell biology and attractive options for novel therapies.  

We have recruited a unique cohort of 296 children (Feb 2016) referred for ALPS evaluation, for which we have clinical data and variable immune phenotyping. While 72 patients have ALPS and various molecular diagnoses were established in another 23 patients, 201 patients remain without genetic diagnosis. Using next generation sequencing, we will try to identify new genetic diseases of T cell homeostasis, complemented by in-depth phenotypic and functional immune cell analysis. Candidate genes will be validated by appropriate genetic reconstitution experiments and other studies.

Methods

  • Flow cytometry
  • Functional immune cell analysis
  • Cell culture
  • RNA seq
  • Genetic manipulation of human T cells
  • Metabolic studies

Collaborations

  • Klaus Schwarz, Institut für Transfusionsmedizin, Ulm, Germany
  • Andreas Mackensen, Erlangen, Germany
  • Frederic Rieux-Laucat, Institut Imagine, Paris, France
  • Sven Kracker, Institut Imagine, Paris, France

Funding

  • BMBF: PID-NET consortium „Genetic and immunological variability in patients with autoimmunity and lymphoproliferation.“ (2015-2018)
  • Industry: translational research agreement with UCB

Publications

  • Gray platelet syndrome can mimic autoimmune lymphoproliferative syndrome. Rensing-Ehl A, Pannicke U, Zimmermann SY, Lorenz MR, Neven B, Fuchs I, Salzer U, Speckmann C, Strauss A, Maaβ E, Collet B, Enders A, Favier R, Alessi MC, Rieux-Laucat F, Zieger B, Schwarz K, Ehl S. Blood. 2015 Oct 15;126(16):1967-9.
  • Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency.Stepensky P, Rensing-Ehl A, Gather R, Revel-Vilk S, Fischer U, Nabhani S, Beier F, Brümmendorf TH, Fuchs S, Zenke S, Firat E, Pessach VM, Borkhardt A, Rakhmanov M, Keller B, Warnatz K, Eibel H, Niedermann G, Elpeleg O, Ehl S. Blood. 2015 Jan 29;125(5):753-61.
  • Abnormally differentiated CD4+ or CD8+ T cells with phenotypic and genetic features of double negative T cells in human Fas deficiency. Rensing-Ehl A, Völkl S, Speckmann C, Lorenz MR, Ritter J, Janda A, Abinun M, Pircher H, Bengsch B, Thimme R, Fuchs I, Ammann S, Allgäuer A, Kentouche K, Cant A, Hambleton S, Bettoni da Cunha C, Huetker S, Kühnle I, Pekrun A, Seidel MG, Hummel M, Mackensen A, Schwarz K, Ehl S. Blood. 2014 Aug 7;124(6):851-60.
  • Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia. Rensing-Ehl A, Janda A, Lorenz MR, Gladstone BP, Fuchs I, Abinun M, Albert M, Butler K, Cant A, Cseh AM, Ebinger M, Goldacker S, Hambleton S, Hebart H, Houet L, Kentouche K, Kühnle I, Lehmberg K, Mejstrikova E, Niemeyer C, Minkov M, Neth O, Dückers G, Owens S, Rösler J, Schilling FH, Schuster V, Seidel MG, Smisek P, Sukova M, Svec P, Wiesel T, Gathmann B, Schwarz K, Vach W, Ehl S, Speckmann C. Haematologica. 2013 Dec;98(12):1948-55.

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

Publications

PubMed

Team

Group Leader
Stephan Ehlstephan.ehl@uniklinik-freiburg.de270-77300

Independent Junior Group Leader
Jan Rohrjan.rohr@uniklinik-freiburg.de270-43090


Office

Simone Schruhlsimone.schruhl@uniklinik-freiburg.de270-77550


Research Coordinator (SFB1160)


Heike Ufheilheike.ufheil@uniklinik-freiburg.de270-71020
www.sfb1160.uni-freiburg.de

Post-Docs
Carla Castrocarla.noemi.castro@uniklinik-freiburg.de270-71120
Sabine Jäglesabine.jaegle@uniklinik-freiburg.de270-71080
Anne Rensing-Ehlanne.rensing-ehl@uniklinik-freiburg.de270-71080

PhD Students
Julia Braunjulia.braun@uniklinik-freiburg.de203-6647
Miriam Großmiriam.gross@uniklinik-freiburg.de270-71080
Patrick Kurypatrick.kury@uniklinik-freiburg.de270-77724
Simon Zenkesimon.zenke@uniklinik-freiburg.de203-6550


MCs Students

Lara Althaus lara.althaus@uniklinik-freiburg.de270-71120
Sarah Grünsarah.gruen@uniklinik-freiburg.de270-77724

MD Students
Sarah Schlaffer sarah.schlaffer@uniklinik-freiburg.de203-6550
Contact

Prof. Dr. med. Stephan Ehl

MEDICAL CENTER - UNIVERSITY OF FREIBURG
Center for Chronic Immunodeficiency
at Center for Translational Cell Research

Breisacher Str. 115
79106 Freiburg
Germany

Phone: +49 (0)761 270-77550 (Secretary)
Fax: +49 (0)761 270-77600
stephan.ehl@uniklinik-freiburg.de