Centrum für Chronische Immundefizienz - CCI

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.