Combined immunodeficiencies - understanding the limiting factors in T cell mediated control of viral infections and immune homeostasis.

• Applicants: Professor Dr. Stephan Ehl; Dr. Klaus Schwarz
• Subject Area: Immunology ; Pediatric and Adolescent Medicine
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260998172

• Final Report Year: 2019

Final Report Abstract

This project proposed to study individual patients and patient cohorts with CID and analyze mouse models of human CID to better define the limiting factors for T cell mediated control of infections and of immune homeostasis. For this endeavor two approaches were implemented: Analysis of the phenotypic and functional basis of combined immunodeficiency and Identification of genetic defects causing combined immunodeficiency. CID patients frequently present with elevated proportions of γδ T lymphocytes. Increased γδ T lymphocytes were present in approximately 60% of patients with “leaky SCID”, a genetically defined subgroup of CID. Elevated proportions of γδ T cells and the occurrence of CMV infections and autoimmune cytopenias correlated, suggesting that CMV infections might trigger an expansion of γδ T lymphocytes, which could drive the development of autoimmune disease. We further characterized the consequences of one particular "leaky" X-SCID mutation that leads to an unusually severe phenotype despite near-normal T cell numbers. A detailed analysis of T, B, and NK cells, including quantitative STAT phosphorylation and functional responses to the cytokines IL-2, IL-4, IL-15, and IL-21 in one patient with the IL2RG(R222C) mutation exhibited a differential impact of IL2RG(R222C) on cytokine signal transduction, with a gradient IL-4

Publications

• Patients with T⁺/low NK⁺ IL-2 receptor γ chain deficiency have differentially-impaired cytokine signaling resulting in severe combined immunodeficiency. Eur J Immunol. 2014 Oct;44(10):3129-40
  Fuchs, Sebastian; Rensing‐Ehl, Anne; Erlacher, Miriam; Vraetz, Thomas; Hartjes, Lara; Janda, Ales; Rizzi, Marta; Lorenz, Myriam R.; Gilmour, Kimberly; de Saint‐Basile, Geneviève; Roifman, Chaim M.; Cheuk, Steven; Gennery, Andrew; Thrasher, Adrian J.; Fuchs, Ilka; Schwarz, Klaus; Speckmann, Carsten & Ehl, Stephan
  
• Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency. Blood. 2015 Jan 29;125(5):753-61
  Stepensky, Polina; Rensing-Ehl, Anne; Gather, Ruth; Revel-Vilk, Shoshana; Fischer, Ute; Nabhani, Schafiq; Beier, Fabian; Brümmendorf, Tim H.; Fuchs, Sebastian; Zenke, Simon; Firat, Elke; Pessach, Vered Molho; Borkhardt, Arndt; Rakhmanov, Mirzokhid; Keller, Bärbel; Warnatz, Klaus; Eibel, Hermann; Niedermann, Gabriele; Elpeleg, Orly; ... & Ehl, Stephan
  
• Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency Blood. 2015 Oct 1;126(14):1658-69
  Fuchs, Sebastian; Rensing-Ehl, Anne; Pannicke, Ulrich; Lorenz, Myriam R.; Fisch, Paul; Jeelall, Yogesh; Rohr, Jan; Speckmann, Carsten; Vraetz, Thomas; Farmand, Susan; Schmitt-Graeff, Annette; Krüger, Marcus; Strahm, Brigitte; Henneke, Philipp; Enders, Anselm; Horikawa, Keisuke; Goodnow, Christopher; Schwarz, Klaus & Ehl, Stephan
  
• P-CID study of the Inborn Errors Working Party of the EBMT A prospective study on the natural history of patients with profound combined immunodeficiency: An interim analysis. J Allergy Clin Immunol. 2017 Apr;139(4):1302-1310.e4
  Speckmann, Carsten; Doerken, Sam; Aiuti, Alessandro; Albert, Michael H.; Al-Herz, Waleed; Allende, Luis M.; Scarselli, Alessia; Avcin, Tadej; Perez-Becker, Ruy; Cancrini, Caterina; Cant, Andrew; Di Cesare, Silvia; Finocchi, Andrea; Fischer, Alain; Gaspar, H. Bobby; Ghosh, Sujal; Gennery, Andrew; Gilmour, Kimberly; González-Granado, Luis I.; ... & Ehl, Stephan
  
• T+ NK+ IL-2 Receptor γ Chain Mutation: a Challenging Diagnosis of Atypical Severe Combined Immunodeficiency. J Clin Immunol. 2018 May;38(4):527-536
  Stepensky, Polina; Keller, Baerbel; Shamriz, Oded; von Spee-Mayer, Caroline; Friedmann, David; Shadur, Bella; Unger, Susanne; Fuchs, Sebastian; NaserEddin, Adeeb; Rumman, Nisreen; Amro, Sara; Molho Pessach, Vered; Abuzaitoun, Omar; Somech, Raz; Elpeleg, Orly; Ehl, Stephan & Warnatz, Klaus
  
• Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease. J Allergy Clin Immunol. 2019 Apr;143(4):1482-1495
  Dorjbal, Batsukh; Stinson, Jeffrey R.; Ma, Chi A.; Weinreich, Michael A.; Miraghazadeh, Bahar; Hartberger, Julia M.; Frey-Jakobs, Stefanie; Weidinger, Stephan; Moebus, Lena; Franke, Andre; Schäffer, Alejandro A.; Bulashevska, Alla; Fuchs, Sebastian; Ehl, Stephan; Limaye, Sandhya; Arkwright, Peter D.; Briggs, Tracy A.; Langley, Claire; Bethune, Claire; ... & Snow, Andrew L.
  
• Increased proportions of γδ T lymphocytes in atypical SCID associate with disease manifestations. Clin Immunol. 2019 Apr;201:30-34
  Tometten, Inga; Felgentreff, Kerstin; Hönig, Manfred; Hauck, Fabian; Albert, Michael H.; Niehues, Tim; Perez, Ruy; Ghosh, Sujal; Picard, Capucine; Stary, Jan; Formankova, Renata; Worth, Austen; Soler-Palacín, Pere; García-Prat, Marina; Allende, Luis M.; Gonzalez-Granado, Luis Ignacio; Stepensky, Polina; Di Cesare, Silvia; Scarselli, Alessia; ... & Rohr, Jan C.