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 S, Rensing-Ehl A, Erlacher M, Vraetz T, Hartjes L, Janda A, Rizzi M, Lorenz MR, Gilmour K, de Saint-Basile G, Roifman CM, Cheuk S, Gennery A, Thrasher AJ, Fuchs I, Schwarz K, Speckmann C, Ehl S
  (See online at https://doi.org/10.1002/eji.201444689)
• Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency. Blood. 2015 Jan 29;125(5):753-61
  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
  (See online at https://doi.org/10.1182/blood-2014-08-593202)
• 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 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
  (See online at https://doi.org/10.1182/blood-2015-03-631374)
• 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 C, Doerken S, Aiuti A, Albert MH, Al-Herz W, Allende LM, Scarselli A, Avcin T, Perez-Becker R, Cancrini C, Cant A, Di Cesare S, Finocchi A, Fischer A, Gaspar HB, Ghosh S, Gennery A, Gilmour K, González-Granado LI, Martinez-Gallo M, Hambleton S, Hauck F, Hoenig M, Moshous D, Neven B, Niehues T, Notarangelo L, Picard C, Rieber N, Schulz A, Schwarz K, Seidel MG, Soler-Palacin P, Stepensky P, Strahm B, Vraetz T, Warnatz K25, Winterhalter C, Worth A, Fuchs S, Uhlmann A, Ehl S
  (See online at https://doi.org/10.1016/j.jaci.2016.07.040)
• 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 P, Keller B, Shamriz O, von Spee-Mayer C, Friedmann D, Shadur B, Unger S, Fuchs S, NaserEddin A, Rumman N, Amro S, Molho Pessach V, Abuzaitoun O, Somech R, Elpeleg O, Ehl S, Warnatz K
  (See online at https://doi.org/10.1007/s10875-018-0514-y)
• 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 B, Stinson JR, Ma CA, Weinreich MA, Miraghazadeh B, Hartberger JM, Frey- Jakobs S, Weidinger S, Moebus L, Franke A, Schäffer AA, Bulashevska A, Fuchs S, Ehl S, Limaye S, Arkwright PD, Briggs TA, Langley C, Bethune C, Whyte AF, Alachkar H, Nejentsev S, DiMaggio T, Nelson CG, Stone KD, Nason M, Brittain EH, Oler AJ, Veltri DP, Leahy TR, Conlon N, Poli MC, Borzutzky A, Cohen JI, Davis J, Lambert MP, Romberg N, Sullivan KE, Paris K, Freeman AF, Lucas L, Chandrakasan S, Savic S, Hambleton S, Patel SY, Jordan MB, Theos A, Lebensburger J, Atkinson TP, Torgerson TR, Chinn IK, Milner JD, Grimbacher B, Cook MC, Snow AL
  (See online at https://doi.org/10.1016/j.jaci.2018.08.013)
• Increased proportions of γδ T lymphocytes in atypical SCID associate with disease manifestations. Clin Immunol. 2019 Apr;201:30-34
  Tometten I, Felgentreff K, Hönig M, Hauck F, Albert MH, Niehues T, Perez R, Ghosh S, Picard C, Stary J, Formankova R, Worth A, Soler-Palacín P, García-Prat M, Allende LM, Gonzalez-Granado LI, Stepensky P, Di Cesare S, Scarselli A, Cancrini C, Speckmann C, Gilmour K, Notarangelo L, Ehl S, Rohr JC
  (See online at https://doi.org/10.1016/j.clim.2018.11.006)