We study three immunodeficiency states representing models for different aspects of T cell immunity:
- Hemophagocytic Lymphohistiocytosis (HLH)
- Profound Combined Immunodeficiencies (P-CID)
- Autoimmune-lymphoproliferative primary immunodeficiencies (AL-PID)
Hemophagocytic lymphohistiocytosis (HLH) is one of the most dramatic and life-threatening human inflammatory diseases. Patients with HLH offer a unique opportunity to study the molecular regulation of lymphocyte cytotoxicity and intracellular vesicle trafficking. We characterize the uncontrolled T cell response in HLH to better understand the pathophysiological basis of the disease. Patients without a genetic diagnosis are evaluated by whole exome sequencing in search of novel genetic causes. We coordinate a world-wide international registry and a clinical study platform for experimental treatment studies on HLH (TREAT-HLH). We are using observations in human patients and in MUNC13 deficient mice to prepare gene therapy for human patients with FHL3.
Combined immunodeficiencies (CID) present with a wide range of infectious diseases and manifestations of impaired immune regulation such as autoimmunity. The common immunological abnormality is a gentic impairment of T cell immunity. 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. 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 combine genome analysis with functional assays to elucidate novel genetic causes for CID. These findings are related to the particular clinical phenotypes to better understand infection control and immune regulation in humans. The overall goal is to understand how human T cell immunity works under limiting conditions
Benign lymphoproliferation and autoimmunity, in particular autoimmune cytopenia, is observed in a number of primary immunodeficiencies (AL-PID). The most prevalent disorder is autoimmune lymphoproliferative syndrome (ALPS), which is mostly associated with germline or somatic mutations in CD95. 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, we have contributed to the discovery of several new diseases associated with lymphoproliferation and autoimmunity have been discovered. 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.
- Long-term robustness of a T-cell system emerging from somatic rescue of a genetic block in T-cell development. Kury P, Führer M, Fuchs S, Lorenz MR, Giorgetti OB, Bakhtiar S, Frei AP, Fisch P, Boehm T, Schwarz K, Speckmann C, Ehl S. EBioMedicine. 2020 Aug 22;59:102961. doi: 10.1016/j.ebiom.2020.102961. PMID: 32841837
- A distinct CD38+CD45RA+ population of CD4+, CD8+ and double-negative T cells is controlled by FAS. Maccari ME, Fuchs S, Kury P,….Ehl S*, Rensing-Ehl A*. J Exp Med. 2020, in press. (*equal contribution).
- NCKAP1L defects lead to a novel syndrome combining immunodeficiency, lymphoproliferation and hyperinflammation. Castro, C.*, Rosenzwajg, M.*, Carapito, R.*, Shahrooei, M.*, …, Ehl, S.*, Alroq, F.*, Parvaneh, N.*, Bahram, S.* J Exp Med, 2020 Aug; 217(12) e20192275 (*equal contribution).
- Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis. Blincoe A*, Heeg M*, Campbell PK, Hines M, Khojah A, Klein-Gitelman M, Talano JA, Speckmann C, Touzot F, Lankester A, Legger GE, Rivière JG, Garcia-Prat M, Alonso L, Putti MC, Lehmberg K, Maier S, El Chazli Y, Elmaksoud MA, Astigarraga I, Kurjane N, Bulina I, Kenina V, Bryceson Y, Rascon J, Lortie A, Goldstein G, Booth C, Worth A, Wassmer E, Schmitt EG, Warren JT, Bednarski JJ, Ali S, Chiang KY, Krueger J, Henry MM, Holland SM, Marsh RA, Ehl S*, Haddad E*. J Clin Immunol., 2020, in press * equal contribution
- Functional flow cytometry of monocytes for routine diagnosis of innate primary immunodeficiencies. Ammann S, Fuchs S, Martin-Martin L, Castro CN, Spielberger B, Klemann C, Elling R, Heeg M, Speckmann C, Hainmann I, Kaiser-Labusch P, Horneff G, Thalhammer J, Bredius RG, Stadt UZ, Lehmberg K, Fuchs I, von Spee-Mayer C, Henneke P, Ehl S. J Allergy Clin Immunol. 2019 Sep 14. pii: S0091-6749(19)31186-8.
- A prospective study on the natural history of patients with profound combined immunodeficiency: An interim analysis. 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 K, Winterhalter C, Worth A, Fuchs S, Uhlmann A, Ehl S; P-CID study of the Inborn Errors Working Party of the EBMT. J Allergy Clin Immunol. 2017 Apr;139(4):1302-1310
- 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, Strauss A, von Bernuth H, Zur Stadt U, Grieve S, Griffiths GM, Lehmberg K, Hennies HC, Ehl S. Blood. 2016 Feb 25;127(8):997-1006.
Complete list of publications: https://www.ncbi.nlm.nih.gov/pubmed/?term=Ehl%2C+Stephan%5BAuthor%5D