Centrum für Chronische Immundefizienz - CCI

We use human genetic disorders of T cell immunity as a window to understand T cell differentiation and homeostasis.

Research focus

Group Rensing-Ehl
Differentiation and lifespan of T cells have to be precisely balanced to maintain homeostasis and self-tolerance. We recently described a FAS-controlled (FC) subset of TCRαβ+ T cells that is characterized by a unique molecular signature unambiguously separating it from other known conventional T cell subsets. FC T cells include CD4+, CD8+ and double negative T cells (DNT) and are exceptionally sensitive to FAS-induced apoptosis. They are present in healthy individuals at low frequency, but massively expand in FAS-deficient patients with autoimmune lymphoproliferative syndrome (ALPS). Origin, cell fate induction, differentiation and function of this highly proliferative T cell subset are currently not understood. Further characterization of this unusual T cell population offers an opportunity to identify key steps in the control of differentiation and proliferation of human T cells with potential implications for other benign and malignant lymphoproliferative diseases.

Group Maccari
​​​​​​​Inborn errors of immunity (IEI) are genetic diseases that lead to a dysfunction of the immune system. Traditionally, these diseases have been mainly linked to a specific increase in infection susceptibility. However, immune dysregulation, chronic lymphoproliferation and increased risk for lymphoid malignancies have recently emerged as key manifestations of some IEI. The clinical course of these diseases is often highly variable and this variability makes it difficult to delineate the best treatment approach, which can range from immunosuppression to hematopoietic stem cell transplantation (HSCT) and gene therapy approaches.
The further study of the pathophysiology of immune cell abnormalities typical of these diseases and the precise definition of their natural history are the main research focus of the group.

Current projects

• Identification of new defects and genetic constellations causing autoimmune lymphoproliferative syndrome (ALPS) (Rensing-Ehl). 
• Delineation of natural history, response to treatment and prognosis of patients with Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS) (Maccari).
• Establishment of gene-therapy clinical studies for monogenic immunohematological disorders at the Freiburg Children’s Hospital (Maccari).
• Role of FAS Ligand mutations in the pathogenesis of ALPS (joint project).
• Delineation of the ontogeny and differentiation of human and murine FAS controlled T cells (joint project).
• Characterization of the physiological niche, fate inducing signals and function of FAS controlled T cells (joint project).
• Definition of ontogeny, specificity and function of FAS controlled (FC) T cells, a physiological T-cell population expanded in the Autoimmune Lymphoproliferative Syndrome (ALPS); particular focus on the lymphnode as micro-anatomical niche for FC T cells induction (joint project).

Collaborations

• Prof. Stephan Ehl, Institute for Immunodeficiency, Medical Center - University of Freiburg
• Dr. Peter Aichele, Institute for Immunodeficiency, Medical Center - University of Freiburg
• Prof. Klaus Schwarz, Institut für Klinische Transfusionsmedizin und Immungenetik Ulm (IKT)
• Prof. Marta Rizzi, Department of Rheumatology and Clinical Immunology, Freiburg
• Prof. Tomas Kalina, Faculty of Medicine, Charles University Prague
• Prof. Herve Luche, CIPHE Department, University Marseille
• Prof. Dr. Toni Cathomen, Institute for Transfusion Medicine and Gene Therapy, Medical Center - University of Freiburg
• Prof. Dr. Frederic Rieux-Laucat, Aude Magerus, Institute Imagine, Paris

CV

Dr. Maria Elena Maccari

Publications

• Maccari, M. E., S. Fuchs, P. Kury, G. Andrieux, S. Volkl, B. Bengsch, M. R. Lorenz, M. Heeg, J. Rohr, S. Jagle, C. N. Castro, M. Gross, U. Warthorst, C. Konig, I. Fuchs, C. Speckmann, J. Thalhammer, F. G. Kapp, M. G. Seidel, G. Duckers, S. Schonberger, C. Schutz, M. Fuhrer, R. Kobbe, D. Holzinger, C. Klemann, P. Smisek, S. Owens, G. Horneff, R. Kolb, N. Naumann-Bartsch, M. Miano, J. Staniek, M. Rizzi, T. Kalina, P. Schneider, A. Erxleben, R. Backofen, A. Ekici, C. M. Niemeyer, K. Warnatz, B. Grimbacher, H. Eibel, A. Mackensen, A. P. Frei, K. Schwarz, M. Boerries, S. Ehl, and A. Rensing-Ehl. 2021. A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS. J Exp Med 218: pii: 211525. doi: 10.1084/jem.20192191.
• Klemann, C., M. Esquivel, A. Magerus-Chatinet, M. R. Lorenz, I. Fuchs, N. Neveux, M. Castelle, J. Rohr, C. B. da Cunha, M. Ebinger, R. Kobbe, B. Kremens, F. Kollert, E. Gambineri, K. Lehmberg, M. G. Seidel, K. Siepermann, T. Voelker, V. Schuster, S. Goldacker, K. Schwarz, C. Speckmann, C. Picard, A. Fischer, F. Rieux-Laucat, S. Ehl, A. Rensing-Ehl^#, and B. Neven^#. 2017. Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome. Haematologica 102: e52-e56. doi: 10.3324/haematol.2016.153411.
• Volkl, S.*, A. Rensing-Ehl*, A. Allgauer, E. Schreiner, M. R. Lorenz, J. Rohr, C. Klemann, I. Fuchs, V. Schuster, A. O. von Bueren, N. Naumann-Bartsch, E. Gambineri, K. Siepermann, R. Kobbe, M. Nathrath, P. D. Arkwright, M. Miano, K. D. Stachel, M. Metzler, K. Schwarz, A. N. Kremer, C. Speckmann, S. Ehl, and A. Mackensen. 2016. Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome. Blood 128: 227-238. doi: 10.1182/blood-2015-11-685024.
• 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. 2015. Omenn syndrome associated with a functional reversion due to a somatic second-site mutation in CARD11 deficiency. Blood. 126: 1658-69. doi: 10.1182/blood-2015-03-631374.
• 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. 2015. Gray platelet syndrome can mimic autoimmune lymphoproliferative syndrome. Blood. 126: 1967-9. doi: 10.1182/blood-2015-06-654145.
• 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. 2015. Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency. Blood. 125: 753-61. doi: 10.1182/blood-2014-08-593202.
• Rensing-Ehl, A., S. Volkl, C. Speckmann, M. R. Lorenz, J. Ritter, A. Janda, M. Abinun, H. Pircher, B. Bengsch, R. Thimme, I. Fuchs, S. Ammann, A. Allgauer, K. Kentouche, A. Cant, S. Hambleton, C. Bettoni da Cunha, S. Huetker, I. Kuhnle, A. Pekrun, M. G. Seidel, M. Hummel, A. Mackensen, K. Schwarz, and S. Ehl. 2014. Abnormally differentiated CD4+ or CD8+ T-cells with phenotypic and genetic features of double negative T-cells in human Fas deficiency. Blood 124: 851-60. doi: 10.1182/blood-2014-03-564286.
• Rensing-Ehl A, A. Janda, M. R. Lorenz, B. P. Gladstone, I. Fuchs, M. Abinun, M. Albert, K. Butler, A. Cant, A. M. Cseh, M. Ebinger, S. Goldacker, S. Hambleton, H. Hebart, L. Houet, K. Kentouche, I. Kuhnle, K. Lehmberg, E. Mejstrikova, C. Niemeyer, M. Minkov, O. Neth, G. Duckers, S. Owens, J. Rosler, F. H. Schilling, V. Schuster, M. G. Seidel, P. Smisek, M. Sukova, P. Svec, T. Wiesel, B. Gathmann, K. Schwarz, W. Vach, S. Ehl, and C. Speckmann. 2013. Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia. 2013. Haematologica 98: 1948-55. doi: 10.3324/haematol.2012.081901.
• Pannicke, U., B. Baumann, S. Fuchs, P. Henneke, A. Rensing-Ehl, M. Rizzi, A. Janda, K. Hese, M. Schlesier, K. Holzmann, S. Borte, C. Laux, E. M. Rump, A. Rosenberg, T. Zelinski, H. Schrezenmeier, T. Wirth, S. Ehl, M. L. Schroeder*, and K. Schwarz*. 2013. Deficiency of innate and acquired immunity caused by an IKBKB mutation. N Engl J Med 369: 2504-2514. doi: 10.1056/NEJMoa1309199.
• Maul-Pavicic, A., S. C. Chiang, A. Rensing-Ehl, B. Jessen, C. Fauriat, S. M. Wood, S. Sjoqvist, M. Hufnagel, I. Schulze, T. Bass, W. W. Schamel, S. Fuchs, H. Pircher, C. A. McCarl, K. Mikoshiba, K. Schwarz, S. Feske, Y. T. Bryceson, and S. Ehl. 2011. ORAI1-mediated calcium influx is required for human cytotoxic lymphocyte degranulation and target cell lysis. Proc Natl Acad Sci USA 108: 3324-3329. doi: 10.1073/pnas.1013285108.
• Maccari ME, Schneider P, Smulski CR, Meinhardt A, Pinto F, Gonzalez-Granado LI, Schuetz C, Sica MP, Gross M, Fuchs I, Kury P, Heeg M, Vocat T, Willen L, Thomas C, Hühn R, Magerus A, Lorenz M, Schwarz K, Rieux-Laucat F, Ehl S, Rensing-Ehl A. Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations. J Allergy Clin Immunol. 2023 Jan 5:S0091-6749(23)00001-5. doi: 10.1016/j.jaci.2022.11.028. Epub ahead of print. PMID: 36621650.
• Dimitrova D, Nademi Z, Maccari ME, Ehl S, Uzel G, Tomoda T, Okano T, Imai K, Carpenter B, Ip W, Rao K, Worth AJJ, Laberko A, Mukhina A, Néven B, Moshous D, Speckmann C, Warnatz K, Wehr C, Abolhassani H, Aghamohammadi A, Bleesing JJ, Dara J, Dvorak CC, Ghosh S, Kang HJ, Markelj G, Modi A, Bayer DK, Notarangelo LD, Schulz A, Garcia-Prat M, Soler-Palacín P, Karakükcü M, Yilmaz E, Gambineri E, Menconi M, Masmas TN, Holm M, Bonfim C, Prando C, Hughes S, Jolles S, Morris EC, Kapoor N, Koltan S, Paneesha S, Steward C, Wynn R, Duffner U, Gennery AR, Lankester AC, Slatter M, Kanakry JA. International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome. J Allergy Clin Immunol. 2021 May 22:S0091- 6749(21)00810-1. doi: 10.1016/j.jaci.2021.04.036. PMID: 34033842.
• Rosenberg JM, Maccari ME, Barzaghi F, Allenspach EJ, Pignata C, Weber G, Torgerson TR, Utz PJ, Bacchetta R. Neutralizing Anti-Cytokine Autoantibodies Against Interferon-α in Immunodysregulation Polyendocrinopathy Enteropathy X-Linked. Front Immunol. 2018 Mar 29;9:544. doi: 10.3389/fimmu.2018.00544. eCollection 2018. PubMed PMID: 29651287; PubMed Central PMCID: PMC5885158.
• Maccari ME, Abolhassani H, Aghamohammadi A, Aiuti A, Aleinikova O, Bangs C, Baris S, Barzaghi F, Baxendale H, Buckland M, Burns SO, Cancrini C, Cant A, Cathébras P, Cavazzana M, Chandra A, Conti F, Coulter T, Devlin LA, Edgar JDM, Faust S, Fischer A, Garcia-Prat M, Hammarström L, Heeg M, Jolles S, Karakoc-Aydiner E, Kindle G, Kiykim A, Kumararatne D, Grimbacher B, Longhurst H, Mahlaoui N, Milota T, Moreira F, Moshous D, Mukhina A, Neth O, Neven B, Nieters A, Olbrich P, Ozen A, Pachlopnik Schmid J, Picard C, Prader S, Rae W, Reichenbach J, Rusch S, Savic S, Scarselli A, Scheible R, Sediva A, Sharapova SO, Shcherbina A, Slatter M, Soler-Palacin P, Stanislas A, Suarez F, Tucci F, Uhlmann A, van Montfrans J, Warnatz K, Williams AP, Wood P, Kracker S, Condliffe AM, Ehl S. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3- Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front Immunol. 2018 Mar 16;9:543. doi: 10.3389/fimmu.2018.00543. PMID: 29599784; PMCID: PMC5863269.

*contributed equally
^#joint senior authors

Team

Group members