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, Medical Center - University of 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, Institute Imagine, Paris
• Prof. Dr. Aude Magerus, Institute Imagine, Paris

CV

Dr. Maria Elena Maccari

Publications

PUBMED search Maccari

PUBMED search Rensing-Ehl

• Whalen, J., A. Chandra, S. Kracker, S. Ehl, M.G. Seidel, I. Gulas, L. Dron, R. Velummailum, C. Nagamuthu, S. Liu, J. Tutein Nolthenius, and M.E. Maccari. 2025. Comparative efficacy of leniolisib (CDZ173) versus standard of care on rates of respiratory tract infection and serum immunoglobulin M (IgM) levels among individuals with activated phosphoinositide 3-kinase delta (PI3Kdelta) syndrome (APDS): an externally controlled study. Clin Exp Immunol 219. doi:10.1093/cei/uxae107.

• Hagele, P., P. Staus, R. Scheible, A. Uhlmann, M. Heeg, C. Klemann, M.E. Maccari, H. Ritterbusch, M. Armstrong, I. Cutcutache, K.S. Elliott, H. von Bernuth, T.R. Leahy, J. Leyh, D. Holzinger, K. Lehmberg, P. Svec, K. Masjosthusmann, S. Hambleton, M. Jakob, M. Sparber-Sauer, L. Kager, A. Puzik, M. Wolkewitz, M.R. Lorenz, K. Schwarz, C. Speckmann, A. Rensing-Ehl, S. Ehl, and A.s. group. 2024. Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study. Lancet Haematol 11:e114-e126. doi:10.1016/S2352-3026(23)00362-9.

• Pelle, O.*, S. Moreno*, M.R. Lorenz*, Q. Riller, M. Fuehrer, M.C. Stolzenberg, M.E. Maccari, C. Lenoir, M. Cheminant, T. Hinze, H.F. Hebart, C. Konig, A. Schvartz, Y. Schmitt, A. Vinit, E. Henry, A. Touzart, P. Villarese, P. Isnard, N. Neveux, J. Landman-Parker, C. Picard, F. Fouyssac, B. Neven, B. Grimbacher, C. Speckmann, A. Fischer, S. Latour, K. Schwarz, S. Ehl*, F. Rieux-Laucat*, A. Rensing-Ehl*, and A. Magerus*. 2024. Combined germline and somatic human FADD mutations cause autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol 153:203-215. doi:10.1016/j.jaci.2023.09.028.

• Rensing-Ehl, A.*, M.R. Lorenz*, M. Fuhrer*, W. Willenbacher, E. Willenbacher, S. Sopper, M. Abinun, M.E. Maccari, C. Konig, P. Haegele, S. Fuchs, C. Castro, P. Kury, O. Pelle, C. Klemann, M. Heeg, J. Thalhammer, O. Wegehaupt, M. Fischer, S. Goldacker, B. Schulte, S. Biskup, P. Chatelain, V. Schuster, K. Warnatz, B. Grimbacher, A. Meinhardt, D. Holzinger, P.T. Oommen, T. Hinze, H. Hebart, K. Seeger, K. Lehmberg, T.R. Leahy, A. Claviez, S. Vieth, F.H. Schilling, I. Fuchs, M. Gross, F. Rieux-Laucat, A. Magerus, C. Speckmann, K. Schwarz*, S. Ehl*, and A.S. Group. 2024. Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing. J Allergy Clin Immunol 153:297-308 e212. doi:10.1016/j.jaci.2023.11.006.

• Staniek, J., T. Kalina, G. Andrieux, M. Boerries, I. Janowska, M. Fuentes, P. Diez, M. Bakardjieva, J. Stancikova, J. Raabe, J. Neumann, S. Schwenk, L. Arpesella, J. Stuchly, V. Benes, R. Garcia Valiente, J. Fernandez Garcia, R. Carsetti, E. Piano Mortari, A. Catala, O. de la Calle, G. Sogkas, B. Neven, F. Rieux-Laucat, A. Magerus, O. Neth, P. Olbrich, R.E. Voll, L. Alsina, L.M. Allende, L.I. Gonzalez-Granado, C. Bohler, J. Thiel, N. Venhoff, R. Lorenzetti, K. Warnatz, S. Unger, M. Seidl, D. Mielenz, P. Schneider, S. Ehl, A. Rensing-Ehl, C.R. Smulski, and M. Rizzi. 2024. Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells. Sci Immunol 9:eadj5948. doi:10.1126/sciimmunol.adj5948.

• Magerus, A., A. Rensing-Ehl, V.K. Rao, D.T. Teachey, F. Rieux-Laucat, and S. Ehl. 2024. Autoimmune lymphoproliferative immunodeficiencies (ALPIDs): A proposed approach to redefining ALPS and other lymphoproliferative immune disorders. J Allergy Clin Immunol 153:67-76. doi:10.1016/j.jaci.2023.11.004.

• Maccari, M.E., C. Tron, C. Speckmann, and H.H.s. group. 2023a. JAKi Salvage Therapy Followed by Curative Cord Blood Transplantation in a XIAP-Deficient Infant with Relapsing HLH. J Clin Immunol 43:1178-1181. doi:10.1007/s10875-023-01522-7.

• Maccari, M.E., M. Wolkewitz, C. Schwab, T. Lorenzini, J.W. Leiding, N. Aladjdi, H. Abolhassani, W. Abou-Chahla, A. Aiuti, S. Azarnoush, S. Baris, V. Barlogis, F. Barzaghi, U. Baumann, M. Bloomfield, N. Bohynikova, D. Bodet, D. Boutboul, G. Bucciol, M.S. Buckland, S.O. Burns, C. Cancrini, P. Cathebras, M. Cavazzana, M. Cheminant, M. Chinello, P. Ciznar, T.I. Coulter, M. D'Aveni, O. Ekwall, Z. Eric, E. Eren, A. Fasth, P. Frange, B. Fournier, M. Garcia-Prat, M. Gardembas, C. Geier, S. Ghosh, V. Goda, L. Hammarstrom, F. Hauck, M. Heeg, E. Heropolitanska-Pliszka, A. Hilfanova, S. Jolles, E. Karakoc-Aydiner, G.R. Kindle, A. Kiykim, C. Klemann, P. Koletsi, S. Koltan, I. Kondratenko, J. Korholz, R. Kruger, E. Jeziorski, R. Levy, G. Le Guenno, G. Lefevre, V. Lougaris, A. Marzollo, N. Mahlaoui, M. Malphettes, A. Meinhardt, E. Merlin, I. Meyts, T. Milota, F. Moreira, D. Moshous, A. Mukhina, O. Neth, J. Neubert, B. Neven, A. Nieters, R. Nove-Josserand, E. Oksenhendler, A. Ozen, P. Olbrich, A. Perlat, M. Pac, J.P. Schmid, L. Pacillo, A. Parra-Martinez, O. Paschenko, I. Pellier, A.P. Sefer, A. Plebani, D. Plantaz, S. Prader, L. Raffray, H. Ritterbusch, J.G. Riviere, B. Rivalta, S. Rusch, I. Sakovich, S. Savic, R. Scheible, N. Schleinitz, C. Schuetz, A. Schulz, A. Sediva, M. Semeraro, S.O. Sharapova, A. Shcherbina, M.A. Slatter, G. Sogkas, P. Soler-Palacin, C. Speckmann, J.L. Stephan, F. Suarez, A. Tommasini, J. Truck, A. Uhlmann, K.J. van Aerde, J. van Montfrans, H. von Bernuth, K. Warnatz, T. Williams, A.J.J. Worth, W. Ip, C. Picard, E. Catherinot, Z. Nademi, B. Grimbacher, L.R. Forbes Satter, S. Kracker, A. Chandra, A.M. Condliffe, S. Ehl, and P. European Society for Immunodeficiencies Registry Working. 2023b. Activated phosphoinositide 3-kinase delta syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity. J Allergy Clin Immunol 152:984-996 e910. doi:10.1016/j.jaci.2023.06.015.

*contributed equally
 

Team

Group members