Non-SCID combined immunodeficiencies: a diagnostic and therapeutic challenge
Final Report Abstract
Non-SCID combined immunodeficiencies (CID) are rare immunodeficiencies defined by impaired T cell immunity leading to severe infections, autoimmunity and malignancies. Hematopoietic stem cell transplantation (HSCT) is curative, but due to lack of data on the genetic basis of CID, its natural history and prognostic biomarkers, the criteria for HSCT remain unclear. This limitation gains relevance with the implementation of newborn screening for SCID, which also identifies a proportion of CID patients prior to disease symptoms. EuroCID members have initiated in 2011 a prospective observational study on the natural history of patients with profound CID (P-CID study). In the context of EuroCID we extended the P-CID study concept to CID patients identified by TREC-based newborn screening (nbCID) and to patients with Nijmegen Breakage Syndrome (NBS). Within the funding period we improved the definition of the genetic landscape of combined immunodeficiencies, including descriptions of new genes associated with CID. Diagnostic gene panels for PID were established and validated. Nanopore sequencing was successfully validated as a novel technology for genetic diagnosis of CID. We used single informative patients and patient cohort to characterize the diversity, differentiation pattern and function of limited human T cell systems over time. New assays have been developed and used to assess T cell immunity in primary immunodeficiencies. A pilot study on newborn screening was completed in France. Important insights relevant for patient management were also gained in a large cohort study on Nijmegen Breakage Syndrome, a frequent CID in eastern Europe. Thus, the outcome of cancer in NBS is poor, but a beneficial effect of HSCT on the long-term survival of NBS patients, especially concerning patients in their first complete remission of cancer could clearly be documented. The EuroCID consortium has also significantly improved patient recruitment, documentation and immunologic and genetic characterization in the (15 year) prospective natural history study on profound CID (now 136 patients). This study (terminated in 2022) will provide key data on the natural history and treatment interventions in this group of T cell disorders. One key problem faced by the consortium was the unexpectedly slow implementation of newborn screening. At the beginning of the funding period, NBS had already been implemented in the US and we had hoped for more rapid approval also in European countries. Although we have used the time for some preparatory work in the individual countries, it will take another consortium to scientifically accompany this important step for primary immunodeficiencies at a European scale.
Publications
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2016. A prospective study on the natural history of patients with profound combined immunodeficiency: An interim analysis. J Allergy Clin Immunol. 139: 1302-1310
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
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2017. First Year of Israeli Newborn Screening for Severe Combined Immunodeficiency-Clinical Achievements and Insights. Front Immunol 8: 1448
Rechavi, E., A. Lev, A. J. Simon, T. Stauber, S. Daas, T. Saraf-Levy, A. Broides, A. Nahum, N. Marcus, S. Hanna, P. Stepensky, O. Toker, I. Dalal, A. Etzioni, S. Almashanu, and R. Somech
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2017. Large Deletion of MAGT1 Gene in a Patient with Classic Kaposi Sarcoma, CD4 Lymphopenia, and EBV Infection. J Clin Immunol. 37: 32-35
Brigida I, Chiriaco M, Di Cesare S, Cittaro D, Di Matteo G, Giannelli S, Lazarevic D, Zoccolillo M, Stupka E, Jenkner A, Francalanci P, Livadiotti S, Morawski A, Ravell J, Lenardo M, Cancrini C, Aiuti A, Finocchi A
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2017. Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol 139: 232- 245
Stray-Pedersen, A. et al.
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2018. CD57 identifies T cells with functional senescence before terminal differentiation and relative telomere shortening in patients with activated PI3 kinase delta syndrome. Immunol Cell Biol 96: 1060-1071
Cura Daball, P., M. S. Ventura Ferreira, S. Ammann, C. Klemann, M. R. Lorenz, U. Warthorst, T. R. Leahy, N. Conlon, J. Roche, P. Soler-Palacin, M. Garcia-Prat, I. Fuchs, S. Fuchs, F. Beier, T. H. Brummendorf, C. Speckmann, P. Olbrich, O. Neth, K. Schwarz, S. Ehl, and A. Rensing-Ehl
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2018. Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans. Nat Med. 24: 1683-1690
Scala S, Basso-Ricci L, Dionisio F, Pellin D, Giannelli S, Salerio FA, Leonardelli L, Cicalese MP, Ferrua F, Aiuti A, Biasco L
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2018. T-cell defects in patients with ARPC1B germline mutations account for combined immunodeficiency. Blood 132: 2362-2374
Brigida, I., M. Zoccolillo, M. P. Cicalese, L. Pfajfer, F. Barzaghi, S. Scala, C. Oleaga-Quintas, J. A. Alvarez- Alvarez, L. Sereni, S. Giannelli, C. Sartirana, F. Dionisio, L. Pavesi, M. Benavides-Nieto, L. Basso-Ricci, P. Capasso, B. Mazzi, J. Rosain, N. Marcus, Y. N. Lee, R. Somech, M. Degano, G. Raiola, R. Caorsi, P. Picco, M. Moncada Velez, J. Khourieh, A. A. Arias, A. Bousfiha, T. Issekutz, A. Issekutz, B. Boisson, K. Dobbs, A. Villa, A. Lombardo, B. Neven, D. Moshous, J. L. Casanova, J. L. Franco, L. D. Notarangelo, C. Scielzo, S. Volpi, L. Dupre, J. Bustamante, M. Gattorno, and A. Aiuti
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2019. A combined immunodeficiency with severe infections, inflammation, and allergy caused by ARPC1B deficiency. J Allergy Clin Immunol. 143: 2296-2299
Volpi, S. et al.
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2019. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function. J Exp Med. 216: 2778-2799
Lam MT, Coppola S, Krumbach OHF, Prencipe G, Insalaco A, Cifaldi C, Brigida I, Zara E, Scala S, Di Cesare S, Martinelli S, Di Rocco M, Pascarella A, Niceta M, Pantaleoni F, Ciolfi A, Netter P, Carisey AF, Diehl M, Akbarzadeh M, Conti F, Merli P, Pastore A, Levi Mortera S, Camerini S, Farina L, Buchholzer M, Pannone L, Cao TN, Coban-Akdemir ZH, Jhangiani SN, Muzny DM, Gibbs RA, Basso-Ricci L, Chiriaco M, Dvorsky R, Putignani L, Carsetti R, Janning P, Stray-Pedersen A, Erichsen HC, Horne A, Bryceson YT, Torralba-Raga L, Ramme K, Rosti V, Bracaglia C, Messia V, Palma P, Finocchi A, Locatelli F, Chinn IK, Lupski JR, Mace EM, Cancrini C, Aiuti A, Ahmadian MR, Orange JS, De Benedetti F, Tartaglia M
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2019. ESID Registry Working Party and collaborators. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract. 7: 1763-1770
Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, Scheible R, Rusch S, Gasteiger LM, Grimbacher B, Mahlaoui N, Ehl S
