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9 results on '"Smulski, Cristian Roberto"'

1. Defects in B-lymphopoiesis and B-cell maturation underlie prolonged B-cell depletion in ANCA-associated vasculitis.

Author

Thiel, Jens, Schmidt, Franziska M., Lorenzetti, Raquel, Troilo, Arianna, Janowska, Iga, Nießen, Lena, Pfeiffer, Sophie, Staniek, Julian, Benassini, Bruno, Bott, Marei-Theresa, Korzhenevich, Jakov, Konstantinidis, Lukas, Burgbacher, Frank, Dufner, Ann-Katrin, Frede, Natalie, Voll, Reinhard E., Stuchly, Jan, Bakardjieva, Marina, Kalina, Tomas, and Smulski, Cristian Roberto

Published
2024
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2. Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells

Author

Fuentes, Manuel [0000-0002-7305-3766], Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72], Staniek, Julian, Kalina, Tomas, Andrieux, Geoffroy, Boerries, Melanie, Janowska, Iga, Fuentes, Manuel, Díez, Paula, Bakardjieva, Marina, Stancikova, Jitka, Raabe, Jan, Neumann, Julika, Schwenk, Sabine, Arpesella, Leonardo, Stuchly, Jan, Benes, Vladimir, García-Valiente, Rodrigo, Fernández-García, Jonatan, Carsetti, Rita, Piano Mortari, Eva, Catala, Albert, Calle, Oscar de la, Sogkas, Georgios, Neven, Bénédicte, Rieux-Laucat, Frédéric, Magerus, Aude, Neth, Olaf, Olbrich, Peter, Voll, Reinhard E., Alsina, Laia, Allende, Luis, González-Granado, Luis, Böhler, Chiara, Thiel, Jens, Venhoff, Nils, Lorenzetti, Raquel, Warnatz, Klaus, Unger, Susanne, Seidl, Maximilian, Mielenz, Dirk, Schneider, Pascal, Ehl, Stephan, Rensing-Ehl, Anne, Smulski, Cristian Roberto, Rizzi, Marta, Fuentes, Manuel [0000-0002-7305-3766], Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72], Staniek, Julian, Kalina, Tomas, Andrieux, Geoffroy, Boerries, Melanie, Janowska, Iga, Fuentes, Manuel, Díez, Paula, Bakardjieva, Marina, Stancikova, Jitka, Raabe, Jan, Neumann, Julika, Schwenk, Sabine, Arpesella, Leonardo, Stuchly, Jan, Benes, Vladimir, García-Valiente, Rodrigo, Fernández-García, Jonatan, Carsetti, Rita, Piano Mortari, Eva, Catala, Albert, Calle, Oscar de la, Sogkas, Georgios, Neven, Bénédicte, Rieux-Laucat, Frédéric, Magerus, Aude, Neth, Olaf, Olbrich, Peter, Voll, Reinhard E., Alsina, Laia, Allende, Luis, González-Granado, Luis, Böhler, Chiara, Thiel, Jens, Venhoff, Nils, Lorenzetti, Raquel, Warnatz, Klaus, Unger, Susanne, Seidl, Maximilian, Mielenz, Dirk, Schneider, Pascal, Ehl, Stephan, Rensing-Ehl, Anne, Smulski, Cristian Roberto, and Rizzi, Marta

Abstract

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.

Published
2024

3. Revisiting autoimmune lymphoproliferative syndrome caused by Fas ligand mutations

Author

Maccari, Maria Elena, primary, Schneider, Pascal, additional, Smulski, Cristian Roberto, additional, Meinhardt, Andrea, additional, Pinto, Fernando, additional, Gonzalez-Granado, Luis Ignacio, additional, Schuetz, Catharina, additional, Sica, Mauricio Pablo, additional, Gross, Miriam, additional, Fuchs, Ilka, additional, Kury, Patrick, additional, Heeg, Maximilian, additional, Vocat, Tatjana, additional, Willen, Laure, additional, Thomas, Caroline, additional, Hühn, Regina, additional, Magerus, Aude, additional, Lorenz, Myriam, additional, Schwarz, Klaus, additional, Rieux-Laucat, Frederic, additional, Ehl, Stephan, additional, and Rensing-Ehl, Anne, additional

Published
2023
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4. Assessing the Functional Relevance of Variants in the IKAROS Family Zinc Finger Protein 1 (IKZF1) in a Cohort of Patients With Primary Immunodeficiency

Author

Eskandarian, Zoya, Fliegauf, Manfred, Bulashevska, Alla, Proietti, Michele, Hague, Rosie, Smulski, Cristian Roberto, Schubert, Desirée, Warnatz, Klaus, and Grimbacher, Bodo

Subjects
purl.org/becyt/ford/1 [https], CVID, IKAROS, NUCLEAR LOCALIZATION, TRAIL DNA BINDING, purl.org/becyt/ford/1.6 [https], MONOGENIC DEFECTS
Abstract

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency. Patients with CVID are prone to recurrent bacterial infection due to the failure of adequate immunoglobulin production. Monogenetic defects have been identified in ~25% of CVID patients. Recently, mutations in IKZF1, encoding the zinc-finger transcription factor IKAROS which is broadly expressed in hematopoietic cells, have been associated with a CVID-like phenotype. Herein we describe 11 patients with heterozygous IKZF1 variants from eight different families with autosomal dominant CVID and two siblings with an IKZF1 variant presenting with inflammatory bowel disease (IBD). This study shows that mutations affecting the DNA binding domain of IKAROS can impair the interaction with the target DNA sequence thereby preventing heterochromatin and pericentromeric localization (HC-PC) of the protein. Our results also indicate an impairment of pericentromeric localization of IKAROS by overexpression of a truncated variant, caused by an immature stop codon in IKZF1. We also describe an additional variant in TNFSF10, encoding Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), additionally presented in individuals of Family A. Our results indicate that this variant may impair the TRAIL-induced apoptosis in target cell lines and prohibit the NFκB activation by TRAIL and may act as a modifier in Family A. Fil: Eskandarian, Zoya. Albert Ludwigs University of Freiburg; Alemania Fil: Fliegauf, Manfred. Albert Ludwigs University of Freiburg; Alemania Fil: Bulashevska, Alla. Albert Ludwigs University of Freiburg; Alemania Fil: Proietti, Michele. Albert Ludwigs University of Freiburg; Alemania Fil: Hague, Rosie. Royal Hospital For Children; Reino Unido Fil: Smulski, Cristian Roberto. Albert Ludwigs University of Freiburg; Alemania. Comisión Nacional de Energía Atómica. Centro Atómico Bariloche; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; Argentina Fil: Schubert, Desirée. Albert Ludwigs University of Freiburg; Alemania Fil: Warnatz, Klaus. Albert Ludwigs University of Freiburg; Alemania Fil: Grimbacher, Bodo. Albert Ludwigs University of Freiburg; Alemania. University College London; Reino Unido

Published
2019
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5. Abatacept modulates CD80 and CD86 expression and memory formation in human B-cells

Author

Lorenzetti, Raquel, primary, Janowska, Iga, additional, Smulski, Cristian Roberto, additional, Frede, Natalie, additional, Henneberger, Nadine, additional, Walter, Lea, additional, Schleyer, Marei-Theresa, additional, Hüppe, Janika M., additional, Staniek, Julian, additional, Salzer, Ulrich, additional, Venhoff, Ana, additional, Troilo, Arianna, additional, Voll, Reinhard Edmund, additional, Venhoff, Nils, additional, Thiel, Jens, additional, and Rizzi, Marta, additional

Published
2019
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7. TRAIL-R1 and TRAIL-R2 Mediate TRAIL-Dependent Apoptosis in Activated Primary Human B Lymphocytes

Author

Staniek, Julian, primary, Lorenzetti, Raquel, additional, Heller, Bianca, additional, Janowska, Iga, additional, Schneider, Pascal, additional, Unger, Susanne, additional, Warnatz, Klaus, additional, Seidl, Maximilian, additional, Venhoff, Nils, additional, Thiel, Jens, additional, Smulski, Cristian Roberto, additional, and Rizzi, Marta, additional

Published
2019
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9. Non-apoptotic FAS signaling controls mTOR activation and extrafollicular maturation in human B cells.

Author

Staniek J, Kalina T, Andrieux G, Boerries M, Janowska I, Fuentes M, Díez P, Bakardjieva M, Stancikova J, Raabe J, Neumann J, Schwenk S, Arpesella L, Stuchly J, Benes V, García Valiente R, Fernández García J, Carsetti R, Piano Mortari E, Catala A, de la Calle O, Sogkas G, Neven B, Rieux-Laucat F, Magerus A, Neth O, Olbrich P, Voll RE, Alsina L, Allende LM, Gonzalez-Granado LI, Böhler C, Thiel J, Venhoff N, Lorenzetti R, Warnatz K, Unger S, Seidl M, Mielenz D, Schneider P, Ehl S, Rensing-Ehl A, Smulski CR, and Rizzi M

Subjects
Humans, Apoptosis genetics, Germinal Center, TOR Serine-Threonine Kinases, Hypergammaglobulinemia, Lymphoproliferative Disorders genetics
Abstract

Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.

Published
2024
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