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1. Single-hit genome editing optimized for maturation in B cells redirects their specificity toward tumor antigens

Author: Natsuko Ueda, Marine Cahen, Jenny Leonard, Laurent Deleurme, Stéphane Dreano, Christophe Sirac, Anne Galy, Jérôme Moreaux, Yannic Danger, and Michel Cogné
Subjects: Medicine, Science
Abstract: Abstract T-cell-based adoptive immunotherapy is a new pillar of cancer care. Tumor-redirected B cells could also contribute to therapy if their manipulation to rewire immunoglobulin (Ig) genes is mastered. We designed a single-chain Ig-encoding cassette (“scFull-Ig”) that redirects antigen specificity when inserted at a single position of the IgH locus. This design, which places combined IgH and IgL variable genes downstream of a pVH promoter, nevertheless preserves all Ig functional domains and the intrinsic mechanisms that regulate expression from the IgM B cell receptor (BCR) expression to Ig secretion, somatic hypermutation and class switching. This single-locus editing provides an efficient and safe strategy to both disrupt endogenous Ig expression and encode a new Ig paratope. As a proof of concept, the functionality of scFull BCR and/or secreted Ig was validated against two different classical human tumor antigens, HER2 and hCD20. Once validated in cell lines, the strategy was extended to primary B cells, confirming the successful engineering of BCR and Ig expression and the ability of scFull-Ig to undergo further class switching. These results further pave the way for future B cell-based adoptive immunotherapy and strategies to express a therapeutic mAb with a variety of switched H-chains that provide complementary functions.
Published: 2024
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2. The immunoglobulin heavy chain super enhancer controls class switch recombination in developing B cells

Author: Audrey Dauba, Emmanuelle Näser, Dylan Andrieux, Michel Cogné, Yves Denizot, and Ahmed Amine Khamlichi
Subjects: Early B cells, IgH locus, Super-enhancer, Class switch recombination, Switch transcription, Medicine, Science
Abstract: Abstract Class switch recombination (CSR) plays an important role in adaptive immune response by enabling mature B cells to replace the initial IgM by another antibody class (IgG, IgE or IgA). CSR is preceded by transcription of the IgH constant genes and is controlled by the super-enhancer 3′ regulatory region (3′RR) in an activation-specific manner. The 3’RR is composed of four enhancers (hs3a, hs1-2, hs3b and hs4). In mature B cells, 3’RR activity correlates with transcription of its enhancers. CSR can also occur in primary developing B cells though at low frequency, but in contrast to mature B cells, the transcriptional elements that regulate the process in developing B cells are ill-known. In particular, the role of the 3’RR in the control of constant genes’ transcription and CSR has not been addressed. Here, by using a mouse line devoid of the 3’RR and a culture system that highly enriches in pro-B cells, we show that the 3’RR activity is indeed required for switch transcription and CSR, though its effect varies in an isotype-specific manner and correlates with transcription of hs4 enhancer only.
Published: 2024
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3. Corrigendum: Follicular lymphoma regulatory T-cell origin and function

Author: Stéphane Rodriguez, Mehdi Alizadeh, Claire Lamaison, Alexis Saintamand, Céline Monvoisin, Rachel Jean, Laurent Deleurme, Jose Ignacio Martin-Subero, Céline Pangault, Michel Cogné, Patricia Amé-Thomas, and Karin Tarte
Subjects: follicular regulatory T cells, follicular helper T cells, follicular lymphoma, regulatory T cells, TCR repertoire, Immunologic diseases. Allergy, RC581-607
Published: 2024
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4. Follicular lymphoma regulatory T-cell origin and function

Author: Stéphane Rodriguez, Mehdi Alizadeh, Claire Lamaison, Alexis Saintamand, Céline Monvoisin, Rachel Jean, Laurent Deleurme, Jose Ignacio Martin-Subero, Céline Pangault, Michel Cogné, Patricia Amé-Thomas, and Karin Tarte
Subjects: follicular regulatory T cells, follicular helper T cells, follicular lymphoma, regulatory T cells, TCR repertoire, Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionFollicular Lymphoma (FL) results from the malignant transformation of germinal center (GC) B cells. FL B cells display recurrent and diverse genetic alterations, some of them favoring their direct interaction with their cell microenvironment, including follicular helper T cells (Tfh). Although FL-Tfh key role is well-documented, the impact of their regulatory counterpart, the follicular regulatory T cell (Tfr) compartment, is still sparse.MethodsThe aim of this study was to characterize FL-Tfr phenotype by cytometry, gene expression profile, FL-Tfr origin by transcriptomic analysis, and functionality by in vitro assays.ResultsCD4+CXCR5+CD25hiICOS+ FL-Tfr displayed a regulatory program that is close to classical regulatory T cell (Treg) program, at the transcriptomic and methylome levels. Accordingly, Tfr imprinting stigmata were found on FL-Tfh and FL-B cells, compared to their physiological counterparts. In addition, FL-Tfr co-culture with autologous FL-Tfh or cytotoxic FL-CD8+ T cells inhibited their proliferation in vitro. Finally, although FL-Tfr shared many characteristics with Treg, TCR sequencing analyses demonstrated that part of them derived from precursors shared with FL-Tfh. DiscussionAltogether, these findings uncover the role and origin of a Tfr subset in FL niche and may be useful for lymphomagenesis knowledge and therapeutic management.
Published: 2024
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5. Attempts to evaluate locus suicide recombination and its potential role in B cell negative selection in the mouse

Author: Nicolas Denis-Lagache, Christelle Oblet, Tiffany Marchiol, Audrey Baylet, Ophélie Têteau, Iman Dalloul, Zeinab Dalloul, Lina Zawil, Ophélie Dézé, Jeanne Cook-Moreau, Alexis Saintamand, Hend Boutouil, Ahmed Amine Khamlichi, Claire Carrion, Sophie Péron, Sandrine Le Noir, Brice Laffleur, and Michel Cogné
Subjects: antibody, immunoglobulin, lymphocyte, enhancer, recombination, mouse model, Immunologic diseases. Allergy, RC581-607
Abstract: IntroductionIn mature B cells, activation-induced deaminase reshapes Ig genes through somatic hypermutation and class switch recombination of the Ig heavy chain (IgH) locus under control of its 3’ cis-regulatory region (3’RR). The 3’RR is itself transcribed and can undergo “locus suicide recombination” (LSR), then deleting the constant gene cluster and terminating IgH expression. The relative contribution of LSR to B cell negative selection remains to be determined.MethodsHere, we set up a knock-in mouse reporter model for LSR events with the aim to get clearer insights into the circumstances triggering LSR. In order to explore the consequences of LSR defects, we reciprocally explored the presence of autoantibodies in various mutant mouse lines in which LSR was perturbed by the lack of Sµ or of the 3’RR.ResultsEvaluation of LSR events in a dedicated reporter mouse model showed their occurrence in various conditions of B cell activation, notably in antigen-experienced B cells Studies of mice with LSR defects evidenced increased amounts of self-reactive antibodies.DiscussionWhile the activation pathways associated with LSR are diverse, in vivo as well as in vitro, this study suggests that LSR may contribute to the elimination of self-reactive B cells.
Published: 2023
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6. Demultiplexing Ig repertoires by parallel mRNA/DNA sequencing shows major differential alterations in severe COVID-19

Author: Virginie Pascal, Marine Dupont, Paco de Rouault, David Rizzo, Delphine Rossille, Robin Jeannet, Thomas Daix, Bruno François, Steve Genebrier, Marie Cornic, Guillaume Monneret, Fabienne Venet, Juliette Ferrant, Mikael Roussel, Florian Reizine, Mathieu Le Souhaitier, Jean-Marc Tadié, Karin Tarte, Jean Feuillard, and Michel Cogné
Subjects: Immunology, Respiratory medicine, Science
Abstract: Summary: To understand the fine differential elements that can lead to or prevent acute respiratory distress syndrome (ARDS) in COVID-19 patients, it is crucial to investigate the immune response architecture. We herein dissected the multiple layers of B cell responses by flow cytometry and Ig repertoire analysis from acute phase to recovery. Flow cytometry with FlowSOM analysis showed major changes associated with COVID-19 inflammation such as an increase of double-negative B-cells and ongoing plasma cell differentiation. This paralleled COVID-19-driven expansion of two disconnected B-cell repertoires. Demultiplexing successive DNA and RNA Ig repertoire patterns characterized an early expansion of IgG1 clonotypes with atypically long and uncharged CDR3, the abundance of this inflammatory repertoire being correlated with ARDS and likely pejorative. A superimposed convergent response included convergent anti-SARS-CoV-2 clonotypes. It featured progressively increasing somatic hypermutation together with normal-length or short CDR3 and it persisted until a quiescent memory B-cell stage after recovery.
Published: 2023
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7. Venoarterial extracorporeal membrane oxygenation induces early immune alterations

Author: Aurélien Frerou, Mathieu Lesouhaitier, Murielle Gregoire, Fabrice Uhel, Arnaud Gacouin, Florian Reizine, Caroline Moreau, Aurélie Loirat, Adel Maamar, Nicolas Nesseler, Amedeo Anselmi, Erwan Flecher, Jean-Philippe Verhoye, Yves Le Tulzo, Michel Cogné, Mikael Roussel, Karin Tarte, and Jean-Marc Tadié
Subjects: VA-ECMO, Immunosuppression, MDSC, Lymphocyte exhaustion, Lymphopenia, Acquired infections, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract: Abstract Background Venoarterial extracorporeal membrane oxygenation (VA-ECMO) provides heart mechanical support in critically ill patients with cardiogenic shock. Despite important progresses in the management of patients under VA-ECMO, acquired infections remain extremely frequent and increase mortality rate. Since immune dysfunctions have been described in both critically ill patients and after surgery with cardiopulmonary bypass, VA-ECMO initiation may be responsible for immune alterations that may expose patients to nosocomial infections (NI). Therefore, in this prospective study, we aimed to study immune alterations induced within the first days by VA-ECMO initiation. Methods We studied immune alterations induced by VA-ECMO initiation using cytometry analysis to characterize immune cell changes and enzyme-linked immunosorbent assay (ELISA) to explore plasma cytokine levels. To analyze specific changes induced by VA-ECMO initiation, nine patients under VA-ECMO (VA-ECMO patients) were compared to nine patients with cardiogenic shock (control patients). Results Baseline immune parameters were similar between the two groups. VA-ECMO was associated with a significant increase in circulating immature neutrophils with a significant decrease in C5a receptor expression. Furthermore, we found that VA-ECMO initiation was followed by lymphocyte dysfunction along with myeloid-derived suppressor cells (MDSC) expansion. ELISA analysis revealed that VA-ECMO initiation was followed by an increase in pro-inflammatory cytokines such as IL-6, IL-8 and TNF-α along with IL-10, a highly immunosuppressive cytokine. Conclusion VA-ECMO is associated with early immune changes that may be responsible for innate and adaptive immune alterations that could confer an increased risk of infection.
Published: 2021
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8. Anti-FcαRI Monoclonal Antibodies Resolve IgA Autoantibody-Mediated Disease

Author: Amelie Bos, Esil Aleyd, Lydia P. E. van der Steen, P. J. Winter, Niels Heemskerk, Stephan M. Pouw, Louis Boon, Rene J. P. Musters, Jantine E. Bakema, Cassian Sitaru, Michel Cogné, and Marjolein van Egmond
Subjects: FcαRI, CD89, IgA, neutrophils, LABD, Immunologic diseases. Allergy, RC581-607
Abstract: Immunoglobulin A (IgA) is generally considered as a non-inflammatory regulator of mucosal immunity, and its importance in diversifying the gut microbiota is increasingly appreciated. IgA autoantibodies have been found in several autoimmune or chronic inflammatory diseases, but their role in pathophysiology is ill-understood. IgA can interact with the Fc receptor FcαRI on immune cells. We now established a novel IgA autoimmune blistering model, which closely resembles the human disease linear IgA bullous disease (LABD) by using genetically modified mice that produce human IgA and express human FcαRI. Intravital microscopy demonstrated that presence of IgA anti-collagen XVII, - the auto-antigen in LABD-, resulted in neutrophil activation and extravasation from blood vessels into skin tissue. Continued exposure to anti-collagen XVII IgA led to massive neutrophil accumulation, severe tissue damage and blister formation. Importantly, treatment with anti-FcαRI monoclonal antibodies not only prevented disease, but was also able to resolve existing inflammation and tissue damage. Collectively, our data reveal a novel role of neutrophil FcαRI in IgA autoantibody-mediated disease and identify FcαRI as promising new therapeutic target to resolve chronic inflammation and tissue damage.
Published: 2022
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9. Editorial: Germinal Centers in Lymphoid and Non-Lymphoid Tissues: Adaptive and Evolving Structures

Author: Michel Cogné, Thierry Fest, and Said Aoufouchi
Subjects: germinal center (GC) B cell, affinity maturation, humoral immune response, Tertiary Lymphoid Structures (TLS), GC B cell outcomes, cell fate decision, Immunologic diseases. Allergy, RC581-607
Published: 2022
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10. Impact of HIV-1 Vpr manipulation of the DNA repair enzyme UNG2 on B lymphocyte class switch recombination

Author: Patrick Eldin, Sophie Péron, Anastasia Galashevskaya, Nicolas Denis-Lagache, Michel Cogné, Geir Slupphaug, and Laurence Briant
Subjects: Uracil DNA glycosylase 2, Human immunodeficiency virus, Vpr, Uracilation, Class switch recombination, Medicine
Abstract: Abstract Background HIV-1 Vpr encodes a 14 kDa protein that has been implicated in viral pathogenesis through modulation of several host cell functions. In addition to pro-apoptotic and cytostatic properties, Vpr can redirect cellular E3 ubiquitin ligases (such as DCAF1-Cul4A E3 ligase complex) to target many host proteins and interfere with their functions. Among them, Vpr binds the uracil DNA glycosylase UNG2, which controls genome uracilation, and induces its specific degradation leading to loss of uracil removal activity in infected cells. Considering the essential role of UNG2 in antibody diversification in B-cells, we evaluated the impact of Vpr on UNG2 fate in B lymphocytes and examined the functional consequences of UNG2 modulations on class switch recombination (CSR). Methods The impact of Vpr-induced UNG2 deregulation on CSR proficiency was evaluated by using virus-like particles able to deliver Vpr protein to target cells including the murine model CSR B cell line CH12F3 and mouse primary B-cells. Co-culture experiments were used to re-examine the ability of Vpr to be released by HIV-1 infected cells and to effectively accumulate in bystander B-cells. Vpr-mediated UNG2 modulations were monitored by following UNG2 protein abundance and uracil removal enzymatic activity. Results In this study we report the ability of Vpr to reduce immunoglobulin class switch recombination (CSR) in immortalized and primary mouse B-cells through the degradation of UNG2. We also emphasize that Vpr is released by producing cells and penetrates bystander B lymphocytes. Conclusions This work therefore opens up new perspectives to study alterations of the B-cell response by using Vpr as a specific CSR blocking tool. Moreover, our results raise the question of whether extracellular HIV-1 Vpr detected in some patients may manipulate the antibody diversification process that engineers an adapted response against pathogenic intruders and thereby contribute to the intrinsic B-cell humoral defect reported in infected patients.
Published: 2020
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11. Roles of G4-DNA and G4-RNA in Class Switch Recombination and Additional Regulations in B-Lymphocytes

Author: Ophélie Dézé, Brice Laffleur, and Michel Cogné
Subjects: G-quadruplex DNA, G4-ligand, class switch recombination, transcriptional regulation, B lymphocytes, G4-RNA, Organic chemistry, QD241-441
Abstract: Mature B cells notably diversify immunoglobulin (Ig) production through class switch recombination (CSR), allowing the junction of distant “switch” (S) regions. CSR is initiated by activation-induced deaminase (AID), which targets cytosines adequately exposed within single-stranded DNA of transcribed targeted S regions, with a specific affinity for WRCY motifs. In mammals, G-rich sequences are additionally present in S regions, forming canonical G-quadruplexes (G4s) DNA structures, which favor CSR. Small molecules interacting with G4-DNA (G4 ligands), proved able to regulate CSR in B lymphocytes, either positively (such as for nucleoside diphosphate kinase isoforms) or negatively (such as for RHPS4). G4-DNA is also implicated in the control of transcription, and due to their impact on both CSR and transcriptional regulation, G4-rich sequences likely play a role in the natural history of B cell malignancies. Since G4-DNA stands at multiple locations in the genome, notably within oncogene promoters, it remains to be clarified how it can more specifically promote legitimate CSR in physiology, rather than pathogenic translocation. The specific regulatory role of G4 structures in transcribed DNA and/or in corresponding transcripts and recombination hereby appears as a major issue for understanding immune responses and lymphomagenesis.
Published: 2023
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12. Committed Human CD23-Negative Light-Zone Germinal Center B Cells Delineate Transcriptional Program Supporting Plasma Cell Differentiation

Author: Kathleen Santamaria, Fabienne Desmots, Simon Leonard, Gersende Caron, Marion Haas, Céline Delaloy, Fabrice Chatonnet, Delphine Rossille, Amandine Pignarre, Céline Monvoisin, Marine Seffals, Claire Lamaison, Michel Cogné, Karin Tarte, and Thierry Fest
Subjects: germinal center (GC), germinal center (GC) B cells, CD23+ B cells, B cell differentiation, plasmablasts/plasma cells, GC Light-Zone B cells, Immunologic diseases. Allergy, RC581-607
Abstract: B cell affinity maturation occurs in the germinal center (GC). Light-zone (LZ) GC B cells (BGC-cells) interact with follicular dendritic cells (FDCs) and compete for the limited, sequential help from T follicular helper cells needed to escape from apoptosis and complete their differentiation. The highest-affinity LZ BGC-cells enter the cell cycle and differentiate into PCs, following a dramatic epigenetic reorganization that induces transcriptome changes in general and the expression of the PRDM1 gene in particular. Human PC precursors are characterized by the loss of IL-4/STAT6 signaling and the absence of CD23 expression. Here, we studied the fate of human LZ BGC-cells as a function of their CD23 expression. We first showed that CD23 expression was restricted to the GC LZ, where it was primarily expressed by FDCs; less than 10% of tonsil LZ BGC-cells were positive. Sorted LZ BGC-cells left in culture and stimulated upregulated CD23 expression but were unable to differentiate into PCs – in contrast to cells that did not upregulate CD23 expression. An in-depth analysis (including single-cell gene expression) showed that stimulated CD23-negative LZ BGC-cells differentiated into plasmablasts and time course of gene expression changes delineates the transcriptional program that sustains PC differentiation. In particular, we identified a B cell proliferation signature supported by a transient MYC gene expression. Overall, the CD23 marker might be of value in answering questions about the differentiation of normal BGC-cells and allowed us to propose an instructive LZ BGC-cells maturation and fate model.
Published: 2021
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13. UnAIDed Class Switching in Activated B-Cells Reveals Intrinsic Features of a Self-Cleaving IgH Locus

Author: Iman Dalloul, Brice Laffleur, Zeinab Dalloul, Batoul Wehbi, Florence Jouan, Baptiste Brauge, Paco Derouault, Jeanne Moreau, Sven Kracker, Alain Fischer, Anne Durandy, Sandrine Le Noir, and Michel Cogné
Subjects: B lymphocyte, class switch DNA recombination (CSR), AICDA, immunoglobulin, class switch, Immunologic diseases. Allergy, RC581-607
Abstract: Activation-induced deaminase (AID) is the major actor of immunoglobulin (Ig) gene diversification in germinal center B-cells. From its first description, it was considered as mandatory for class switch recombination (CSR), and this discovery initiated a long quest for all of the AID-interacting factors controlling its activity. The mechanisms focusing AID-mediated DNA lesions to given target sequences remain incompletely understood with regards the detailed characterization of optimal substrates in which cytidine deamination will lead to double strand breaks (DSBs) and chromosomal cleavage. In an effort to reconsider whether such CSR breaks absolutely require AID, we herein provide evidence, based on deep-sequencing approaches, showing that this dogma is not absolute in both human and mouse B lymphocytes. In activated B-cells from either AID-deficient mice or human AID-deficient patients, we report an intrinsic ability of the IgH locus to undergo “on-target” cleavage and subsequent synapsis of broken regions in conditions able to yield low-level CSR. DNA breaks occur in such conditions within the same repetitive S regions usually targeted by AID, but their repair follows a specific pathway with increased usage of microhomology-mediated repair. These data further demonstrate the role of AID machinery as not initiating de novo chromosomal cleavage but rather catalyzing a process which spontaneously initiates at low levels in an appropriately conformed IgH locus.
Published: 2021
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14. Comparative immune profiling of acute respiratory distress syndrome patients with or without SARS-CoV-2 infection

Author: Mikael Roussel, Juliette Ferrant, Florian Reizine, Simon Le Gallou, Joelle Dulong, Sarah Carl, Matheiu Lesouhaitier, Murielle Gregoire, Nadège Bescher, Clotilde Verdy, Maelle Latour, Isabelle Bézier, Marie Cornic, Angélique Vinit, Céline Monvoisin, Birgit Sawitzki, Simon Leonard, Stéphane Paul, Jean Feuillard, Robin Jeannet, Thomas Daix, Vijay K. Tiwari, Jean Marc Tadié, Michel Cogné, and Karin Tarte
Subjects: Medicine (General), R5-920
Abstract: Summary: Acute respiratory distress syndrome (ARDS) is the main complication of coronavirus disease 2019 (COVID-19), requiring admission to the intensive care unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS differs from other causes of ARDS remains unknown. To address this question, here, we build 3 cohorts of patients categorized in COVID-19−ARDS+, COVID-19+ARDS+, and COVID-19+ARDS−, and compare, by high-dimensional mass cytometry, their immune landscape. A cell signature associating S100A9/calprotectin-producing CD169+ monocytes, plasmablasts, and Th1 cells is found in COVID-19+ARDS+, unlike COVID-19−ARDS+ patients. Moreover, this signature is essentially shared with COVID-19+ARDS− patients, suggesting that severe COVID-19 patients, whether or not they experience ARDS, display similar immune profiles. We show an increase in CD14+HLA-DRlow and CD14lowCD16+ monocytes correlating to the occurrence of adverse events during the ICU stay. We demonstrate that COVID-19-associated ARDS displays a specific immune profile and may benefit from personalized therapy in addition to standard ARDS management.
Published: 2021
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15. An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence

Author: Chang-Han Lee, Tae Hyun Kang, Ophélie Godon, Makiko Watanabe, George Delidakis, Caitlin M. Gillis, Delphine Sterlin, David Hardy, Michel Cogné, Lynn E. Macdonald, Andrew J. Murphy, Naxin Tu, Jiwon Lee, Jonathan R. McDaniel, Emily Makowski, Peter M. Tessier, Aaron S. Meyer, Pierre Bruhns, and George Georgiou
Subjects: Science
Abstract: Lee et al. report an engineered IgG1 Fc domain that behaves like an hFcRn binding pH toggle switch. The authors show that this new half-life extension Fc domain confers improved pharmacokinetics in new humanized knock-in mouse strains that recapitulate the key processes for antibody persistence in circulation.
Published: 2019
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16. IgH 3' regulatory region increases ectopic class switch recombination.

Author: Sandrine Le Noir, Amélie Bonaud, Bastien Hervé, Audrey Baylet, François Boyer, Sandrine Lecardeur, Zeliha Oruc, Christophe Sirac, and Michel Cogné
Subjects: Genetics, QH426-470
Abstract: DNA lesions inflicted by activation-induced deaminase (AID) instrumentally initiate the processes reshaping immunoglobulin genes in mature B-cells, from local somatic hypermutation (SHM) to junctions of distant breaks during class switch recombination (CSR). It remains incompletely understood how these divergent outcomes of AID attacks are differentially and temporally focused, with CSR strictly occurring in the Ig heavy chain (IgH) locus while SHM concentrates on rearranged V(D)J regions in the IgH and Ig light chain loci. In the IgH locus, disruption of either the 3'Regulatory Region (3'RR) super-enhancer or of switch (S) regions preceding constant genes, profoundly affects CSR. Reciprocally, we now examined if these elements are sufficient to induce CSR in a synthetic locus based on the Igκ locus backbone. Addition of a surrogate "core 3'RR" (c3'RR) and of a pair of transcribed and spliced Switch regions, together with a reporter system for "κ-CSR" yielded a switchable Igκ locus. While the c3'RR stimulated SHM at S regions, it also lowered the local SHM threshold necessary for switch recombination to occur. The 3'RR thus both helps recruit AID to initiate DNA lesions, but then also promotes their resolution through long-distance synapses and recombination following double-strand breaks.
Published: 2021
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17. Bromodomain and extraterminal (BET) protein inhibition of IgG/IgE production in murine B cells is counter‐balanced by a strong Th2 bias

Author: Zeinab Dalloul, Marie Best, Pauline Chenuet, Iman Dalloul, Sandrine Le Noir, Dieudonnée Togbé, Mylène Gador, Bernhard Ryffel, Valerie FJ Quesniaux, Yolla El Makhour, François Boyer, Jean‐Claude Aldigier, Jeanne Cook‐Moreau, Nicolas Fazilleau, and Michel Cogné
Subjects: allergic inflammation, antibody class switching, bromodomain inhibition, immune response, Immunologic diseases. Allergy, RC581-607
Abstract: Abstract Objectives Inhibitors of bromodomain and extra terminal domain (BET) proteins are a new and growing class of anti‐cancer drugs, which decrease oncogene expression by targeting superenhancers. Antibody production is another physiological process relying on superenhancers, and it remains to be clarified whether potential immunomodulatory properties of BET inhibitors might impact humoral immunity and allergy. Methods We thus evaluated humoral immune responses and their Th2 context in vitro and in vivo in mice following treatment with the classical BET‐inhibitor JQ1. We quantified immunoglobulin (Ig) and antibody production by B cells either stimulated in vitro or obtained from immunised mice. JQ1 effects on class switching and activation‐induced deaminase loading were determined, together with modifications of B, T follicular helper (Tfh) and T helper 2 (Th2) populations. JQ1 was finally tested in B‐cell‐dependent models of immune disorders. Results Bromodomain and extra terminal domain inhibition reduced class switching, Ig expression on B cells and antibody secretion and was correlated with decreased numbers of Tfh cells. However, JQ1 strongly increased the proportion of GATA3+ Th2 cells and the secretion of corresponding cytokines. In a mouse allergic model of lung inflammation, JQ1 did not affect eosinophil infiltration or mucus production but enhanced Th2 cytokine production and aggravated clinical manifestations. Conclusion Altogether, BET inhibition thus interweaves intrinsic negative effects on B cells with a parallel complex reshaping of T‐cell polarisation which can increase type 2 cytokines and eventually promote B‐cell‐dependent immunopathology. These opposite and potentially hazardous immunomodulatory effects raise concerns for clinical use of BET inhibitors in patients with immune disorders.
Published: 2021
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18. Locus suicide recombination actively occurs on the functionally rearranged IgH allele in B-cells from inflamed human lymphoid tissues.

Author: Iman Dalloul, François Boyer, Zeinab Dalloul, Amandine Pignarre, Gersende Caron, Thierry Fest, Fabrice Chatonnet, Céline Delaloy, Anne Durandy, Robin Jeannet, Emilie Lereclus, Hend Boutouil, Jean-Claude Aldigier, Sophie Péron, Sandrine Le Noir, Jeanne Cook-Moreau, and Michel Cogné
Subjects: Genetics, QH426-470
Abstract: B-cell activation yields abundant cell death in parallel to clonal amplification and remodeling of immunoglobulin (Ig) genes by activation-induced deaminase (AID). AID promotes affinity maturation of Ig variable regions and class switch recombination (CSR) in mature B lymphocytes. In the IgH locus, these processes are under control of the 3' regulatory region (3'RR) super-enhancer, a region demonstrated in the mouse to be both transcribed and itself targeted by AID-mediated recombination. Alternatively to CSR, IgH deletions joining Sμ to "like-switch" DNA repeats that flank the 3' super-enhancer can thus accomplish so-called "locus suicide recombination" (LSR) in mouse B-cells. Using an optimized LSR-seq high throughput method, we now show that AID-mediated LSR is evolutionarily conserved and also actively occurs in humans, providing an activation-induced cell death pathway in multiple conditions of B-cell activation. LSR either focuses on the functional IgH allele or is bi-allelic, and its signature is mainly detected when LSR is ongoing while it vanishes from fully differentiated plasma cells or from "resting" blood memory B-cells. Highly diversified breakpoints are distributed either within the upstream (3'RR1) or downstream (3'RR2) copies of the IgH 3' super-enhancer and all conditions activating CSR in vitro also seem to trigger LSR although TLR ligation appeared the most efficient. Molecular analysis of breakpoints and junctions confirms that LSR is AID-dependent and reveals junctional sequences somehow similar to CSR junctions but with increased usage of microhomologies.
Published: 2019
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19. Deciphering the importance of the palindromic architecture of the immunoglobulin heavy-chain 3’ regulatory region

Author: Alexis Saintamand, Christelle Vincent-Fabert, Armand Garot, Pauline Rouaud, Zeliha Oruc, Virginie Magnone, Michel Cogné, and Yves Denizot
Subjects: Science
Abstract: The IgH3’ regulatory region contains an evolutionarily conserved palindromic sequence flanking important enhancer elements. Here the authors show that the palindrome is required for generating antibody diversity.
Published: 2016
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20. Comprehensive molecular characterization of a heavy chain deposition disease case

Author: Sébastien Bender, Maria Victoria Ayala, Vincent Javaugue, Amélie Bonaud, Michel Cogné, Guy Touchard, Arnaud Jaccard, Frank Bridoux, and Christophe Sirac
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2018
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21. Self-Restrained B Cells Arise following Membrane IgE Expression

Author: Brice Laffleur, Sophie Duchez, Karin Tarte, Nicolas Denis-Lagache, Sophie Péron, Claire Carrion, Yves Denizot, and Michel Cogné
Subjects: Biology (General), QH301-705.5
Abstract: Among immunoglobulins (Igs), IgE can powerfully contribute to antimicrobial immunity and severe allergy despite its low abundance. IgE protein and gene structure resemble other Ig classes, making it unclear what constrains its production to thousand-fold lower levels. Whether class-switched B cell receptors (BCRs) differentially control B cell fate is debated, and study of the membrane (m)IgE class is hampered by its elusive in vivo expression. Here, we demonstrate a self-controlled mIgE+ B cell stage. Primary or transfected mIgE+ cells relocate the BCRs into spontaneously internalized lipid rafts, lose mobility to chemokines, and change morphology. We suggest that combined proapoptotic mechanisms possibly involving Hax1 prevent mIgE+ memory lymphocyte accumulation. By uncoupling in vivo IgE switching from cytokine and antigen stimuli, we show that these features are independent from B cell stimulation and instead result from mIgE expression per se. Consequently, few cells survive IgE class switching, which might ensure minimal long-term IgE memory upon differentiation into plasma cells.
Published: 2015
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22. B Cell Intrinsic Mechanisms Constraining IgE Memory

Author: Brice Laffleur, Orianne Debeaupuis, Zeinab Dalloul, and Michel Cogné
Subjects: IgE, B cell receptor, B-lymphocytes, IgE regulation, IgE memory, Immunologic diseases. Allergy, RC581-607
Abstract: Memory B cells and long-lived plasma cells are key elements of adaptive humoral immunity. Regardless of the immunoglobulin class produced, these cells can ensure long-lasting protection but also long-lasting immunopathology, thus requiring tight regulation of their generation and survival. Among all antibody classes, this is especially true for IgE, which stands as the most potent, and can trigger dramatic inflammatory reactions even when present in minute amounts. IgE responses and memory crucially protect against parasites and toxic components of venoms, conferring selective advantages and explaining their conservation in all mammalian species despite a parallel broad spectrum of IgE-mediated immunopathology. Long-term memory of sensitization and anaphylactic responses to allergens constitute the dark side of IgE responses, which can trigger multiple acute or chronic pathologic manifestations, some punctuated with life-threatening events. This Janus face of the IgE response and memory, both necessary and potentially dangerous, thus obviously deserves the most elaborated self-control schemes.
Published: 2017
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23. Characterization of human FCRL4-positive B cells.

Author: Michel Jourdan, Nicolas Robert, Maïlys Cren, Coraline Thibaut, Christophe Duperray, Alboukadel Kassambara, Michel Cogné, Karin Tarte, Bernard Klein, and Jérôme Moreaux
Subjects: Medicine, Science
Abstract: FCRL4 is an immunoregulatory receptor that belongs to the Fc receptor-like (FCRL) family. In healthy individuals, FCRL4 is specifically expressed by memory B cells (MBCs) localized in sub-epithelial regions of lymphoid tissues. Expansion of FCRL4+ B cells has been observed in blood and other tissues in various infectious and autoimmune disorders. Currently, the mechanisms involved in pathological FCRL4+ B cell generation are actively studied, but they remain elusive. As in vivo FCRL4+ cells are difficult to access and to isolate, here we developed a culture system to generate in vitro FCRL4+ B cells from purified MBCs upon stimulation with soluble CD40 ligand and/or CpG DNA to mimic T-cell dependent and/or T-cell independent activation, respectively. After 4 days of stimulation, FCRL4+ B cells represented 17% of all generated cells. Transcriptomic and phenotypic analyses of in vitro generated FCRL4+ cells demonstrated that they were closely related to FCRL4+ tonsillar MBCs. They strongly expressed inhibitory receptor genes, as observed in exhausted FCRL4+ MBCs from blood samples of HIV-infected individuals with high viremia. In agreement, cell cycle genes were significantly downregulated and the number of cell divisions was two-fold lower in in vitro generated FCRL4+ than FCRL4- cells. Finally, due to their reduced proliferation and differentiation potential, FCRL4+ cells were less prone to differentiate into plasma cells, differently from FCRL4- cells. Our in vitro model could be of major interest for studying the biology of normal and pathological FCRL4+ cells.
Published: 2017
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24. Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence

Author: Chang-Han Lee, Tae Hyun Kang, Ophélie Godon, Makiko Watanabe, George Delidakis, Caitlin M. Gillis, Delphine Sterlin, David Hardy, Michel Cogné, Lynn E. Macdonald, Andrew J. Murphy, Naxin Tu, Jiwon Lee, Jonathan R. McDaniel, Emily Makowski, Peter M. Tessier, Aaron S. Meyer, Pierre Bruhns, and George Georgiou
Subjects: Science
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Published: 2019
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25. Activation-induced deaminase in B lymphocyte maturation and beyond

Author: Michel Cogné
Subjects: Activation-induced deaminase, class-switching, hypermutation, locus suicide, lymphomagenesis, Medicine (General), R5-920, Biology (General), QH301-705.5
Abstract: Activation-induced deaminase (AID), a member of the AID/apolipoprotein B mRNA-editing enzyme-catalytic (APOBEC) family, deaminates DNA cytidines into uridines and is the major trans-acting player of immunoglobulin (Ig) genes' diversification in mature B lymphocytes. It allows multiple antigen-driven Ig modifications through gene conversion and/or somatic hypermutation of variable region genes and also permits to switch from IgM expression to other antibody classes after class switch recombination, or to stop Ig expression after locus suicide recombination. AID is expressed at high levels into germinal center activated B cells with a very stringent temporal and spatial regulation. Despite multiple levels of regulation, off-target effects of AID are quite frequent in the B cell lineage and can affect a number of non-Ig genes, albeit at lower level than Ig genes. Beyond the immune system, AID also contributes to cytosine demethylation in undifferentiated cells by deaminating methylcytosines into thymines which are further processed by thymidine glycosylase. This contributes to the maintenance of pluripotency and to the limitation of genetic imprinting. Since AID attacks on DNA can induce replication errors, base excision repair, or mismatch repair, they are strongly mutagenic and are also driving forces of tumorigenesis, not only in B cell malignancies but also in some non-lymphoid tumors involving ectopic AID expression.
Published: 2013
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26. Anti-CD20 IgA can protect mice against lymphoma development: evaluation of the direct impact of IgA and cytotoxic effector recruitment on CD20 target cells

Author: Virginie Pascal, Brice Laffleur, Arnaud Debin, Armelle Cuvillier, Marjolein van Egmond, Daniel Drocourt, Laurent Imbertie, Céline Pangault, Karin Tarte, Gérard Tiraby, and Michel Cogné
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Abstract: Background While most antibody-based therapies use IgG because of their well-known biological properties, some functional limitations of these antibodies call for the development of derivatives with other therapeutic functions. Although less abundant than IgG in serum, IgA is the most abundantly produced Ig class in humans. Besides the specific targeting of its dimeric form to mucosal areas, IgA was shown to recruit polymorphonuclear neutrophils against certain targets more efficiently than does IgG1.Design and Methods In this study, we investigated the various pathways by which anti-tumor effects can be mediated by anti-CD20 IgA against lymphoma cells.Results We found that polymeric human IgA was significantly more effective than human IgG1 in mediating direct killing or growth inhibition of target cells in the absence of complement. We also demonstrated that this direct killing was able to indirectly induce the classical pathway of the complement cascade although to a lesser extent than direct recruitment of complement by IgG. Recruitment of the alternative complement pathway by specific IgA was also observed. In addition to activating complement for lysis of lymphoma cell lines or primary cells from patients with lymphoma, we showed that monomeric anti-CD20 IgA can effectively protect mice against tumor development in a passive immunization strategy and we demonstrated that this protective effect may be enhanced in mice expressing the human FcαRI receptor on their neutrophils.Conclusions We show that anti-CD20 IgA antibodies have original therapeutic properties against lymphoma cells, with strong direct effects, ability to recruit neutrophils for cell cytotoxicity and even recruitment of complement, although largely through an indirect way.
Published: 2012
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27. G4-DNA, Class Switch Recombination and Potential Additional Regulations in B-Lymphocytes

Author: Ophélie Dezé, Brice Laffleur, and Michel Cogné
Subjects: immunology
Abstract: Mature B cells notably diversify immunoglobulin (Ig) production through class switch recombination (CSR), allowing the junction of distant “switch” (S) regions. CSR is initiated by activation-induced deaminase (AID) which targets cytosines adequately exposed within single-stranded DNA of transcribed targeted S regions, with a specific affinity for WRCY motifs. In mammals, G-rich sequences are additionally present in S regions, forming canonical G-quadruplexes (G4s) DNA structures which favor CSR. Small molecules interacting with G4-DNA (G4 ligands), proved able to regulate CSR in B lymphocytes, either positively (such as for nucleoside diphosphate kinase isoforms) or negatively (such as for RHPS4). G4-DNA is also implicated in the control of transcription, and due to their impact on both CSR and transcriptional regulation, G4-rich sequences likely play a role in the natural history of B cell malignancies. Since G4-DNA stands at multiple locations in the genome, and notably within oncogene promoters, it remains to be clarified how it can more specifically promote legitimate CSR in physiology, rather than pathogenic translocation. The specific regulatory role of G4 structures in transcribed DNA and/or in corresponding transcripts and recombination hereby appears as a major issue for understanding immune responses and lymphomagenesis.
Published: 2022

28. Single-hit genome edition for expression of single-chain immunoglobulins by edited B cells

Author: Natsuko Ueda, Marine Cahen, Christophe Sirac, Anne Galy, Jérôme Moreaux, Yannic Danger, and Michel Cogné
Abstract: Lymphocytes have become attractive agents for adoptive immunotherapy but only the reformatting of T cells is efficiently mastered. Despite some recent breakthroughs, B cells remain challenging targets, with regard to both their long-term survival after in vitro manipulation and the rewiring of immunoglobulin (Ig) expression. Working on these two aspects, we have designed a new format of single-chain Ig (“scFull-Ig”) coding cassette, the insertion of which at a single genomic position can redirect B cells toward a new antigen specificity, while preserving all functional domains of the B cell receptor. Precise genomic edition at a single locus then provides the most efficient and safe strategy to both disrupt endogenous Ig expression while encoding a new Ig paratope. As proofs of concept, functionality of such scFull BCR was validated by checking specific binding of two different classical targets of tumor immunotherapy, HER2 and CD20. Once the strategy validated in cell lines, it was also validated in primary B cells, again showing successful engineering of BCR expression. These results contribute to pave the way for future B cell-based adoptive cell therapy.
Published: 2022

29. SARS-CoV-2-Induced ARDS Associates with MDSC Expansion, Lymphocyte Dysfunction, and Arginine Shortage

Author: Joelle Dulong, Kieran Pinceaux, Claude Bendavid, Benoit Painvin, Mikael Roussel, Pierre Tattevin, Murielle Gregoire, Yoann Launey, Simon Le Gallou, Jean-Marc Tadié, Audrey Le Bot, Thomas Lebouvier, Berengère Cador-Rousseau, Karin Tarte, Christophe Camus, Adel Maamar, Caroline Moreau, Mathieu Lesouhaitier, Mathieu Lederlin, Michel Cogné, Delphine Rossille, Arnaud Gacouin, Matthieu Revest, Florian Reizine, Yves Le Tulzo, Alice Ballerie, Maelle Latour, Clotilde Verdy, Chard-Hutchinson, Xavier, CHU Pontchaillou [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), University hospital of Rennes, France, Fondation pour la Recherche MedicaleFondation pour la Recherche Medicale, Agence Nationale de la Recherche (ANR, Flash CoViD 'HARMONICOV ') grantFrench National Research Agency (ANR), Fondation de l'Avenir grant (Prix des donateurs, Mutualite Fonction Publique), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and ANR-20-COVI-0039,HARMONICOV,Immunomonitoring haute définition & caractérisation d'anticorps spécifiques chez des patients CoV-2 critiques versus en rémission(2020)
Subjects: Male, 0301 basic medicine, ARDS, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Lymphocyte, MDSC, Immunology, Arginine, Severity of Illness Index, law.invention, 03 medical and health sciences, 0302 clinical medicine, Cross infection, law, Lymphopenia, medicine, Humans, Immunology and Allergy, Prospective Studies, Lymphocytes, Aged, Mechanical ventilation, Respiratory Distress Syndrome, SARS-CoV-2, business.industry, Myeloid-Derived Suppressor Cells, Mortality rate, Immunosuppression, Middle Aged, medicine.disease, Intensive care unit, 3. Good health, [SDV] Life Sciences [q-bio], Arginase, Pneumonia, 030104 developmental biology, medicine.anatomical_structure, Original Article, Female, Covid-19, business, 030215 immunology
Abstract: Purpose The SARS-CoV-2 infection can lead to a severe acute respiratory distress syndrome (ARDS) with prolonged mechanical ventilation and high mortality rate. Interestingly, COVID-19-associated ARDS share biological and clinical features with sepsis-associated immunosuppression since lymphopenia and acquired infections associated with late mortality are frequently encountered. Mechanisms responsible for COVID-19-associated lymphopenia need to be explored since they could be responsible for delayed virus clearance and increased mortality rate among intensive care unit (ICU) patients. Methods A series of 26 clinically annotated COVID-19 patients were analyzed by thorough phenotypic and functional investigations at days 0, 4, and 7 after ICU admission. Results We revealed that, in the absence of any difference in demographic parameters nor medical history between the two groups, ARDS patients presented with an increased number of myeloid-derived suppressor cells (MDSC) and a decreased number of CD8pos effector memory cell compared to patients hospitalized for COVID-19 moderate pneumonia. Interestingly, COVID-19-related MDSC expansion was directly correlated to lymphopenia and enhanced arginase activity. Lastly, T cell proliferative capacity in vitro was significantly reduced among COVID-19 patients and could be restored through arginine supplementation. Conclusions The present study reports a critical role for MDSC in COVID-19-associated ARDS. Our findings open the possibility of arginine supplementation as an adjuvant therapy for these ICU patients, aiming to reduce immunosuppression and help virus clearance, thereby decreasing the duration of mechanical ventilation, nosocomial infection acquisition, and mortality. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-020-00920-5.
Published: 2021

30. Homéostasie de la réponse IgA et microbiote

Author: Margaux Hiblot, Batoul Wehbi, Virginie Pascal, Jean-Claude Aldigier, Michel Cogné, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Rennes] (EFS Bretagne), Les auteurs ont bénéficié du soutien d’un contrat de l’Agence nationale de la recherche (ANR-16-CE15-0019-01) et de l’Institut national contre le cancer (INCA-12642)., and ANR-16-CE15-0019,Ig-MemImpact,Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique(2016)
Subjects: 0303 health sciences, biology, [SDV]Life Sciences [q-bio], medicine.medical_treatment, General Medicine, Immunotherapy, medicine.disease, Mucosal vaccine, Inflammatory bowel disease, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Antigen, Immunology, medicine, biology.protein, Superantigen, Antibody, Mucosal immunity, Homeostasis, 030304 developmental biology, 030215 immunology
Abstract: L’immunité muqueuse s’établit en réponse à un ensemble de microorganismes qui sont surtout commensaux mais aussi, parfois, pathogènes. À cette dualité, les immunoglobulines de classe A (IgA) opposent une balance fonctionnelle allant de la tolérance à la protection, voire à une hyper-inflammation. Des travaux récents ont révélé la liaison d’IgA polyréactives naturelles ou, à l’inverse, d’IgA spécifiquement affines et protectrices, au microbiote commensal, mais aussi à des super-antigènes ou encore à des vaccins muqueux. Différents types de réponse humorale s’associent ainsi pour composer, ensemble, l’homéostasie de l’immunité muqueuse. Leur connaissance devrait ainsi influencer les stratégies de vaccination muqueuse et également les immunothérapies ciblant les maladies inflammatoires chroniques de l’intestin.
Published: 2021

31. A comparison of Sars-Cov-2 vaccine platforms: the CoviCompare project

Author: Diana Molino, Christine Durier, Anne Radenne, Corinne Desaint, Jacques Ropers, Soizic Courcier, Louis Victorien Vieillard, Claire Rekacewicz, Beatrice Parfait, Victor Appay, Frédéric Batteux, Emmanuel Barillot, Michel Cogné, Béhazine Combadière, Christiane S. Eberhardt, Guy Gorochov, Philippe Hupé, Laetitia Ninove, Stéphane Paul, Isabelle Pellegrin, Sylvie van der Werf, Maeva Lefebvre, Elisabeth Botelho-Nevers, Inmaculada Ortega-Perez, Marie Jaspard, Samba Sow, Jean Daniel Lelièvre, Xavier de Lamballerie, Marie Paule Kieny, Eric Tartour, Odile Launay, CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), F-CRIN, Innovative clinical research network in vaccinology (I-REIVAC), Essais Thérapeutiques et Maladies Infectieuses, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière] (CIC Paris-Est), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Composantes innées de la réponse immunitaire et différenciation (CIRID), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Faculté de médecine [Genève], Biologie Cellulaire et Cancer, Institut Curie [Paris]-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche pour le Développement (IRD), Physiologie cellulaire des régulations hormonale, nutritionnelles et pharmacologiques (UMR-S-530), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Alliance for International medical Action (ALIMA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre pour le Développement des Vaccins [Mali], Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Biochimie des Lipides, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Ministere des Solidarites et de la Sante, Ministere de l'Enseignement Superieur, de la Recherche et de l'Innovation, Coalition for Epidemic Preparedness Innovations (CEPI), ANRS \Emerging Infectious Diseases, ANR-20-COV3-0004,CoMemRep,Caractérisation des complexes de réplication associés à la membrane du SARS CoV 2(2020), Unité de Recherche Clinique des hôpitaux Pitié-Salpêtrière – Charles Foix [CHU Pitié Salpêtrière] (URC PSL-CFX), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Direction de la Recherche Clinique et de l'Innovation [AP-HP] (DRCI), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Chard-Hutchinson, Xavier, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
Subjects: [SDV] Life Sciences [q-bio], COVID-19 Vaccines, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, SARS-CoV-2, [SDV]Life Sciences [q-bio], Spike Glycoprotein, Coronavirus, COVID-19, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, General Medicine, General Biochemistry, Genetics and Molecular Biology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2022

32. Beneficial effects of citrulline enteral administration on sepsis-induced T cell mitochondrial dysfunction

Author: Florian Reizine, Murielle Grégoire, Mathieu Lesouhaitier, Valentin Coirier, Juliette Gauthier, Céline Delaloy, Elise Dessauge, Florent Creusat, Fabrice Uhel, Arnaud Gacouin, Frédéric Dessauge, Cécile Le Naoures, Caroline Moreau, Claude Bendavid, Yoann Daniel, Kilian Petitjean, Valérie Bordeau, Claire Lamaison, Caroline Piau, Vincent Cattoir, Mikael Roussel, Bernard Fromenty, Christian Michelet, Yves Le Tulzo, Jaroslaw Zmijewski, Ronan Thibault, Michel Cogné, Karin Tarte, Jean-Marc Tadié, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Etablissement Français du Sang Bretagne, EFS, Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie, Environnement et Génétique pour l'Animal et les Systèmes d'Elevage [Rennes] (PEGASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Agro Rennes Angers, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ARN régulateurs bactériens et médecine (BRM), Centre National de Référence de la Résistance aux Antibiotiques [CHU Rennes] (CNR), University of Alabama at Birmingham [ Birmingham] (UAB), This work was supported by funding from the Société de Réanimation de Langue Française (SRLF, Bourses Master 2 SRLF). We also thank the animal house Animalerie Rennaise Centre d’Hébergement et d’Expérimentation (ARCHE) platform and H2P2 platform (Structure Fédérative de Recherche [SFR] Biosit), and Aude Bodin for her help with mitochondrial functions analysis., Jonchère, Laurent, and Center of Experimental and Molecular Medicine
Subjects: Immunosuppression Therapy, Multidisciplinary, Myeloid-Derived Suppressor Cells, T-Lymphocytes, [SDV]Life Sciences [q-bio], Biological Availability, T cell, [SDV.CAN]Life Sciences [q-bio]/Cancer, Arginine, Lymphocyte Activation, T-Lymphocytes, Regulatory, Mitochondria, Mice, Inbred C57BL, [SDV] Life Sciences [q-bio], Disease Models, Animal, Mice, [SDV.CAN] Life Sciences [q-bio]/Cancer, Sepsis, Immune Tolerance, Animals, Cytokines, Citrulline, Female
Abstract: International audience; Severe sepsis induces a sustained immune dysfunction associated with poor clinical behavior. In particular, lymphopenia along with increased lymphocyte apoptosis and decreased lymphocyte proliferation, enhanced circulating regulatory T cells (Treg), and the emergence of myeloid-derived suppressor cells (MDSCs) have all been associated with persistent organ dysfunction, secondary infections, and late mortality. The mechanisms involved in MDSC-mediated T cell dysfunction during sepsis share some features with those described in malignancies such as arginine deprivation. We hypothesized that increasing arginine availability would restore T cell function and decrease sepsis-induced immunosuppression. Using a mouse model of sepsis based on cecal ligation and puncture and secondary pneumonia triggered by methicillin-resistant Staphylococcus aureus inoculation, we demonstrated that citrulline administration was more efficient than arginine in increasing arginine plasma levels and restoring T cell mitochondrial function and proliferation while reducing sepsis-induced Treg and MDSC expansion. Because there is no specific therapeutic strategy to restore immune function after sepsis, we believe that our study provides evidence for developing citrulline-based clinical studies in sepsis.
Published: 2022

33. Demultiplexing Ig Repertoires by Parallel mRNA/DNA Sequencing Shows Major Differential Alterations in Severe COVID-19

Author: Virginie Pascal, Marine Dupont, Paco de Rouault, David Rizzo, Delphine Rossille, Robin Jeannet, Thomas Daix, Bruno François, Guillaume Monneret, Fabienne Venet, Juliette Ferrant, Mikael Roussel, Florian Reizine, Mathieu Le Souhaitier, Jean-Marc Tadié, Karin Tarte, Jean Feuillard, and Michel Cogné
Published: 2022

34. Distinct B-Cell Specific Transcriptional Contexts of the BCL2 Oncogene Impact Pre-Malignant Development in Mouse Models

Author: Lina Zawil, Tiffany Marchiol, Baptiste Brauge, Alexis Saintamand, Claire Carrion, Elise Dessauge, Christelle Oblet, Sandrine Le Noir, Frédéric Mourcin, Mylène Brousse, Paco Derouault, Mehdi Alizadeh, Yolla El Makhour, Céline Monvoisin, Julien Saint-Vanne, Simon Léonard, Stéphanie Durand-Panteix, Karin Tarte, Michel Cogné, Chard-Hutchinson, Xavier, Laboratoires d'excellence - Immunothérapies Grand Ouest - - IGO2011 - ANR-11-LABX-0016 - LABX - VALID, Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique - - Ig-MemImpact2016 - ANR-16-CE15-0019 - AAPG2016 - VALID, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-OmégaHealth (ΩHealth), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Microenvironment and B-cells: Immunopathology,Cell Differentiation, and Cancer (MOBIDIC), Université de Rennes (UR)-Etablissement français du sang [Rennes] (EFS Bretagne)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Dupuytren [CHU Limoges], Lebanese University [Beirut] (LU), CHU Pontchaillou [Rennes], LabEX IGO Immunothérapie Grand Ouest, Nantes Université (Nantes Univ), Fondation ARC pour la Recherche sur le Cancer [PGA RF20180207070], Institut National du cancer [INCA 2018-133], Agence Nationale de la Recherche (ANR) [ANR-16-CE15-0019-01/03], Leukemia Lymphoma Society [TRP 6593-20], Rennes Metropole, LabEx IGO program - 'Investment into the Future' French Government program [ANR-11-LABX-0016], ANR-11-LABX-0016,IGO,Immunothérapies Grand Ouest(2011), and ANR-16-CE15-0019,Ig-MemImpact,Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique(2016)
Subjects: [SDV] Life Sciences [q-bio], Cancer Research, oncogene deregulation, Oncology, germinal center, [SDV]Life Sciences [q-bio], translocation, lymphoma, plasmacytosis
Abstract: International audience; Simple Summary Beyond the classical t(14;18) translocation associated with follicular lymphoma, BCL2 is deregulated in multiple B-cell malignancies, including some cases of myeloma, and through diverse genetic anomalies. It is currently unclear how the various deregulation patterns mechanistically impact the phenotype of theses malignancies. We designed two different BCL2 deregulation models in transgenic mice, whereby the oncogene was either associated with the IgH3 ' RR superenhancer, as in t(14;18), or inserted into the kappa light chain locus. We compared the impact of these models on B-cell fate and lymphoid tissues. Linkage to the IgH superenhancer showed a quite specific impact on germinal center B cell populations. The Ig kappa model was much less specific and strongly boosted the plasma cell in-flow and the accumulation of long-lived plasma cells. Upregulated expression of the anti-apoptotic BCL2 oncogene is a common feature of various types of B-cell malignancies, from lymphoma to leukemia or myeloma. It is currently unclear how the various patterns of deregulation observed in pathology eventually impact the phenotype of malignant B cells and their microenvironment. Follicular lymphoma (FL) is the most common non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells, and its major hallmark is the t(14:18) translocation occurring in B cell progenitors and placing the BCL2 gene under the control of the immunoglobulin heavy chain locus regulatory region (IgH 3 ' RR), thus exposing it to constitutive expression and hypermutation. Translocation of BCL2 onto Ig light chain genes, BCL2 gene amplification, and other mechanisms yielding BCL2 over-expression are, in contrast, rare in FL and rather promote other types of B-cell lymphoma, leukemia, or multiple myeloma. In order to assess the impact of distinct BCL2 deregulation patterns on B-cell fate, two mouse models were designed that associated BCL2 and its full P1-P2 promoter region to either the IgH 3 ' RR, within a "3 ' RR-BCL2" transgene mimicking the situation seen in FL, or an Ig light chain locus context, through knock-in insertion at the Ig kappa locus ("Ig kappa-BCL2" model). While linkage to the IgH 3 ' RR mostly yielded expression in GC B-cells, the Ig kappa-driven up-regulation culminated in plasmablasts and plasma cells, boosting the plasma cell in-flow and the accumulation of long-lived plasma cells. These data demonstrate that the timing and level of BCL2 deregulation are crucial for the behavior of B cells inside GC, an observation that could strongly impact the lymphomagenesis process triggered by secondary genetic hits.
Published: 2022

35. 212Pb α-Radioimmunotherapy Targeting CD38 in Multiple Myeloma: A Preclinical Study

Author: Michel Cogné, Stéphanie Durand-Panteix, Amal Saidi, Jérémy Mounier, Jacques Monteil, Isabelle Quelven, Audrey Bayout, Julie Garrier, and Magali Sage
Subjects: 0301 basic medicine, Biodistribution, medicine.medical_treatment, Plasma cell, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Radiology, Nuclear Medicine and imaging, Basic, α-radioimmunotherapy, Multiple myeloma, business.industry, Radionuclide Therapy, Daratumumab, medicine.disease, Acute toxicity, multiple myeloma, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Radioimmunotherapy, Toxicity, Cancer research, 212Pb, business, CD38
Abstract: Multiple myeloma (MM) is a plasma cell cancer and represents the second most frequent hematologic malignancy. Despite new treatments and protocols, including high-dose chemotherapy associated with autologous stem cell transplantation, the prognosis of MM patients is still poor. α-radioimmunotherapy (α-RIT) represents an attractive treatment strategy because of the high-linear-energy transfer and short pathlength of α-radiation in tissues, resulting in high tumor cell killing and low toxicity to surrounding tissues. In this study, we investigated the potential of α-RIT with 212Pb-daratumumab (anti-hCD38), in both in vitro and in vivo models, as well as an antimouse CD38 antibody using in vivo models. Methods: Inhibition of cell proliferation after incubation of the RPMI8226 cell line with an increasing activity (0.185–3.7 kBq/mL) of 212Pb-isotypic control or 212Pb-daratumumab was evaluated. Biodistribution was performed in vivo by SPECT/CT imaging and after death. Dose-range–finding and acute toxicity studies were conducted. Because daratumumab does not bind the murine CD38, biodistribution and dose-range finding were also determined using an antimurine CD38 antibody. To evaluate the in vivo efficacy of 212Pb-daratumumab, mice were engrafted subcutaneously with 5 × 106 RPMI8226 cells. Mice were treated 13 d after engraftment with an intravenous injection of 212Pb-daratumumab or control solution. Therapeutic efficacy was monitored by tumor volume measurements and overall survival. Results: Significant inhibition of proliferation of the human myeloma RPMI8226 cell line was observed after 3 d of incubation with 212Pb-daratumumab, compared with 212Pb-isotypic control or cold antibodies. Biodistribution studies showed a specific tumoral accumulation of daratumumab. No toxicity was observed with 212Pb-daratumumab up to 370 kBq because of lack of cross-reactivity. Nevertheless, acute toxicity experiments with 212Pb-anti-mCD38 established a toxic activity of 277.5 kBq. To remain within realistically safe treatment activities for efficacy studies, mice were treated with 185 kBq or 277.5 kBq of 212Pb-daratumumab. Marked tumor growth inhibition compared with controls was observed, with a median survival of 55 d for 277.5 kBq of 212Pb-daratumumab instead of 11 d for phosphate-buffered saline. Conclusion: These results showed 212Pb-daratumumab to have efficacy in xenografted mice, with significant tumor regression and increased survival. This study highlights the potency of α-RIT in MM treatment.
Published: 2019

36. Fam72a enforces error-prone DNA repair during antibody diversification

Author: Michel Cogné, Brice Laffleur, Ophelie Martin, Bernardo Reina-San-Martin, Mélanie Rogier, Isabelle Robert, Jacques Moritz, Katia Capitani, Arthur Abello, Eric Pinaud, Florence Jouan, Ludovic Deriano, Anne-Sophie Thomas-Claudepierre, Vincent Heyer, Evi Soutoglou, Karin Tarte, Chloé Lescale, Morgane Thomas, Silvestro G. Conticello, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Intégrité du génome, immunité et cancer - Genome integrity, Immunity and Cancer, Institut Pasteur [Paris], Physiopathologie du système immunitaire (Inserm U1223), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], University of Sussex, Università degli Studi di Siena = University of Siena (UNISI), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), This study was supported by grants from the Fondation Recherche Médicale (Equipe FRM EQU201903007818 to B.R.-S.-M.), Institut National du Cancer (INCa_13852 to L.D. and B.R.-S.-M.), Fondation ARC (ARCPJA32020060002061 to B.R.-S.-M.), the Ligue Nationale contre le Cancer (Equipe labellisée to L.D.) and by the grant ANR-10-LABX-0030-INRT, a French state fund managed by the Agence Nationale de la Recherche under the program Investissements d’Avenir labelled ANR-10-IDEX-0002-02., ANR-10-LABX-0030,INRT,Integrative Biology : Nuclear dynamics- Regenerative medicine - Translational medicine(2010), ANR-10-IDEX-0002,UNISTRA,Par-delà les frontières, l'Université de Strasbourg(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), and Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Male, DNA damage, DNA repair, Somatic hypermutation, DNA Mismatch Repair, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Cytidine deamination, Animals, Uracil, 030304 developmental biology, 0303 health sciences, B-Lymphocytes, Multidisciplinary, Genome, Mutagenesis, Immunoglobulin Class Switching, 3. Good health, Cell biology, Immunoglobulin Switch Region, Up-Regulation, chemistry, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Uracil-DNA glycosylase, Mutation, DNA mismatch repair, Female, Somatic Hypermutation, Immunoglobulin, CRISPR-Cas Systems, DNA
Abstract: Efficient humoral responses rely on DNA damage, mutagenesis and error-prone DNA repair. Diversification of B cell receptors through somatic hypermutation and class-switch recombination are initiated by cytidine deamination in DNA mediated by activation-induced cytidine deaminase (AID)1 and by the subsequent excision of the resulting uracils by uracil DNA glycosylase (UNG) and by mismatch repair proteins1–3. Although uracils arising in DNA are accurately repaired1–4, how these pathways are co-opted to generate mutations and double-strand DNA breaks in the context of somatic hypermutation and class-switch recombination is unknown1–3. Here we performed a genome-wide CRISPR–Cas9 knockout screen for genes involved in class-switch recombination and identified FAM72A, a protein that interacts with the nuclear isoform of UNG (UNG2)5 and is overexpressed in several cancers5. We show that the FAM72A–UNG2 interaction controls the levels of UNG2 and that class-switch recombination is defective in Fam72a−/− B cells due to the upregulation of UNG2. Moreover, we show that somatic hypermutation is reduced in Fam72a−/− B cells and that its pattern is skewed upon upregulation of UNG2. Our results are consistent with a model in which FAM72A interacts with UNG2 to control its physiological level by triggering its degradation, regulating the level of uracil excision and thus the balance between error-prone and error-free DNA repair. Our findings have potential implications for tumorigenesis, as reduced levels of UNG2 mediated by overexpression of Fam72a would shift the balance towards mutagenic DNA repair, rendering cells more prone to acquire mutations. FAM72A interacts with UNG2 to regulate the balance between error-prone and error-free DNA repair.
Published: 2021

37. RNA-based immunoglobulin repertoire sequencing is a new tool for the management of monoclonal gammopathy of renal (kidney) significance

Author: Alexis Saintamand, Frank Bridoux, Sarah Nasraddine, Mathilde Dargelos, Michel Cogné, Estelle Desport, Sabrina Bouyer, Mehdi Alizadeh, Vincent Javaugue, Paco Derouault, Sébastien Bender, Matthieu Filloux, Virginie Pascal, Christophe Sirac, Arnaud Jaccard, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre hospitalier universitaire de Poitiers (CHU Poitiers), CHU Limoges, Etablissement français du sang [Rennes] (EFS Bretagne), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Chard-Hutchinson, Xavier, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and This work was supported by grants from AREN Poitou-Charentes, Comitéd’Orientation de la Recherche en Cancérologie (CORC), Limousin committees of Liguenationale contre le cancer, Agence régionale de la santé, Institut Universitaire de France,'Association Française contre l’Amylose' and 'Fondation Française pour la Recherche contrele Myélome et les Gammapathies' The authors acknowledge A. Rinsant and A. Lehericy fortheir technical assistance and E. Guerin of the sequencing technical plateform of CHU Limoges
Subjects: Ig, [SDV]Life Sciences [q-bio], Clone (cell biology), Paraproteinemias, Somatic hypermutation, monoclonal gammopathy of renal significance, Biology, Immunoglobulin light chain, Kidney, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, AL-amyloidosis, 030304 developmental biology, 0303 health sciences, medicine.disease, Isotype, Molecular biology, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, MRNA Sequencing, Nephrology, 030220 oncology & carcinogenesis, biology.protein, RNA, Immunoglobulin Light Chains, Kidney Diseases, next-generation sequencing, Bone marrow, Antibody, Kidney disease
Abstract: International audience; The diagnostic approach of monoclonal gammopathy of renal significance is based on the detection of a monoclonal immunoglobulin in the blood and urine, and the identification of the underlying clone through bone marrow and/or peripheral blood cytologic and flow cytometry analysis. However, the monoclonal component and its corresponding clone may be undetectable using these routine techniques. Since clone identification is the cornerstone for guiding therapy and assessing disease response, more sensitive methods are required. We recently developed a high-throughput sequencing assay from bone marrow mRNA encoding immunoglobulins (RACE-RepSeq). This technique provides both full-length V(D)J region (variable, diversity and joining genes that generate unique receptors as antigen receptors) of the monoclonal immunoglobulin and the dominant immunoglobulin repertoire. This allows analysis of mutational patterns, immunoglobulin variable gene frequencies and diversity due to somatic hypermutation. Here, we evaluated the diagnostic performance of RACE-RepSeq in 16 patients with monoclonal-associated kidney lesions, and low serum monoclonal immunoglobulin and free light chain levels at diagnosis. Bone marrow immunohistochemical analysis was negative in all 11 patients so tested and 7 of 12 patients had no detectable clone matching the kidney deposits using flow cytometry analysis. By contrast, RACE-RepSeq detected a dominant clonal light chain sequence of matched isotype with respect to kidney deposits in all patients. Thus, high throughput mRNA sequencing appears highly sensitive to detect subtle clonal disorders in monoclonal gammopathy of renal significance and suggest this novel approach could help improve the management of this kidney disease.
Published: 2021

38. Targeting IgE polyadenylation signal with antisense oligonucleotides decreases IgE secretion and plasma cell viability

Author: Jeanne Moreau, Claire Carrion, Christelle Oblet, Michel Cogné, Laurent Delpy, Anne Marchalot, Catherine Horiot, Jean-Marie Lambert, Justine Pollet, Brice Laffleur, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Intégrative Santé Chimie Environnement (BISCEm), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement Français du Sang Bretagne, EFS, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANR, Fondation ARC pour la Recherche sur Le Cancer, Inserm Transfert SA, ANR-17-CE15-0024,TIE-Skip,Impact des immunoglobulines tronquées produites par saut d'exon dans les plasmocytes : vers des approches thérapeutiques utilisant des oligonucléotides antisens(2017), and Chard-Hutchinson, Xavier
Subjects: antisense oligonucleotide, [SDV.IMM] Life Sciences [q-bio]/Immunology, Cell Survival, Genetic enhancement, [SDV]Life Sciences [q-bio], Immunology, B-cell receptor, Plasma cell, Immunoglobulin E, plasma cells, Mice, 03 medical and health sciences, 0302 clinical medicine, Hypersensitivity, medicine, Animals, Humans, Immunology and Allergy, Secretion, Viability assay, polyadenylation, Receptor, cell viability, 030304 developmental biology, 0303 health sciences, B cells, biology, Receptors, IgE, Chemistry, Oligonucleotides, Antisense, allergy, Molecular biology, gene therapy, 3. Good health, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Apoptosis, 030220 oncology & carcinogenesis, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Multiple Myeloma
Abstract: International audience; BACKGROUND: Allergy regroups numerous complex and various diseases classified as IgE-dependent or non-IgE-dependent hypersensitivities. IgEs are expressed as membrane and secreted forms by B cells and plasma cells, respectively. In IgE-mediated hypersensitivity, IgE secretion and binding to the high-affinity IgE receptor FcεRI on effector cells are responsible for the onset of allergic symptoms; in contrast, surface IgE expression as a B-cell receptor is barely detectable. OBJECTIVE: Our aim was to test an innovative antisense approach to reducing IgE secretion. METHODS: We designed an antisense oligonucleotide (ASO) targeting the polyadenylation signal of human secreted IgE to redirect IgE transcript polyadenylation from the secreted form to the membrane form. ASO treatments were performed on B cells from transgenic mice expressing humanized IgE (InEps mice), as well as on human primary B cells and myeloma cells. In vivo ASO delivery was tested by using an InEps mouse model. RESULTS: We demonstrated that treatment with a morpholino ASO targeting the secreted IgE polyadenylation signal drastically decreased IgE secretion and inversely increased membrane IgE mRNA expression. In addition, ASO treatment induced apoptosis of IgE-expressing U266 myeloma cells, and RNA sequencing revealed attenuation of their plasma cell phenotype. Remarkably, systemic administration of an ASO coupled with Pip6a as an arginine-rich cell-penetrating peptide decreased IgE secretion in vivo. CONCLUSION: Altogether, this ASO strategy could be an effective way to decrease IgE secretion and allergic symptoms in patients with IgE-dependent allergies, and it could also promote allergen tolerance through apoptosis of IgE(+) antibody-secreting cells.
Published: 2021

39. Diverse B-cell specific transcriptional contexts of the BCL2 oncogene in mouse models impacts pre-malignant development

Author: Lina Zawil, Tiffany Marchiol, Baptiste Brauge, Alexis Saint-Amand, Claire Carrion, Elise Dessauge, Christelle Oblet, Sandrine Le Noir, Frédéric Mourcin, Florence Jouan, Mylène Brousse, Paco Derouault, Mehdi Alizadeh, Yolla El Makhour, Céline Monvoisin, Simon Léonard, Stéphanie Durand-Panteix, Karin Tarte, and Michel Cogné
Subjects: immune system diseases, hemic and lymphatic diseases, biological phenomena, cell phenomena, and immunity, neoplasms
Abstract: Follicular lymphoma (FL) is the most common indolent form of non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells. The genetic hallmark that leads to the development of FL is the t(14:18) which occurs early in the bone marrow during B cell development, thereby placing the anti-apoptotic BCL2 gene under the direct control of the transcriptional enhancers in 3’ of immunoglobulin heavy chain locus (IgH 3’RR) and leading to the constitutive expression of the BCL2 protein. To assess the impact of the BCL2 deregulation on B-cell fate and try to reproduce FL development in mice, two models were designed: the Igκ-BCL2 (Knock in of the BCL2 in the light chain Ig kappa locus) and the 3’RR-BCL2 (Transgene containing BCL2 and a micro-3’RR), both containing the full BCL2 promoter region.
Published: 2021

40. Preclinical study of (212)Pb alpha-radioimmunotherapy targeting CD20 in non-Hodgkin lymphoma

Author: Michel Cogné, Magali Sage, Stéphanie Durand-Panteix, Armand Garot, Amal Saidi, Julien Torgue, Marie Clavel, Isabelle Quelven, and Jacques Monteil
Subjects: Male, Cancer Research, Biodistribution, medicine.medical_treatment, Spleen, Article, Mice, immune system diseases, In vivo, hemic and lymphatic diseases, medicine, Potency, Animals, Humans, CD20, biology, business.industry, Lymphoma, Non-Hodgkin, Radioimmunotherapy, medicine.disease, Antigens, CD20, In vitro, Lymphoma, Disease Models, Animal, medicine.anatomical_structure, Oncology, Lead, Cancer research, biology.protein, business
Abstract: BACKGROUND: Despite therapeutic advances, Non-Hodgkin lymphoma (NHL) relapses can occur. The development of radioimmunotherapy (RIT) with α-emitters is an attractive alternative. In this study, we investigated the potential of α-RIT in conjunction with (212)Pb-rituximab for the treatment of NHL. METHODS: EL4-hCD20-Luc cells (mouse lymphoma cell line) were used for in vitro and in vivo studies. Biodistribution and efficacy studies were performed on C57BL/6 mice injected intravenously with 25 × 10(3) cells. RESULTS: (212)Pb-rituximab (0.925–7.4 kBq/mL) inhibit proliferation of EL4-hCD20-Luc cells in vitro. Biodistribution of (203/212)Pb-rituximab in mice showed a significant tumour uptake and suggested that the liver, spleen, and kidneys were the organs at risk. For efficacy studies, mice were treated at either 11 days (early stage) or 20–30 days after injection of tumour cells (late stage). Treatment with 277.5 kBq (212)Pb-rituximab significantly prolonged survival. Even at an advanced tumour stage, significant tumour regression occurred, with an increase in the median survival time to 28 days, compared with 9 days in the controls. CONCLUSIONS: These results show the efficacy of (212)Pb-rituximab in a murine syngeneic lymphoma model, in terms of significant tumour regression and increased survival, thereby highlighting the potency of α-RIT for the treatment of NHL.
Published: 2021

41. History of IgA Nephropathy Mouse Models

Author: Lina Zawil, Michel Cogné, Virginie Pascal, Batoul Wehbi, Jean-Claude Aldigier, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Region Nouvelle-AquitaineRegion Nouvelle-Aquitaine, Chaire d'Immuno-pathologie des Maladies Renales, Limoges University, Association Limousine pour l'Utilisation du Rein Artificiel a Domicile, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Chard-Hutchinson, Xavier
Subjects: 0301 basic medicine, kidney mesangium, mouse model, [SDV]Life Sciences [q-bio], 030232 urology & nephrology, Review, Disease, urologic and male genital diseases, Subclass, Nephropathy, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Immune system, Medicine, business.industry, Glomerulonephritis, General Medicine, IgA nephropathy, medicine.disease, Pathophysiology, 3. Good health, [SDV] Life Sciences [q-bio], 030104 developmental biology, Mesangium, Immunology, business, IgA
Abstract: International audience; IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. It was first described in 1968 by Jean Berger and Nicole Hinglais as the presence of intercapillary deposits of IgA. Despite this simple description, patients with IgAN may present very broad clinical features ranging from the isolated presence of IgA in the mesangium without clinical or biological manifestations to rapidly progressive kidney failure. These features are associated with a variety of histological lesions, from the discrete thickening of the mesangial matrix to diffuse cell proliferation. Immunofluorescence on IgAN kidney specimens shows the isolated presence of IgA or its inconsistent association with IgG and complement components. This clinical heterogeneity of IgAN clearly echoes its complex and multifactorial pathophysiology in humans, inviting further analyses of its various aspects through the use of experimental models. Small-animal models of IgAN provide the most pertinent strategies for studying the multifactorial aspects of IgAN pathogenesis and progression. Although only primates have the IgA1 subclass, several murine models have been developed in which various aspects of immune responses are deregulated and which are useful in the understanding of IgAN physiopathology as well as in the assessment of IgAN therapeutic approaches. In this manuscript, we review all murine IgAN models developed since 1968 and discuss their remarkable contribution to understanding the disease.
Published: 2021

42. Transcription/Replication Conflicts in Tumorigenesis and Their Potential Role as Novel Therapeutic Targets in Multiple Myeloma

Author: Raphaël Rodriguez, Jérôme Moreaux, Yea-Lih Lin, Philippe Pasero, Malik Lutzmann, Laure Dutrieux, Michel Cogné, Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Chimie biologique des membranes et ciblage thérapeutique (CBMCT - UMR 3666 / U1143), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Lapeyronie [Montpellier] (CHU), Université Paul-Valéry - Montpellier 3 (UPVM), INCa (Institut National du Cancer)Institut National du Cancer (INCA) France [PLBIO18-362 PIT-MM, PLBIO19-098 INCA_13832], ANR (the French National Research Agency) under the \'Investissements d'avenir\' program [ANR-16-IDEX-0006], ANR French National Research Agency (ANR) [2017-CE15-002401, ANR-18-CE15-0010-01], SIRIC Montpellier Cancer [INCaDGOS-Inserm_12553], Labex EpiGenMed, Institut Universitaire de France, Ligue Nationale Contre le Cancer LNCC, Centre de recherche de l'Institut Curie [Paris], Institut Curie [Paris], Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), ANR-16-IDEX-0006,MUSE,MUSE(2016), ANR-18-CE15-0010,PLASMADIFF-3D,Rôle de l'organisation tridimensionnelle et de la dynamique de la chromatine au cours de la différenciation plasmocytaire(2018), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC), Rodriguez, Raphaël, MUSE - - MUSE2016 - ANR-16-IDEX-0006 - IDEX - VALID, and APPEL À PROJETS GÉNÉRIQUE 2018 - Rôle de l'organisation tridimensionnelle et de la dynamique de la chromatine au cours de la différenciation plasmocytaire - - PLASMADIFF-3D2018 - ANR-18-CE15-0010 - AAPG2018 - VALID
Subjects: 0301 basic medicine, Genome instability, [SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology, Cancer Research, transcription replication conflicts, [SDV.CAN]Life Sciences [q-bio]/Cancer, Review, medicine.disease_cause, plasma cells, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, stomatognathic system, Transcription (biology), [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Secretion, Gene, Multiple myeloma, RC254-282, biology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, R-loops, medicine.disease, genomic instability, G-quadruplexes, 3. Good health, Cell biology, multiple myeloma, tumorigenesis, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Antibody, Carcinogenesis
Abstract: Simple Summary Multiple myeloma is a hematologic cancer characterized by the accumulation of malignant plasma cells in the bone marrow. It remains a mostly incurable disease due to the inability to overcome refractory disease and drug-resistant relapse. Oncogenic transformation of PC in multiple myeloma is thought to occur within the secondary lymphoid organs. However, the precise molecular events leading to myelomagenesis remain obscure. Here, we identified genes involved in the prevention and the resolution of conflicts between the replication and transcription significantly overexpressed during the plasma cell differentiation process and in multiple myeloma cells. We discussed the potential role of these factors in myelomagenesis and myeloma biology. The specific targeting of these factors might constitute a new therapeutic strategy in multiple myeloma. Abstract Plasma cells (PCs) have an essential role in humoral immune response by secretion of antibodies, and represent the final stage of B lymphocytes differentiation. During this differentiation, the pre-plasmablastic stage is characterized by highly proliferative cells that start to secrete immunoglobulins (Igs). Thus, replication and transcription must be tightly regulated in these cells to avoid transcription/replication conflicts (TRCs), which could increase replication stress and lead to genomic instability. In this review, we analyzed expression of genes involved in TRCs resolution during B to PC differentiation and identified 41 genes significantly overexpressed in the pre-plasmablastic stage. This illustrates the importance of mechanisms required for adequate processing of TRCs during PCs differentiation. Furthermore, we identified that several of these factors were also found overexpressed in purified PCs from patients with multiple myeloma (MM) compared to normal PCs. Malignant PCs produce high levels of Igs concomitantly with cell cycle deregulation. Therefore, increasing the TRCs occurring in MM cells could represent a potent therapeutic strategy for MM patients. Here, we describe the potential roles of TRCs resolution factors in myelomagenesis and discuss the therapeutic interest of targeting the TRCs resolution machinery in MM.
Published: 2021

43. Comparative immune profiling of acute respiratory distress syndrome patients with or without SARS-CoV2 infection

Author: Karin Tarte, B. Sawitzki, Isabelle Bezier, Joelle Dulong, Thomas Daix, S. Le Gallou, Juliette Ferrant, Jean Feuillard, Céline Monvoisin, Robin Jeannet, Nadège Bescher, Sarah H. Carl, Murielle Gregoire, A. Vinit, Maelle Latour, Simon Léonard, Mikael Roussel, Florian Reizine, C. Verdy, M. Cornic, Michel Cogné, Mathieu Lesouhaitier, Stéphane Paul, Jean-Marc Tadié, Vijay K. Tiwari, Centre Hospitalier Universitaire [Rennes], Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement Français du Sang Bretagne, EFS, LabEX IGO Immunothérapie Grand Ouest, Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytométrie Pitié-Salpêtrière (PASS-CYPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), CHU Limoges, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique de Limoges (CIC1435), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM), Anti-infectieux : supports moléculaires des résistances et innovations thérapeutiques (RESINFIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges, Queen's University [Belfast] (QUB), Etablissement français du sang [Rennes] (EFS Bretagne), This work was supported by the University Hospital of Rennes (CHU Rennes), CFTR2 (COVID-19 Fast Track Recherche Rennes) grant (to F.R.) and by the Fondation pour la Recherche Médicale (FRM) and the Agence Nationale de la Recherche (ANR), Flash Covid-19 joint grant ( HARMONICOV to M. Cogné)., ANR-20-COVI-0039,HARMONICOV,Immunomonitoring haute définition & caractérisation d'anticorps spécifiques chez des patients CoV-2 critiques versus en rémission(2020), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Nantes Université (Nantes Univ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CHU Limoges-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Gestionnaire, Hal Sorbonne Université, and Immunomonitoring haute définition & caractérisation d'anticorps spécifiques chez des patients CoV-2 critiques versus en rémission - - HARMONICOV2020 - ANR-20-COVI-0039 - COVID-19 - VALID
Subjects: Male, Medicine (General), medicine.medical_specialty, ARDS, Sialic Acid Binding Ig-like Lectin 1, [SDV]Life Sciences [q-bio], Lipopolysaccharide Receptors, 030204 cardiovascular system & hematology, Article, Monocytes, General Biochemistry, Genetics and Molecular Biology, S100A9, law.invention, Cohort Studies, Evolution, Molecular, Machine Learning, Immune profiling, 03 medical and health sciences, R5-920, 0302 clinical medicine, Immune system, law, Internal medicine, medicine, Humans, Mass cytometry, Adverse effect, Aged, 030304 developmental biology, Respiratory Distress Syndrome, 0303 health sciences, SARS-CoV-2, business.industry, COVID-19, HLA-DR Antigens, Middle Aged, Th1 Cells, medicine.disease, Intensive care unit, 3. Good health, [SDV] Life Sciences [q-bio], Intensive Care Units, Leukocytes, Mononuclear, Female, business, Complication
Abstract: Acute respiratory distress syndrome (ARDS) is the main complication of COVID-19, requiring admission to Intensive Care Unit (ICU). Despite extensive immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS differs from other causes of ARDS remains unknown. To address this question, we build 3 cohorts of patients categorize in COVID-19negARDSpos, COVID-19posARDSpos, and COVID-19posARDSneg, and compare their immune landscape analyze by high-dimensional mass cytometry on peripheral blood. A cell signature associating S100A9/calprotectin-producing CD169pos monocytes, plasmablasts, and Th1 cells is found in COVID-19posARDSpos, unlike COVID-19negARDSpos patients. Moreover, this signature is essentially share with COVID-19posARDSneg patients, suggesting that severe COVID-19 patients, whatever they experience or not ARDS, display similar immune profiles. We show an increase in CD14posHLA-DRlow and CD14lowCD16pos monocytes correlate to the occurrence of adverse events during ICU stay. We demonstrate that COVID-19-associated ARDS display a specific immune profile, and might benefit from personalize therapy in addition to standard ARDS management., Graphical Abstract, Roussel et al. characterize the immune profile of COVID-19+ and COVID-19- patients, both presenting an acute respiratory distress syndrome (ARDS) and COVID-19+ without ARDS. They identify a COVID-19 signature associating CD169+S100A9+ monocytes, plasmablasts, and Th1 cells. CD14+HLA-DRlo and CD14loCD16+ monocytes increase during the ICU stay correlate with unfavorable clinical course.
Published: 2021

44. Immunotherapy perspectives in the new era of B-cell editing

Author: Natsuko Ueda, Michel Cogné, Christophe Sirac, Yannic Danger, Jérôme Moreaux, Marine Cahen, Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Etablissement français du sang [Rennes] (EFS Bretagne), Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Ueda, Natsuko, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-18-CE18-0022,SYN-B,Syncytines pour l'ingénierie du génome des lymphocytes B(2018)
Subjects: 0301 basic medicine, medicine.drug_class, medicine.medical_treatment, Genetic enhancement, Review Article, Monoclonal antibody, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.IMM.VAC] Life Sciences [q-bio]/Immunology/Vaccinology, Antigen, b-lymphocytes, medicine, Humans, genome editing, cancer, infections, t-lymphocytes, B cell, Gene Editing, Receptors, Chimeric Antigen, business.industry, Hematology, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, gene therapy, Chimeric antigen receptor, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Immunology, immunotherapy, monoclonal antibodies, CRISPR-Cas Systems, cell therapy, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business
Abstract: Since the early days of vaccination, targeted immunotherapy has gone through multiple conceptual changes and challenges. It now provides the most efficient and up-to-date strategies for either preventing or treating infections and cancer. Its most recent and successful weapons are autologous T cells carrying chimeric antigen receptors, engineered purposely for binding cancer-specific antigens and therefore used for so-called adoptive immunotherapy. We now face the merger of such achievements in cell therapy: using lymphocytes redirected on purpose to bind specific antigens and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) revolution, which conferred genome-editing methodologies with both safety and efficacy. This unique affiliation will soon and considerably expand the scope of diseases susceptible to adoptive immunotherapy and of immune cells available for being reshaped as therapeutic tools, including B cells. Following the monumental success story of passive immunotherapy with monoclonal antibodies (mAbs), we are thus entering into a new era, where a combination of gene therapy/cell therapy will enable reprogramming of the patient’s immune system and notably endow his B cells with the ability to produce therapeutic mAbs on their own.
Published: 2021

45. Bromodomain and extraterminal (BET) protein inhibition of IgG/IgE production in murine B cells is counter-balanced by a strong Th2 bias

Author: Bernhard Ryffel, Yolla Makhour, Zeinab Dalloul, Pauline Chenuet, Jean-Claude Aldigier, Michel Cogné, François Boyer, Marie Best, Valérie F. J. Quesniaux, Sandrine Le Noir, Dieudonnée Togbe, Jeanne Cook-Moreau, Mylène Gador, Nicolas Fazilleau, Iman Dalloul, Jonchère, Laurent, Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique - - Ig-MemImpact2016 - ANR-16-CE15-0019 - AAPG2016 - VALID, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Artimmune SAS, Lebanese University [Beirut] (LU), Microenvironment, Cell Differentiation, Immunology and Cancer (MICMAC), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), PGA1 RF20180207070, Fondation ARC pour la Recherche sur le Cancer, ANR‐16‐CE15‐0019‐01, Agence Nationale de la Recherche, 2016‐00110366, European Regional Development Fund, ANR-16-CE15-0019,Ig-MemImpact,Rôle de la classe des Ig / BCR dans les interactions cellulaires supportant la mémoire immune et impact immunopathologique(2016), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)
Subjects: 0301 basic medicine, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunoglobulin E, immune response, Allergic inflammation, 03 medical and health sciences, 0302 clinical medicine, Immune system, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, allergic inflammation, Immunology and Allergy, General Nursing, biology, Chemistry, RC581-607, Eosinophil, Bromodomain, 030104 developmental biology, medicine.anatomical_structure, Immunoglobulin class switching, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, Humoral immunity, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Original Article, Immunologic diseases. Allergy, Antibody, bromodomain inhibition, antibody class switching, 030215 immunology
Abstract: Objectives Inhibitors of bromodomain and extra terminal domain (BET) proteins are a new and growing class of anti‐cancer drugs, which decrease oncogene expression by targeting superenhancers. Antibody production is another physiological process relying on superenhancers, and it remains to be clarified whether potential immunomodulatory properties of BET inhibitors might impact humoral immunity and allergy. Methods We thus evaluated humoral immune responses and their Th2 context in vitro and in vivo in mice following treatment with the classical BET‐inhibitor JQ1. We quantified immunoglobulin (Ig) and antibody production by B cells either stimulated in vitro or obtained from immunised mice. JQ1 effects on class switching and activation‐induced deaminase loading were determined, together with modifications of B, T follicular helper (Tfh) and T helper 2 (Th2) populations. JQ1 was finally tested in B‐cell‐dependent models of immune disorders. Results Bromodomain and extra terminal domain inhibition reduced class switching, Ig expression on B cells and antibody secretion and was correlated with decreased numbers of Tfh cells. However, JQ1 strongly increased the proportion of GATA3+ Th2 cells and the secretion of corresponding cytokines. In a mouse allergic model of lung inflammation, JQ1 did not affect eosinophil infiltration or mucus production but enhanced Th2 cytokine production and aggravated clinical manifestations. Conclusion Altogether, BET inhibition thus interweaves intrinsic negative effects on B cells with a parallel complex reshaping of T‐cell polarisation which can increase type 2 cytokines and eventually promote B‐cell‐dependent immunopathology. These opposite and potentially hazardous immunomodulatory effects raise concerns for clinical use of BET inhibitors in patients with immune disorders., While bromodomain and extra terminal domain inhibition reduces class switching, antibody secretion and T follicular helper cell number, this treatment increases the proportion of GATA3+ T helper 2 cells and the secretion of corresponding cytokines. In a mouse model of lung inflammation, JQ1 thus aggravates rather than improves clinical manifestations.
Published: 2021

46. IgH 3’ regulatory region increases ectopic class switch recombination

Author: Christophe Sirac, Amélie Bonaud, Sandrine Lecardeur, Michel Cogné, Audrey Baylet, Bastien Hervé, François Boyer, Zeliha Oruc, Sandrine Le Noir, Le Noir, Sandrine, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Biologie Intégrative Santé Chimie Environnement (BISCEm), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Cancer Research, B Cells, Physiology, Regulatory Sequences, Nucleic Acid, QH426-470, Biochemistry, White Blood Cells, Peyer's Patches, Mice, chemistry.chemical_compound, Spectrum Analysis Techniques, 0302 clinical medicine, Animal Cells, Immune Physiology, Medicine and Health Sciences, Genetics (clinical), Gene Rearrangement, B-Lymphocytes, 0303 health sciences, Synapsis, Animal Models, Flow Cytometry, Cell biology, Nucleic acids, Experimental Organism Systems, Spectrophotometry, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytophotometry, Cellular Types, Anatomy, Immunoglobulin Heavy Chains, Recombination, Research Article, [SDV.IMM] Life Sciences [q-bio]/Immunology, DNA recombination, Immune Cells, Immunology, DNA repair, Somatic hypermutation, Mouse Models, Mice, Transgenic, Locus (genetics), chemical and pharmacologic phenomena, Biology, Research and Analysis Methods, Immunoglobulin light chain, Lymphatic System, 03 medical and health sciences, Model Organisms, Cytidine Deaminase, Genetics, Animals, Antibody-Producing Cells, Molecular Biology, Gene, Ecology, Evolution, Behavior and Systematics, 030304 developmental biology, Blood Cells, Biology and Life Sciences, Cell Biology, DNA, Immunoglobulin Class Switching, Hematopoiesis, Immunoglobulin class switching, chemistry, Genetic Loci, Animal Studies, Spleen, 030215 immunology
Abstract: DNA lesions inflicted by activation-induced deaminase (AID) instrumentally initiate the processes reshaping immunoglobulin genes in mature B-cells, from local somatic hypermutation (SHM) to junctions of distant breaks during class switch recombination (CSR). It remains incompletely understood how these divergent outcomes of AID attacks are differentially and temporally focused, with CSR strictly occurring in the Ig heavy chain (IgH) locus while SHM concentrates on rearranged V(D)J regions in the IgH and Ig light chain loci. In the IgH locus, disruption of either the 3’Regulatory Region (3’RR) super-enhancer or of switch (S) regions preceding constant genes, profoundly affects CSR. Reciprocally, we now examined if these elements are sufficient to induce CSR in a synthetic locus based on the Igκ locus backbone. Addition of a surrogate “core 3’RR” (c3’RR) and of a pair of transcribed and spliced Switch regions, together with a reporter system for “κ-CSR” yielded a switchable Igκ locus. While the c3’RR stimulated SHM at S regions, it also lowered the local SHM threshold necessary for switch recombination to occur. The 3’RR thus both helps recruit AID to initiate DNA lesions, but then also promotes their resolution through long-distance synapses and recombination following double-strand breaks., Author summary Class switching allows B lymphocytes to replace expression of immunoglobin M with that of immunoglobulins G, A or E. The genetic support of class switching, is a unique and large deletion uniquely occuring within the immunoglobulin heavy chain (IgH) locus. This recombination is triggered after DNA lesions inflicted by the activation-induced deaminase (AID) enzyme. In immunoglobulin light chain loci, AID only stimulates somatic hypermutation. In such a non-IgH locus, we now show that the IgH 3’ superenhancer can promote junctions between distant DNA breaks and ectopic class switch recombination. This study identifies the minimal elements necessary for class-switch recombination to occur instead of hypermutation in a locus targeted by AID, i.e. transcribed (and spliced) target sites for AID in so-called S regions, and the 3’IgH superenhancer which both helps recruit AID for DNA lesions, and helps repair these lesions through distant gene synapsis and recombination.
Published: 2021

47. Mass cytometry and artificial intelligence define CD169 as a specific marker of SARS-CoV2-induced acute respiratory distress syndrome

Author: Murielle Gregoire, Isabelle Bezier, Le Gallou S, Tiwari, Jean Feuillard, Michel Cogné, Juliette Ferrant, C. Verdy, Maelle Latour, Jean-Marc Tadié, Reizine F, Karin Tarte, Joelle Dulong, Sarah H. Carl, Lesouhaitier M, Simon Léonard, Mikael Roussel, M. Cornic, and Nadège Bescher
Subjects: ARDS, business.industry, Acute respiratory distress, medicine.disease, Intensive care unit, S100A9, law.invention, Immune system, law, medicine, Mass cytometry, Artificial intelligence, Complication, business, Adverse effect
Abstract: Acute respiratory distress syndrome (ARDS) is the main complication of COVID-19, requiring admission to Intensive Care Unit (ICU). Despite recent immune profiling of COVID-19 patients, to what extent COVID-19-associated ARDS specifically differs from other causes of ARDS remains unknown, To address this question, we built 3 cohorts of patients categorized in COVID-19negARDSpos, COVID-19posARDSpos, and COVID-19posARDSneg, and compared their immune landscape analyzed by high-dimensional mass cytometry on peripheral blood followed by artificial intelligence analysis. A cell signature associating S100A9/calprotectin-producing CD169pos monocytes, plasmablasts, and Th1 cells was specifically found in COVID-19posARDSpos, unlike COVID-19negARDSpos patients. Moreover, this signature was shared by COVID-19posARDSneg patients, suggesting severe COVID-19 patients, whatever they experienced or not ARDS, displayed similar immune dysfunctions. We also showed an increase in CD14posHLA-DRlow and CD14lowCD16pos monocytes correlated to the occurrence of adverse events during ICU stay. Our study demonstrates that COVID-19-associated ARDS display a specific immune profile, and might benefit from personalized therapy in addition to standard ARDS management.One Sentence SummaryCOVID-19-associated ARDS is biologically distinct from other causes of ARDS.
Published: 2020

48. New models to study plasma cells in mouse based on the restriction of IgJ expression to antibody secreting cells

Author: Michel Cogné, Jean-Marie Lambert, Claire Carrion, Sébastien Bender, Christophe Sirac, Amélie Bonaud, Fabien Lechouane, Virginie Pascal, and Maria Victoria Ayala
Subjects: Genetically modified mouse, medicine.anatomical_structure, biology, biology.protein, medicine, Cre recombinase, Antibody, Plasma cell, Gene, In vitro, B cell, Green fluorescent protein, Cell biology
Abstract: Plasma cells (PC) represent the last stage of B cell development and are mainly characterized by their capacity of secreting large quantities of antibodies. They can be implicated in a broad-spectrum of neoplastic disorders, including Multiple Myeloma, Waldenstrom macroglobulinemia or Monoclonal Gammopathy of Clinical Significance, all characterized by the abnormal proliferation of a PC clone. Up to date, there are only few reporter models to specifically follow PC development, migration and homing in mouse and none allowing the genetic manipulation of these cells. We created a transgenic mouse model in which a green fluorescent protein gene was placed under the control of the well-characterized regulatory elements of the murine immunoglobulin J (IgJ) chain locus. Thanks to this model, we demostrated that IgJ is an early and specific marker of antibody secreting cells (ASCs) and appears before the expression of CD138, making it a good candidate to targeted genetic modifications of plasma cells. Therefore, a conditional deletion model using a Tamoxifen-dependent Cre recombinase inserted into the IgJ locus was characterized. Using a reporter model, we showed that, in contrast with existing models of B cell lineage genetic modification, the activity of the CRE recombinase only affects ASCs after tamoxifen treatment. Additionally, we used this model in a functional in vitro assay, to show that Ig modifications directly affect plasma cell survival. These two new mouse models, IgJGFP and IgJCreERT2 represent exquisite tools to study PCs. In pathology, the IgJCreERT2model opens new frontiers for in vivo genetic modifications of PCs to better reflect the pathophysiology of PC-related diseases.
Published: 2020

49. Immunoglobulin variable domain high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

Author: David Lavergne, Maria Victoria Ayala, Mehdi Alizadeh, Sébastien Bender, Virginie Pascal, Nathalie Gachard, Franck Bridoux, Alexis Saintamand, Arnaud Jaccard, Fabienne Auroy, Matthieu Filloux, Christophe Sirac, Vincent Javaugue, Michel Cogné, Contrôle de la Réponse Immune B et des Lymphoproliférations (CRIBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), CHU Limoges, Centre hospitalier universitaire de Poitiers (CHU Poitiers), Etablissement Français du Sang Bretagne, EFS, Plateforme de Biotechnologies Innovantes (PFBI), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), National Institutes of Health, National Heart, Lung, and Blood Institute United States Department of Health and Human ServicesNational Institutes of Health (NIH) - USA NIH National Heart Lung and Blood Institute (NHLBI) [HL68705], Ligue Nationale Contre le Cancer du Limousin, Fondation Francaise pour la Recherche contre le Myelome et les Gammapathies monoclonales, French Ministry of Research \'Plan maladies rares\', Fondation ARC pour la Recherche sur le Cancer Fondation ARC pour la Recherche sur le Cancer, Jonchère, Laurent, Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), and Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Immunobiology and Immunotherapy, Sequence analysis, [SDV]Life Sciences [q-bio], Biopsy, Immunology, DNA Mutational Analysis, Plasma cell dyscrasia, Biology, Immunoglobulin light chain, Biochemistry, DNA sequencing, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Immunoglobulin lambda-Chains, Bone Marrow, Sequence Analysis, Protein, medicine, Humans, Germ-Line Mutation, 030304 developmental biology, POEMS syndrome, 0303 health sciences, High-Throughput Nucleotide Sequencing, Cell Biology, Hematology, medicine.disease, Molecular biology, 3. Good health, [SDV] Life Sciences [q-bio], Molecular Diagnostic Techniques, 030220 oncology & carcinogenesis, Monoclonal, POEMS Syndrome, biology.protein, Immunoglobulin Light Chains, Lymph Nodes, Antibody
Abstract: Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare multisystem disease resulting from an underlying plasma cell (PC) dyscrasia. The pathophysiology of the disease remains unclear, but the role of the monoclonal immunoglobulin (Ig) light chain (LC) is strongly suspected because of the highly restrictive usage of 2 λ variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations after PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in the case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (rapid amplification of cDNA ends-based repertoire sequencing [RACE-RepSeq]), we detected a λ LC monoclonal expansion in the bone marrow (BM) of 83% of patients with POEMS syndrome, including some in whom BM tests routinely performed to diagnose plasma cell dyscrasia failed to detect λ+ monoclonal PCs. Twenty-four (83%) of the 29 LC clonal sequences found were derived from the IGLV1-40 and IGLV1-44 germline genes, as well as 2 from the closely related IGLV1-36 gene, and all were associated with an IGLJ3*02 junction (J) gene, confirming the high restriction of VJ region usage in POEMS syndrome. RACE-RepSeq VJ full-length sequencing additionally revealed original mutational patterns, the strong specificity of which might crucially help establish or eliminate the diagnosis of POEMS syndrome in uncertain cases. Thus, RACE-RepSeq appears as a sensitive, rapid, and specific tool to detect low-abundance PC clones in BM and assign them to POEMS syndrome, with all the consequences for therapeutic options.
Published: 2020

50. Immunoglobulin light-chain toxicity in a mouse model of monoclonal immunoglobulin light-chain deposition disease

Author: Agnès Paquet, Laurent Delpy, Claire Carrion, Michel Cogné, Sébastien Bender, Maria Victoria Ayala, Mohamad Omar Ashi, Nicolas Pons, Zeliha Oruc, Bastien Hervé, Vincent Javaugue, Frank Bridoux, Alexia Rinsant, François Boyer, Christophe Sirac, Christelle Oblet, Arnaud Jaccard, Amélie Bonaud, Sihem Kaaki, and Guy Touchard
Subjects: 0301 basic medicine, Immunology, Genetic Vectors, Kidney Glomerulus, Paraproteinemias, Mice, Transgenic, Immunoglobulin light chain, Kidney, Kidney Function Tests, Biochemistry, Protein Aggregation, Pathological, Light chain deposition disease, Diabetic nephropathy, 03 medical and health sciences, Immunoglobulin kappa-Chains, Mice, Protein Aggregates, 0302 clinical medicine, Gene Order, medicine, Animals, Renal Insufficiency, biology, Chemistry, Gene Expression Profiling, Cell Cycle, Glomerulosclerosis, Cell Biology, Hematology, medicine.disease, Endoplasmic Reticulum Stress, Flow Cytometry, Molecular biology, Immunohistochemistry, Extracellular Matrix, Disease Models, Animal, 030104 developmental biology, medicine.anatomical_structure, Gene Targeting, biology.protein, Immunoglobulin heavy chain, Immunoglobulin Light Chains, Antibody, Nephrotic syndrome, Biomarkers, 030215 immunology
Abstract: Light chain deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin (Ig) light chain (LC), leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse Ig kappa locus, ensuring its production by all plasma cells (PCs). High free LC levels were achieved after backcrossing with mice presenting increased PC differentiation and no Ig heavy chain (HC) production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria and finally, kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on PCs demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function, but partially reversed kidney lesions. Finally, transcriptome analysis of pre-sclerotic glomeruli revealed that proliferation and extracellular matrix remodelling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy.
Published: 2020

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