Biology subjects

Cogne, M.

Publications and source records attributed to Cogne, M..

10 recordsLinked to original sources

bioRxiv2025

Mucosal B cell memory selection integrates tissue-specific microbial cues via the IgA BCR

B cells engender plasma cells (PCs) and memory B cells (MBCs) to combat recurrent pathogens. While B cell receptor (BCR) affinity dictates fate decisions in clonally-restricted set-ups, the driving factors in more complex systems remain unknown. Here, we show that memory selection during mucosal infection is imprinted by inherent cues from barrier tissues: lungs skew selection towards MBCs while the gut favors PC entry, even in response to the same pathogen. This divergence is linked to differential BCR isotype usage across barrier tissues rather than to affinity. In the gut, the commensal-induced TGF-{beta}-rich milieu promotes B cell class-switching to IgA. Consequently, the IgA BCR bias selection towards PCs, a process that is counteracted by its cytosolic tail domain. Overall, mucosal B cell selection integrates tissue-specific cues by strongly relying on BCR isotype usage rather than affinity, with implications for nasal and oral vaccine development. One sentence summaryDivergent B cell memory strategies evolved in lung and gut mucosa to counteract recurrent pathogens.

immunology↗

bioRxiv2023

REL deregulation stands as a primary hit for AID-imprinted B-cells along the germinal center competition

In diffuse large B-cell lymphomas (DLBCLs), gains and amplifications of the 2p15-16 region, which always encompass the REL gene, are mostly restricted to the germinal center (GC) B- cell DLBCL subtype (GCB-DLBCL) for which c-Rel is the pivotal Rel/NF-{kappa}B subunit. While REL is also known to play a key role in the GC reaction, its contribution to GCB-DLBCL transformation is still unclear. To understand the role of REL in the very first steps of GCB transformation, i.e when B-cells with deregulated REL are competing with other B-cells during chronic antigenic stimulation, we have created a dual-color mouse that allows to induce REL in a limited pool of AID- imprinted B-cells after immunization and to differentially stain AID-imprinted B-cells cells that overexpress REL or not. Our results demonstrate that dysregulation of REL at the GC B-cell stage promotes GC B-cell expansion and favors both class-switch recombination and plasma cell differentiation. Additionally, although REL overexpression was neutral on post-GC memory B-cell differentiation, it did confer a long-term competitive advantage allowing for GC persistence and continuous recirculation of REL-overexpressing B-cells. Functionally, REL enhanced the protection against apoptosis in the early steps of GCB differentiation. REL- overexpressing B-cells can my occasionally transform into in an aggressive B-cell tumor. Highlighting the role of repeated immune responses, our results confirm the role of REL in the germinal center reaction and provide evidence supporting the fact that genetic deregulation of c-Rel expression is most likely a primary event in the aggressive transformation of GC B-cells. Key points- REL provides a long-term competitive advantage allowing for GC B-cell persistence and continuous recirculation of AID-imprinted B-cells - AID-imprinted B-cells overexpressing REL can occasionally transform into aggressive B-cell lymphomas Explanation of the noveltyBy showing in a new dual-color mouse model that dysregulation of REL in a very limited pool of AID-imprinted B-cells confers a strong long-term competitive advantage in the context of repeated immune responses and may occasionally lead to transformation into an aggressive B- cell lymphoma, we provide for the first time experimental evidence supporting the fact that that REL is most likely a primary event in the aggressive transformation of germinal center B-cells.

cancer biology↗

bioRxiv2023

NGFR regulates germinal center B-cell activation and negative selection

The expression of the Nerve growth factor receptor (NGFR) has been described in follicular dendritic cells (FDCs), the major lymphoid stromal cell (LSC) compartment regulating B-cell activation within germinal centers (GCs). However, the role of NGFR in humoral response is not well defined. In this work, we have studied the effect of Ngfr KO in LNs organization and function. Ngfr KO led to spontaneous GC formation and expansion of GC B-cell compartment which were related to Ngfr depletion in non-hematopoietic radioresistant compartment. In agreement, Ngfr KO mice showed alterations in LSC with an increased frequency of FDCs harboring an activated phenotype characterized by the overexpression of CD21/35, MAdCAM-1, and VCAM-1. Moreover, Ngfr KO mice showed GC ectopic location, loss of polarization, impaired high-affinity antibody production, and increased circulating autoantibodies. In addition, Ngfr KO/Bcl2 Tg mice displayed increased levels of autoantibodies, higher incidence of autoimmunity, and decreased overall survival. Our work shows that NGFR maintains GC structure and functionality, being involved in the regulation of antibody production and immune tolerance.

immunology↗

bioRxiv2022

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

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.

immunology↗

bioRxiv2021

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

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 3RR) 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 Ig{kappa}-BCL2 (Knock in of the BCL2 in the light chain Ig kappa locus) and the 3RR-BCL2 (Transgene containing BCL2 and a micro-3RR), both containing the full BCL2 promoter region.

immunology↗

bioRxiv2020

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

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.

immunology↗

bioRxiv2020

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

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.

immunology↗

bioRxiv2019

Full-length immunoglobulin high-throughput sequencing reveals specific novel mutational patterns in POEMS syndrome

POEMS syndrome is a rare multisystem disease due to 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, due to the highly restrictive usage of two {lambda} variable (V) domains (IGLV1-40 and IGLV1-44) and the general improvement of clinical manifestations following PC clone-targeted treatment. However, the diagnostic value of Ig LC sequencing, especially in case of incomplete forms of the disease, remains to be determined. Using a sensitive high-throughput Ig repertoire sequencing on RNA (RACE-RepSeq), we detected a {lambda} LC monoclonal expansion in the bone marrow (BM) of 85% of patients with POEMS syndrome, including some in whom bone marrow tests routinely performed to diagnose plasma cell dyscrasia failed to detect {lambda}+ monoclonal PCs. Twenty-four of the 30 LC clonal sequences found (80%) were derived from the IGLV1-40 and IGLV1-44 germline genes, two 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 hereby.

immunology↗

bioRxiv2019

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

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. High free LC levels were achieved after backcrossing with mice presenting increased plasma cell 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 plasma cells 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.

pathology↗

bioRxiv2018

Locus Suicide Recombination actively occurs on the functionally rearranged IgH allele in B-cells from inflamed human lymphoid tissues

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 by the 3 regulatory region (3RR) 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 S to \"like-switch\" DNA repeats that flank the 3 super-enhancer can thus accomplish so-called \"locus suicide recombination\" (LSR) in mouse B-cells. We now show that AID-mediated LSR also actively occurs in humans, and provides an activation-induced cell death pathway in multiple conditions of B-cell activation. LSR deletions either focus on the functional IgH allele or are bi-allelic, since they can only be detected when they are ongoing and their signature vanishes from fully differentiated plasma cells or from \"resting\" blood memory B-cells, but readily reappears when such memory B-cells are re-stimulated in vitro. Highly diversified breakpoints are distributed either within the upstream (3RR1) or downstream (3RR2) copies of the IgH 3 super-enhancer and all conditions activating CSR in vitro also seem to trigger LSR.\n\nAuthor SummaryClass switch recombination, initiated by the activation-induced deaminase enzyme rearranges immunoglobulin (Ig) genes in order to replace expression of IgM by IgG, IgA or IgE. A variant form of this event, locus suicide recombination (LSR), was previously reported in mouse B-lymphocytes and simply deletes all functional Ig constant genes, thus terminating B-cell function. This study first demonstrates that the structure of the human Ig heavy chain locus provides an ideal target for LSR, and is thus actively (but transiently) affected by this deletional process at the activated B-cell stage. LSR then yields recombined genes that do not support B-cell survival and which thus become undetectable among long-lived memory B-cells or plasma cells.

genetics↗