Almudena R. Ramiro

Spanish National Centre for Cardiovascular Research

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Virginia G. de Yébenes

Spanish National Centre for Cardiovascular Research

Marı́a L. Toribio

Centro de Biología Molecular Severo Ochoa

Michel C. Nussenzweig

Rockefeller University

Pilar Delgado

Universidad Autónoma de Madrid

Ester Marina-Zárate

La Jolla Institute for Immunology

Sonia M. Mur

Spanish National Centre for Cardiovascular Research

Fátima Sánchez‐Cabo

Spanish National Centre for Cardiovascular Research

Ana Dopazo

Spanish National Centre for Cardiovascular Research

Yolanda R. Carrasco

Centro Nacional de Biotecnología

ÁF

Ángel F. Álvarez-Prado

University of Lausanne

Cooperative Institutions

Universidad Autónoma de Madrid

Spanish National Centre for Cardiovascular Research

Instituto de Salud Carlos III

Consejo Superior de Investigaciones Científicas

Centro de Investigación Biomédica en Red

Hospital Universitario de La Princesa

Centro de Biología Molecular Severo Ochoa

Universidad Complutense de Madrid

Centro de Investigación del Cáncer

Spanish National Cancer Research Centre

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Regulation of B‐cell development and function by microRNAs

Immunological Reviews (2013)

Virginia G. de Yébenes Nahikari Bartolomé‐Izquierdo Almudena R. Ramiro

Summary Micro RNA s (mi RNA s) have emerged as a new class of gene expression regulators whose functions influence a myriad of biological processes, from developmental decisions through immune responses and numerous pathologies, including cancer and autoimmunity. mi RNA s are small RNA molecules that drive post‐transcriptional negative regulation of gene expression by promoting the degradation or translational block of their target m RNA s. Here, we review some of the data relating to the role of mi RNA s in the regulation of the B‐cell lineage, with a special focus on results obtained in vivo . We start by giving a general overview of mi RNA activity, including the issue of target specificity and the experimental approaches more widely used to analyze the function of these molecules. We then go on to discuss the function of mi RNA s during B‐cell differentiation in the bone marrow and in the periphery as well as during the humoral immune response. Finally, we describe a few examples of the contribution of mi RNA s, both as oncogenes and tumor suppressors, to the development of B‐cell neoplasias.

10.1111/imr.12046

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Citations (85)

Oncogenic events triggered by AID, the adverse effect of antibody diversification

Carcinogenesis (2007)

Pablo Pérez‐Durán Virginia G. de Yébenes Almudena R. Ramiro

The generation of an efficient immune response depends on highly refined mechanisms of antibody diversification. Two of these mechanisms, somatic hypermutation (SHM) and class switch recombination (CSR), are initiated by activation-induced cytidine deaminase (AID) upon antigen stimulation of mature B cells. AID deaminates cytosines on the DNA of Ig genes thereby generating a lesion that can be processed into a mutation (SHM) or a DNA double-strand break followed by a recombination reaction (CSR). A number of mechanisms are probably responsible for regulating AID function, such as transcriptional regulation, subcellular localization, post-transcriptional modifications and target specificity, but the issue remains of how unwanted DNA damage is fully prevented. Most lymphocyte neoplasias are originated from mature B cells and harbour hallmark chromosome translocations of lymphomagenic potential, such as the c-myc/IgH translocations found in Burkitt lymphomas. It has been recently shown that such translocations are initiated by AID and that ataxia-telangiectasia mutated, p53 and ARF provide surveillance mechanisms to prevent these aberrations. In addition, evidence is accumulating that AID expression can be induced in B cells independently of the germinal centre environment, such as in response to some viral infections, and occasionally in non-B cells, at least in certain inflammation-associated neoplasic situations. The most recent findings on AID expression and function and their relevance to the generation of oncogenic lesions will be discussed.

Activation-induced (cytidine) deaminase

Nijmegen breakage syndrome

10.1093/carcin/bgm201

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Citations (41)

From Loops to Looks: Transcription Factors and Chromatin Organization Shaping Terminal B Cell Differentiation

Trends in Immunology (2019)

Alba Azagra Ester Marina-Zárate Almudena R. Ramiro Biola M. Javierre Maribel Parra

Transcription

10.1016/j.it.2019.11.006

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Citations (21)

Differential Developmental Regulation and Functional Effects on Pre-TCR Surface Expression of Human pTαa and pTαb Spliced Isoforms

The Journal of Immunology (2001)

Almudena R. Ramiro Marı́a N. Navarro Aura Carreira Yolanda R. Carrasco Virginia G. de Yébenes

Abstract Functional rearrangement at the TCRβ locus leads to surface expression on developing pre-T cells of a pre-TCR complex composed of the TCRβ-chain paired with the invariant pre-TCRα (pTα) chain and associated with CD3 components. Pre-TCR signaling triggers the expansion and further differentiation of pre-T cells into TCRαβ mature T cells, a process known as β selection. Besides the conventional pTα transcript (termed pTαa), a second, alternative spliced, isoform of the pTα gene (pTαb) has been described, whose developmental relevance remains unknown. In this study, phenotypic, biochemical, and functional evidence is provided that only pTαa is capable of inducing surface expression of a CD3-associated pre-TCR complex, which seems spontaneously recruited into lipid rafts, while pTαb pairs with and retains TCRβ intracellularly. In addition, by using real-time quantitative RT-PCR approaches, we show that expression of pTαa and pTαb mRNA spliced products is differentially regulated along human intrathymic development, so that pTαb transcriptional onset is developmentally delayed, but β selection results in simultaneous shutdown of both isoforms, with a relative increase of pTαb transcripts in β-selected vs nonselected pre-T cells in vivo. Relative increase of pTαb is also shown to occur upon pre-T cell activation in vitro. Taken together, our data illustrate that transcriptional regulation of pTα limits developmental expression of human pre-TCR to intrathymic stages surrounding β selection, and are compatible with a role for pTαb in forming an intracellular TCRβ-pTαb complex that may be responsible for limiting surface expression of a pTαa-containing pre-TCR and/or may be competent to signal from a subcellular compartment.

10.4049/jimmunol.167.9.5106

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Citations (20)

Bptf determines oncogenic addiction in aggressive B-cell lymphomas

Oncogene (2020)

Laia Richart Irene Felipe‐Abrio Pilar Delgado Mónica P. de Andrés Jaime Prieto

Haploinsufficiency

10.1038/s41388-020-1331-3

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Citations (6)

Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand

Nature Immunology (2003)

Almudena R. Ramiro Pete Stavropoulos Mila Janković Michel C. Nussenzweig

Transcription bubble

Activation-induced (cytidine) deaminase

Transcription

Coding strand

10.1038/ni920

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Citations (428)

Single Cell Clonal Analysis Identifies an AID-Dependent Pathway of Plasma Cell Differentiation

SSRN Electronic Journal (2021)

Carmen Gómez‐Escolar Álvaro Serrano Alberto Benguría Ana Dopazo Fátima Sánchez‐Cabo

Germinal centers (GC) are microstructures where B cells that have been activated by antigen can improve the affinity of their B cell receptors and differentiate into memory B cells (MBCs) or antibody secreting plasma cells. Activation Induced Deaminase (AID) initiates antibody diversification in GCs by somatic hypermutation and class switch recombination. Here we have addressed the role of AID in the terminal differentiation of GC B cells by combining single cell transcriptome and immunoglobulin clonal analysis in a mouse model that traces AID-experienced cells. We identified 8 transcriptional clusters that include dark zone and light zone GC subsets, plasmablasts/plasma cells (PB), 4 subsets of MBCs and a novel prePB subset, which shares the strongest clonal relationships with PBs. Mice lacking AID have various alterations in the size and expression profiles of these transcriptional clusters. We find that AID deficiency leads to a reduced proportion of prePB cells and severely impairs transitions between the prePB and the PB subsets. Thus, AID shapes the differentiation fate of GC B cells by enabling PB generation from a prePB state.

Single-Cell Analysis

10.2139/ssrn.3863577

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Citations (1)

Identification of a myeloid intrathymic pathway of dendritic cell development marked by expression of the granulocyte macrophage–colony-stimulating factor receptor

Blood (2002)

Virginia G. de Yébenes Yolanda R. Carrasco Almudena R. Ramiro Marı́a L. Toribio

Interleukin 3

10.1182/blood.v99.8.2948

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Citations (39)

Single cell clonal analysis identifies an AID-dependent pathway of plasma cell differentiation

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Carmen Gómez‐Escolar Álvaro Serrano Alberto Benguría Ana Dopazo Fátima Sánchez‐Cabo

ABSTRACT Germinal centers (GC) are microstructures where B cells that have been activated by antigen can improve the affinity of their B cell receptors and differentiate into memory B cells (MBCs) or antibody secreting plasma cells. Activation Induced Deaminase (AID) initiates antibody diversification in GCs by somatic hypermutation and class switch recombination. Here we have addressed the role of AID in the terminal differentiation of GC B cells by combining single cell transcriptome and immunoglobulin clonal analysis in a mouse model that traces AID-experienced cells. We identified 8 transcriptional clusters that include dark zone and light zone GC subsets, plasmablasts/plasma cells (PB), 4 subsets of MBCs and a novel prePB subset, which shares the strongest clonal relationships with PBs. Mice lacking AID have various alterations in the size and expression profiles of these transcriptional clusters. We find that AID deficiency leads to a reduced proportion of prePB cells and severely impairs transitions between the prePB and the PB subsets. Thus, AID shapes the differentiation fate of GC B cells by enabling PB generation from a prePB state.

Affinity maturation

Memory B cell

Activation-induced (cytidine) deaminase

Naive B cell

10.1101/2021.06.03.446763

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Citations (3)

miR-217 is an oncogene that enhances the germinal center reaction

Blood (2014)

Virginia G. de Yébenes Nahikari Bartolomé‐Izquierdo Rubén Nogales‐Cadenas Pablo Pérez‐Durán Sonia M. Mur

10.1182/blood-2013-12-543611

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Citations (57)