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Article ; Online: Developmental changes in the rules for B cell selection.

Vergani, Stefano / Yuan, Joan

2021 Volume 300, Issue 1, Page(s) 194–202

Abstract: The autoimmune checkpoint during B cell maturation eliminates self-antigen reactive specificities from the mature B cell repertoire. However, an exception to this rule is illustrated by B-1 cells, an innate-like self-reactive B cell subset that is ... ...

Abstract	The autoimmune checkpoint during B cell maturation eliminates self-antigen reactive specificities from the mature B cell repertoire. However, an exception to this rule is illustrated by B-1 cells, an innate-like self-reactive B cell subset that is positively selected into the mature B cell pool in a self-antigen-driven fashion. The mechanisms by which B-1 cells escape central tolerance have puzzled the field for decades. A key clue comes from their restricted developmental window during fetal and neonatal life. Here we use B-1 cells as a prototypic early life derived B cell subset to explore developmental changes in the constraints of B cell selection. We discuss recent advancements in the understanding of the molecular program, centered around the RNA binding protein Lin28b, that licenses self-reactive B-1 cell output during ontogeny. Finally, we speculate on the possible link between the unique rules of early life B cell tolerance and the establishment of B cell - microbial mutualism to propose an integrated model for how developmental and environmental cues come together to create a protective layer of B cell memory involved in neonatal immune imprinting.
MeSH term(s)	Antibody Specificity ; Autoantigens ; B-Lymphocyte Subsets ; B-Lymphocytes ; Immune Tolerance
Chemical Substances	Autoantigens
Language	English
Publishing date	2021-01-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	391796-4
ISSN	1600-065X ; 0105-2896
ISSN (online)	1600-065X
ISSN	0105-2896
DOI	10.1111/imr.12949
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: B-1 Cells Carry the Memory of Neonatal Immune Imprinting.

Vergani, Stefano / Yuan, Joan

Immunity

2020 Volume 53, Issue 1, Page(s) 11–13

Abstract: Group A Streptococcus is a common pathogen that elicits a protective humoral response against the cell wall component GlcNAc. In this issue of Immunity, New et al. demonstrate the ability of long-lived B-1 cells to be programmed by microbial colonization ...

Abstract	Group A Streptococcus is a common pathogen that elicits a protective humoral response against the cell wall component GlcNAc. In this issue of Immunity, New et al. demonstrate the ability of long-lived B-1 cells to be programmed by microbial colonization and early life immunization to uniquely incorporate GlcNAc reactivity in mice, establishing their critical role in mediating neonatal immune imprinting.
MeSH term(s)	Animals ; B-Lymphocyte Subsets/immunology ; Bacteria ; Immunization ; Mice ; Polysaccharides ; Vaccination
Chemical Substances	Polysaccharides
Keywords	covid19
Language	English
Publishing date	2020-07-27
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2020.06.018
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Article: B-1 Cells Carry the Memory of Neonatal Immune Imprinting

Vergani, Stefano / Yuan, Joan

Immunity

Abstract	Group A Streptococcus is a common pathogen that elicits a protective humoral response against the cell wall component GlcNAc. In this issue of Immunity, New et al. demonstrate the ability of long-lived B-1 cells to be programmed by microbial colonization and early life immunization to uniquely incorporate GlcNAc reactivity in mice, establishing their critical role in mediating neonatal immune imprinting.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #32668222
Database	COVID19

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Article ; Online: Enhanced protein synthesis is a defining requirement for neonatal B cell development.

Åkerstrand, Hugo / Boldrin, Elena / Montano, Giorgia / Vanhee, Stijn / Olsson, Karin / Krausse, Niklas / Vergani, Stefano / Cieśla, Maciej / Bellodi, Cristian / Yuan, Joan

Frontiers in immunology

2023 Volume 14, Page(s) 1130930

Abstract: The LIN28B RNA binding protein exhibits an ontogenically restricted expression pattern and is a key molecular regulator of fetal and neonatal B lymphopoiesis. It enhances the positive selection of CD5+ immature B cells early in life through amplifying ... ...

Abstract	The LIN28B RNA binding protein exhibits an ontogenically restricted expression pattern and is a key molecular regulator of fetal and neonatal B lymphopoiesis. It enhances the positive selection of CD5+ immature B cells early in life through amplifying the CD19/PI3K/c-MYC pathway and is sufficient to reinitiate self-reactive B-1a cell output when ectopically expressed in the adult. In this study, interactome analysis in primary B cell precursors showed direct binding by LIN28B to numerous ribosomal protein transcripts, consistent with a regulatory role in cellular protein synthesis. Induction of LIN28B expression in the adult setting is sufficient to promote enhanced protein synthesis during the small Pre-B and immature B cell stages, but not during the Pro-B cell stage. This stage dependent effect was dictated by IL-7 mediated signaling, which masked the impact of LIN28B through an overpowering stimulation on the c-MYC/protein synthesis axis in Pro-B cells. Importantly, elevated protein synthesis was a distinguishing feature between neonatal and adult B cell development that was critically supported by endogenous
MeSH term(s)	Mice ; Animals ; B-Lymphocytes ; Precursor Cells, B-Lymphoid
Language	English
Publishing date	2023-04-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1130930
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Article: CLL stereotyped B-cell receptor immunoglobulin sequences are recurrent in the B-cell repertoire of healthy individuals: Apparent lack of central and early peripheral tolerance censoring.

Vergani, Stefano / Bagnara, Davide / Agathangelidis, Andreas / Ng, Anita Kar Yun / Ferrer, Gerardo / Mazzarello, Andrea N / Palacios, Florencia / Yancopoulos, Sophia / Yan, Xiao-Jie / Barrientos, Jaqueline C / Rai, Kanti R / Stamatopoulos, Kostas / Chiorazzi, Nicholas

Frontiers in oncology

2023 Volume 13, Page(s) 1112879

Abstract: Introduction: The leukemic cells of patients with chronic lymphocytic leukemia (CLL) are often unique, expressing remarkably similar IGHV-IGHD-IGHJ gene rearrangements, "stereotyped BCRs". The B-cell receptors (BCRs) on CLL cells are also distinctive in ...

Abstract	Introduction: The leukemic cells of patients with chronic lymphocytic leukemia (CLL) are often unique, expressing remarkably similar IGHV-IGHD-IGHJ gene rearrangements, "stereotyped BCRs". The B-cell receptors (BCRs) on CLL cells are also distinctive in often deriving from autoreactive B lymphocytes, leading to the assumption of a defect in immune tolerance. Results: Using bulk and single-cell immunoglobulin heavy and light chain variable domain sequencing, we enumerated CLL stereotype-like IGHV-IGHD-IGHJ sequences (CLL-SLS) in B cells from cord blood (CB) and adult peripheral blood (PBMC) and bone marrow (BM of healthy donors. CLL-SLS were found at similar frequencies among CB, BM, and PBMC, suggesting that age does not influence CLL-SLS levels. Moreover, the frequencies of CLL-SLS did not differ among B lymphocytes in the BM at early stages of development, and only re-circulating marginal zone B cells contained significantly higher CLL-SLS frequencies than other mature B-cell subpopulations. Although we identified CLL-SLS corresponding to most of the CLL major stereotyped subsets, CLL-SLS frequencies did not correlate with those found in patients. Interestingly, in CB samples, half of the CLL-SLS identified were attributed to two IGHV-mutated subsets. We also found satellite CLL-SLS among the same normal samples, and they were also enriched in naïve B cells but unexpectedly, these were ~10-fold higher than standard CLL-SLS. In general, IGHV-mutated CLL-SLS subsets were enriched among antigen-experienced B-cell subpopulations, and IGHV-unmutated CLL-SLS were found mostly in antigen-inexperienced B cells. Nevertheless, CLL-SLS with an IGHV-mutation status matching that of CLL clones varied among the normal B-cell subpopulations, suggesting that specific CLL-SLS could originate from distinct subpopulations of normal B cells. Lastly, using single-cell DNA sequencing, we identified paired IGH and IGL rearrangements in normal B lymphocytes resembling those of stereotyped BCRs in CLL, although some differed from those in patients based on IG isotype or somatic mutation. Discussion: CLL-SLS are present in normal B-lymphocyte populations at all stages of development. Thus, despite their autoreactive profile they are not deleted by central tolerance mechanisms, possibly because the level of autoreactivity is not registered as dangerous by deletion mechanisms or because editing of L-chain variable genes occurred which our experimental approach could not identify.
Language	English
Publishing date	2023-03-17
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1112879
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Article ; Online: Developmental cues license megakaryocyte priming in murine hematopoietic stem cells.

Kristiansen, Trine Ahn / Zhang, Qinyu / Vergani, Stefano / Boldrin, Elena / Krausse, Niklas / André, Oscar / Nordenfelt, Pontus / Sigvardsson, Mikael / Bryder, David / Ungerbäck, Jonas / Yuan, Joan

Blood advances

2022

Abstract: The fetal to adult switch in hematopoietic stem cell (HSC) behavior is characterized by alterations in lineage output and entry into deep quiescence. Here we identify the emergence of megakaryocyte (Mk) biased HSCs as an event coinciding with this ... ...

Abstract	The fetal to adult switch in hematopoietic stem cell (HSC) behavior is characterized by alterations in lineage output and entry into deep quiescence. Here we identify the emergence of megakaryocyte (Mk) biased HSCs as an event coinciding with this developmental switch. Single-cell chromatin accessibility analysis reveals a ubiquitous acquisition of Mk lineage priming signatures in HSCs during the fetal to adult transition. These molecular changes functionally coincide with an increased amplitude of early Mk differentiation events following acute inflammatory insult. Importantly, we identify LIN28B - known for its role in promoting fetal-like self-renewal, as an insulator against the establishment of a Mk biased HSC pool. LIN28B protein is developmentally silenced in the third week of life and its prolonged expression delays emergency platelet output in young adult mice. We propose that developmental regulation of Mk priming may represent a switch for HSCs to toggle between prioritizing self-renewal in the fetus and increased host protection in postnatal life.
Language	English
Publishing date	2022-05-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2021006861
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Article ; Online: Low-dose irradiated mesenchymal stromal cells break tumor defensive properties in vivo.

Stefani, Francesca Romana / Eberstål, Sofia / Vergani, Stefano / Kristiansen, Trine A / Bengzon, Johan

International journal of cancer

2018 Volume 143, Issue 9, Page(s) 2200–2212

Abstract: Solid tumors, including gliomas, still represent a challenge to clinicians and first line treatments often fail, calling for new paradigms in cancer therapy. Novel strategies to overcome tumor resistance are mainly represented by multi-targeted ... ...

Abstract	Solid tumors, including gliomas, still represent a challenge to clinicians and first line treatments often fail, calling for new paradigms in cancer therapy. Novel strategies to overcome tumor resistance are mainly represented by multi-targeted approaches, and cell vector-based therapy is one of the most promising treatment modalities under development. Here, we show that mouse bone marrow-derived mesenchymal stromal cells (MSCs), when primed with low-dose irradiation (irMSCs), undergo changes in their immunogenic and angiogenic capacity and acquire anti-tumoral properties in a mouse model of glioblastoma (GBM). Following grafting in GL261 glioblastoma, irMSCs migrate extensively and selectively within the tumor and infiltrate predominantly the peri-vascular niche, leading to rejection of established tumors and cure in 29% of animals. The therapeutic radiation dose window is narrow, with effects seen between 2 and 15 Gy, peaking at 5 Gy. A single low-dose radiation decreases MSCs inherent immune suppressive properties in vitro as well as shapes their immune regulatory ability in vivo. Intra-tumorally grafted irMSCs stimulate the immune system and decrease immune suppression. Additionally, irMSCs enhance peri-tumoral reactive astrocytosis and display anti-angiogenic properties. Hence, the present study provides strong evidence for a therapeutic potential of low-dose irMSCs in cancer as well as giving new insight into MSC biology and applications.
MeSH term(s)	Animals ; Apoptosis ; Cell Proliferation ; Female ; Glioblastoma/blood supply ; Glioblastoma/immunology ; Glioblastoma/therapy ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology ; Mesenchymal Stem Cells/immunology ; Mesenchymal Stem Cells/radiation effects ; Mice ; Mice, Inbred C57BL ; Tumor Cells, Cultured
Language	English
Publishing date	2018-08-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218257-9
ISSN	1097-0215 ; 0020-7136
ISSN (online)	1097-0215
ISSN	0020-7136
DOI	10.1002/ijc.31599
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Article: Characterizing Features of Human Circulating B Cells Carrying CLL-Like Stereotyped Immunoglobulin Rearrangements.

Bagnara, Davide / Colombo, Monica / Reverberi, Daniele / Matis, Serena / Massara, Rosanna / Cardente, Niccolò / Ubezio, Gianluca / Agostini, Vanessa / Agnelli, Luca / Neri, Antonino / Cardillo, Martina / Vergani, Stefano / Ghiotto, Fabio / Mazzarello, Andrea Nicola / Morabito, Fortunato / Cutrona, Giovanna / Ferrarini, Manlio / Fais, Franco

Frontiers in oncology

2022 Volume 12, Page(s) 894419

Abstract: Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of monoclonal ... ...

Abstract	Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of monoclonal CD5
Language	English
Publishing date	2022-06-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2022.894419
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Article: Novel Method for High-Throughput Full-Length IGHV-D-J Sequencing of the Immune Repertoire from Bulk B-Cells with Single-Cell Resolution.

Vergani, Stefano / Korsunsky, Ilya / Mazzarello, Andrea Nicola / Ferrer, Gerardo / Chiorazzi, Nicholas / Bagnara, Davide

Frontiers in immunology

2017 Volume 8, Page(s) 1157

Abstract: Efficient and accurate high-throughput DNA sequencing of the adaptive immune receptor repertoire (AIRR) is necessary to study immune diversity in healthy subjects and disease-related conditions. The high complexity and diversity of the AIRR coupled with ... ...

Abstract	Efficient and accurate high-throughput DNA sequencing of the adaptive immune receptor repertoire (AIRR) is necessary to study immune diversity in healthy subjects and disease-related conditions. The high complexity and diversity of the AIRR coupled with the limited amount of starting material, which can compromise identification of the full biological diversity makes such sequencing particularly challenging. AIRR sequencing protocols often fail to fully capture the sampled AIRR diversity, especially for samples containing restricted numbers of B lymphocytes. Here, we describe a library preparation method for immunoglobulin sequencing that results in an exhaustive full-length repertoire where virtually every sampled B-cell is sequenced. This maximizes the likelihood of identifying and quantifying the entire IGHV-D-J repertoire of a sample, including the detection of rearrangements present in only one cell in the starting population. The methodology establishes the importance of circumventing genetic material dilution in the preamplification phases and incorporates the use of certain described concepts: (1) balancing the starting material amount and depth of sequencing, (2) avoiding IGHV gene-specific amplification, and (3) using Unique Molecular Identifier. Together, this methodology is highly efficient, in particular for detecting rare rearrangements in the sampled population and when only a limited amount of starting material is available.
Language	English
Publishing date	2017
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2017.01157
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Article ; Online: A self-sustaining layer of early-life-origin B cells drives steady-state IgA responses in the adult gut.

Vergani, Stefano / Muleta, Konjit Getachew / Da Silva, Clément / Doyle, Alexander / Kristiansen, Trine Ahn / Sodini, Selene / Krausse, Niklas / Montano, Giorgia / Kotarsky, Knut / Nakawesi, Joy / Åkerstrand, Hugo / Vanhee, Stijn / Gupta, Sneh Lata / Bryder, David / Agace, William Winston / Lahl, Katharina / Yuan, Joan

Immunity

2022 Volume 55, Issue 10, Page(s) 1829–1842.e6

Abstract: The adult immune system consists of cells that emerged at various times during ontogeny. We aimed to define the relationship between developmental origin and composition of the adult B cell pool during unperturbed hematopoiesis. Lineage tracing ... ...

Abstract	The adult immune system consists of cells that emerged at various times during ontogeny. We aimed to define the relationship between developmental origin and composition of the adult B cell pool during unperturbed hematopoiesis. Lineage tracing stratified murine adult B cells based on the timing of output, revealing that a substantial portion originated within a restricted neonatal window. In addition to B-1a cells, early-life time-stamped B cells included clonally interrelated IgA plasma cells in the gut and bone marrow. These were actively maintained by B cell memory within gut chronic germinal centers and contained commensal microbiota reactivity. Neonatal rotavirus infection recruited recurrent IgA clones that were distinct from those arising by infection with the same antigen in adults. Finally, gut IgA plasma cells arose from the same hematopoietic progenitors as B-1a cells during ontogeny. Thus, a complex layer of neonatally imprinted B cells confer unique antibody responses later in life.
MeSH term(s)	Animals ; B-Lymphocytes ; Germinal Center ; Immunoglobulin A ; Mice ; Microbiota ; Plasma Cells
Chemical Substances	Immunoglobulin A
Language	English
Publishing date	2022-09-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1217235-2
ISSN	1097-4180 ; 1074-7613
ISSN (online)	1097-4180
ISSN	1074-7613
DOI	10.1016/j.immuni.2022.08.018
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