scholarly journals IL-23 Promotes a Coordinated B Cell Germinal Center Program for Class-Switch Recombination to IgG2b in BXD2 Mice

2020 ◽  
Vol 205 (2) ◽  
pp. 346-358
Author(s):  
Huixian Hong ◽  
Min Gao ◽  
Qi Wu ◽  
PingAr Yang ◽  
Shanrun Liu ◽  
...  
Keyword(s):  
B Cell ◽  
Germinal Center ◽  
Class Switch Recombination ◽  
Center Program ◽  
Class Switch

scholarly journals Murine germinal center B cells require functional Fms-like tyrosine kinase 3 signaling for IgG1 class-switch recombination

2015 ◽  
Vol 112 (48) ◽  
pp. E6644-E6653 ◽  
Author(s):  
Mattias N. D. Svensson ◽  
Karin M. E. Andersson ◽  
Caroline Wasén ◽  
Malin C. Erlandsson ◽  
Merja Nurkkala-Karlsson ◽  
...  
Keyword(s):  
B Cells ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Germinal Center ◽  
Germ Line ◽  
Class Switch Recombination ◽  
Flt3 Ligand ◽  
Class Switch ◽  
Deficient Mice ◽  
Germinal Center B Cells

Switched antibody classes are important for efficient immune responses. Aberrant antibody production to otherwise harmless antigens may result in autoimmunity. The protein kinase fms-like tyrosine kinase 3 receptor (Flt3) has an important role during early B-cell development, but the role of Flt3 in peripheral B cells has not been assessed before. Herein we describe a previously unappreciated role for Flt3 in IgG1 class-switch recombination (CSR) and production. We show that Flt3 is reexpressed on B-cell lymphoma 6+ germinal center B cells in vivo and following LPS activation of peripheral B cells in vitro. Absence of Flt3 signaling in Flt3 ligand-deficient mice results in impaired IgG1 CSR and accumulation of IgM-secreting plasma cells. On activated B cells, Flt3 is coexpressed and functions in synergy with the common-gamma chain receptor family. B cells from Flt3 ligand-deficient mice have impaired IL-4R signaling, with reduced phosphorylation of signal transducer and activator of transcription (Stat) 6, and demonstrate a failure to initiate CSR to IgG1 with low expression of γ1 germ-line transcripts, resulting in impaired IgG1 production. Thus, functional synergy between Flt3 and IL-4R signaling is critical for Stat-mediated regulation of sterile γ1 germ-line transcripts and CSR to IgG1.

scholarly journals Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis

2012 ◽  
Vol 209 (2) ◽  
pp. 291-305 ◽  
Author(s):  
Likun Du ◽  
Roujun Peng ◽  
Andrea Björkman ◽  
Noel Filipe de Miranda ◽  
Cornelia Rosner ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Class Switch Recombination ◽  
B Cell Lymphoma ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
End Joining ◽  
Class Switch

Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.

scholarly journals Activated CARD11 accelerates germinal center kinetics, promoting mTORC1 and terminal differentiation

2018 ◽  
Vol 215 (9) ◽  
pp. 2445-2461 ◽  
Author(s):  
Michelle N. Wray-Dutra ◽  
Raghav Chawla ◽  
Kerri R. Thomas ◽  
Brenda J. Seymour ◽  
Tanvi Arkatkar ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Terminal Differentiation ◽  
B Cell Differentiation ◽  
Activating Mutations ◽  
Class Switch ◽  
Mtorc1 Signaling ◽  
Activating Mutation ◽  
Novel Strategy

Activating mutations in the adapter protein CARD11 associated with diffuse large B cell lymphomas (DLBCLs) are predicted to arise during germinal center (GC) responses, leading to inappropriate activation of NF-κB signaling. Here, we modeled the B cell–intrinsic impact of the L251P activating mutation in CARD11 (aCARD11) on the GC response. Global B cell aCARD11 expression led to a modest increase in splenic B cells and a severe reduction in B1 B cell numbers, respectively. Following T cell–dependent immunization, aCARD11 cells exhibited increased rates of GC formation, resolution, and differentiation. Restriction of aCARD11 to GC B cells similarly altered the GC response and B cell differentiation. In this model, aCARD11 promoted dark zone skewing along with increased cycling, AID levels, and class switch recombination. Furthermore, aCard11 GC B cells displayed increased biomass and mTORC1 signaling, suggesting a novel strategy for targeting aCARD11-driven DLBCL. While aCARD11 potently impacts GC responses, the rapid GC contraction suggests it requires collaboration with events that limit terminal differentiation to promote lymphoma.

MicroRNA-directed pathway discovery elucidates an miR-221/222–mediated regulatory circuit in class switch recombination

2021 ◽  
Vol 218 (11) ◽  
Author(s):  
Eric J. Wigton ◽  
Yohei Mikami ◽  
Ryan J. McMonigle ◽  
Carlos A. Castellanos ◽  
Adam K. Wade-Vallance ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Cell Activation ◽  
Class Switch Recombination ◽  
Cell Fate Decisions ◽  
Class Switch ◽  
Mrna Targets ◽  
Regulatory Circuit ◽  
Pathway Discovery

MicroRNAs (miRNAs, miRs) regulate cell fate decisions by post-transcriptionally tuning networks of mRNA targets. We used miRNA-directed pathway discovery to reveal a regulatory circuit that influences Ig class switch recombination (CSR). We developed a system to deplete mature, activated B cells of miRNAs, and performed a rescue screen that identified the miR-221/222 family as a positive regulator of CSR. Endogenous miR-221/222 regulated B cell CSR to IgE and IgG1 in vitro, and miR-221/222–deficient mice exhibited defective IgE production in allergic airway challenge and polyclonal B cell activation models in vivo. We combined comparative Ago2-HITS-CLIP and gene expression analyses to identify mRNAs bound and regulated by miR-221/222 in primary B cells. Interrogation of these putative direct targets uncovered functionally relevant downstream genes. Genetic depletion or pharmacological inhibition of Foxp1 and Arid1a confirmed their roles as key modulators of CSR to IgE and IgG1.

scholarly journals Clinical, Immunological, and Functional Characterization of Six Patients with Very High IgM Levels

2020 ◽  
Vol 9 (3) ◽  
pp. 818 ◽  
Author(s):  
Vera Gallo ◽  
Emilia Cirillo ◽  
Rosaria Prencipe ◽  
Alessio Lepore ◽  
Luigi Del Vecchio ◽  
...  
Keyword(s):  
B Cell ◽  
Somatic Hypermutation ◽  
Functional Characterization ◽  
Class Switch Recombination ◽  
Pathogenic Mutation ◽  
Potential Candidate ◽  
Class Switch ◽  
Potential Candidate Gene ◽  
Very High

Very high IgM levels represent the hallmark of hyper IgM (HIGM) syndromes, a group of primary immunodeficiencies (PIDs) characterized by susceptibility to infections and malignancies. Other PIDs not fulfilling the diagnostic criteria for HIGM syndromes can also be characterized by high IgM levels and susceptibility to malignancies. The aim of this study is to characterize clinical phenotype, immune impairment, and pathogenic mechanism in six patients with very high IgM levels in whom classical HIGM syndromes were ruled out. The immunological analysis included extended B-cell immunophenotyping, evaluation of class switch recombination and somatic hypermutation, and next generation sequencing (NGS). Recurrent or severe infections and chronic lung changes at the diagnosis were reported in five out of six and two out of six patients, respectively. Five out of six patients showed signs of lymphoproliferation and four patients developed malignancies. Four patients showed impaired B-cell homeostasis. Class switch recombination was functional in vivo in all patients. NGS revealed, in one case, a pathogenic mutation in PIK3R1. In a second case, the ITPKB gene, implicated in B- and T-cell development, survival, and activity was identified as a potential candidate gene. Independent of the genetic basis, very high IgM levels represent a risk factor for the development of recurrent infections leading to chronic lung changes, lymphoproliferation, and high risk of malignancies.

scholarly journals Lsh/HELLS is required for B lymphocyte development and immunoglobulin class switch recombination

2020 ◽  
Vol 117 (33) ◽  
pp. 20100-20108
Author(s):  
Yafeng He ◽  
Jianke Ren ◽  
Xiaoping Xu ◽  
Kai Ni ◽  
Andrew Schwader ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
B Cell ◽  
Marrow Transplantation ◽  
Class Switch Recombination ◽  
B Cell Development ◽  
Hematopoietic Cell ◽  
Cell Numbers ◽  
Class Switch

Mutation of HELLS (Helicase, Lymphoid-Specific)/Lsh in human DNA causes a severe immunodeficiency syndrome, but the nature of the defect remains unknown. We assessed here the role of Lsh in hematopoiesis using conditional Lsh knockout mice with expression of Mx1 or Vav Cre-recombinase. Bone marrow transplantation studies revealed that Lsh depletion in hematopoietic stem cells severely reduced B cell numbers and impaired B cell development in a hematopoietic cell-autonomous manner. Lsh-deficient mice without bone marrow transplantation exhibited lower Ig levels in vivo compared to controls despite normal peripheral B cell numbers. Purified B lymphocytes proliferated normally but produced less immunoglobulins in response to in vitro stimulation, indicating a reduced capacity to undergo class switch recombination (CSR). Analysis of germline transcripts, examination of double-stranded breaks using biotin-labeling DNA break assay, and End-seq analysis indicated that the initiation of the recombination process was unscathed. In contrast, digestion–circularization PCR analysis and high-throughput sequencing analyses of CSR junctions and a chromosomal break repair assay indicated an impaired ability of the canonical end-joining pathway in Lsh-deficient B cells. Our data suggest a hematopoietic cell-intrinsic role of Lsh in B cell development and in CSR providing a potential target for immunodeficiency therapy.

scholarly journals CTP:Phosphocholine Cytidylyltransferase α Is Required for B-cell Proliferation and Class Switch Recombination

2009 ◽  
Vol 284 (11) ◽  
pp. 6847-6854 ◽  
Author(s):  
Paolo Fagone ◽  
Christopher Gunter ◽  
Christopher R. Sage ◽  
Kathryn E. Gunn ◽  
Joseph W. Brewer ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Class Switch Recombination ◽  
Class Switch ◽  
Ctp:Phosphocholine Cytidylyltransferase

HIV-1 induces B-cell activation and class switch recombination via spleen tyrosine kinase and c-Jun N-terminal kinase pathways

AIDS ◽  
2014 ◽  
Vol 28 (16) ◽  
pp. 2365-2374 ◽  
Author(s):  
Ana Judith Perisé-Barrios ◽  
Rafael Correa-Rocha ◽  
Susana Álvarez ◽  
Maria Ángeles Muñoz-Fernandez ◽  
Marjorie Pion
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Cell Activation ◽  
Class Switch Recombination ◽  
B Cell Activation ◽  
Spleen Tyrosine Kinase ◽  
Class Switch ◽  
Hiv 1

scholarly journals The mTOR-Bach2 Cascade Controls Cell Cycle and Class Switch Recombination during B Cell Differentiation

2017 ◽  
Vol 37 (24) ◽  
Author(s):  
Toru Tamahara ◽  
Kyoko Ochiai ◽  
Akihiko Muto ◽  
Yukinari Kato ◽  
Nicolas Sax ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Class Switch Recombination ◽  
Cyclin D3 ◽  
Immunoglobulin Gene ◽  
B Cell Differentiation ◽  
Class Switch

ABSTRACT The transcription factor Bach2 regulates both acquired and innate immunity at multiple steps, including antibody class switching and regulatory T cell development in activated B and T cells, respectively. However, little is known about the molecular mechanisms of Bach2 regulation in response to signaling of cytokines and antigen. We show here that mammalian target of rapamycin (mTOR) controls Bach2 along B cell differentiation with two distinct mechanisms in pre-B cells. First, mTOR complex 1 (mTORC1) inhibited accumulation of Bach2 protein in nuclei and reduced its stability. Second, mTOR complex 2 (mTORC2) inhibited FoxO1 to reduce Bach2 mRNA expression. Using expression profiling and chromatin immunoprecipitation assay, the Ccnd3 gene, encoding cyclin D3, was identified as a new direct target of Bach2. A proper cell cycle was lost at pre-B and mature B cell stages in Bach2-deficient mice. Furthermore, AZD8055, an mTOR inhibitor, increased class switch recombination in wild-type mature B cells but not in Bach2-deficient cells. These results suggest that the mTOR-Bach2 cascade regulates proper cell cycle arrest in B cells as well as immunoglobulin gene rearrangement.

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