B Cell Proliferation, Somatic Hypermutation, Class Switch Recombination, and Autoantibody Production in Ectopic Lymphoid Tissue in Murine Lupus

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.

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

Journal of Biological Chemistry ◽

10.1074/jbc.m807338200 ◽

2009 ◽

Vol 284 (11) ◽

pp. 6847-6854 ◽

Cited By ~ 14

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

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LMP1 signaling can replace CD40 signaling in B cells in vivo and has unique features of inducing class-switch recombination to IgG1

Blood ◽

10.1182/blood-2007-10-117655 ◽

2008 ◽

Vol 111 (3) ◽

pp. 1448-1455 ◽

Cited By ~ 69

Author(s):

Julia Rastelli ◽

Cornelia Hömig-Hölzel ◽

Jane Seagal ◽

Werner Müller ◽

Andrea C. Hermann ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Function ◽

Somatic Hypermutation ◽

Class Switch Recombination ◽

Cd40 Ligand ◽

Barr Virus ◽

Class Switch ◽

Epstein Barr

AbstractThe Epstein-Barr virus (EBV) protein LMP1 is considered to be a functional homologue of the CD40 receptor. However, in contrast to the latter, LMP1 is a constitutively active signaling molecule. To compare B cell–specific LMP1 and CD40 signaling in an unambiguous manner, we generated transgenic mice conditionally expressing a CD40/LMP1 fusion protein, which retained the LMP1 cytoplasmic tail but has lost the constitutive activity of LMP1 and needs to be activated by the CD40 ligand. We show that LMP1 signaling can completely substitute CD40 signaling in B cells, leading to normal B-cell development, activation, and immune responses including class-switch recombination, germinal center formation, and somatic hypermutation. In addition, the LMP1-signaling domain has a unique property in that it can induce class-switch recombination to IgG1 independent of cytokines. Thus, our data indicate that LMP1 has evolved to imitate T-helper cell function allowing activation, proliferation, and differentiation of EBV-infected B cells independent of T cells.

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Faculty Opinions recommendation of Class switch recombination and somatic hypermutation in early mouse B cells are mediated by B cell and Toll-like receptors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1088668.542772 ◽

2007 ◽

Author(s):

Janet Stavnezer

Keyword(s):

B Cells ◽

B Cell ◽

Somatic Hypermutation ◽

Class Switch Recombination ◽

Toll Like Receptors ◽

Class Switch ◽

Early Mouse

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The immunoglobulin heavy-chain locus hs3b and hs4 3′ enhancers are dispensable for VDJ assembly and somatic hypermutation

Blood ◽

10.1182/blood-2002-12-3827 ◽

2003 ◽

Vol 102 (4) ◽

pp. 1421-1427 ◽

Cited By ~ 39

Author(s):

Caroline Le Morvan ◽

Eric Pinaud ◽

Catherine Decourt ◽

Armelle Cuvillier ◽

Michel Cogné

Keyword(s):

B Cells ◽

B Cell ◽

Heavy Chain ◽

Somatic Hypermutation ◽

Class Switch Recombination ◽

Immunoglobulin Heavy Chain ◽

Germinal Centers ◽

Affinity Maturation ◽

Class Switch ◽

Endogenous Locus

Abstract The more distal enhancers of the immunoglobulin heavy-chain 3′ regulatory region, hs3b and hs4, were recently demonstrated as master control elements of germline transcription and class switch recombination to most immunoglobulin constant genes. In addition, they were shown to enhance the accumulation of somatic mutations on linked transgenes. Since somatic hypermutation and class switch recombination are tightly linked processes, their common dependency on the endogenous locus 3′ enhancers could be an attractive hypothesis. VDJ structure and somatic hypermutation were analyzed in B cells from mice carrying either a heterozygous or a homozygous deletion of these enhancers. We find that hs3b and hs4 are dispensable both for VDJ assembly and for the occurrence of mutations at a physiologic frequency in the endogenous locus. In addition, we show that cells functionally expressing the immunoglobulin M (IgM) class B-cell receptor encoded by an hs3b/hs4-deficient locus were fully able to enter germinal centers, undergo affinity maturation, and yield specific antibody responses in homozygous mutant mice, where IgG1 antibodies compensated for the defect in other IgG isotypes. By contrast, analysis of Peyer patches from heterozygous animals showed that peanut agglutinin (PNAhigh) B cells functionally expressing the hs3b/hs4-deficient allele were dramatically outclassed by B cells expressing the wild-type locus and normally switching to IgA. This study thus also highlights the role of germinal centers in the competition between B cells for affinity maturation and suggests that membrane IgA may promote recruitment in an activated B-cell compartment, or proliferation of activated B cells, more efficiently than IgM in Peyer patches.

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One-step generation of monoclonal B cell receptor mice capable of class switch recombination and somatic hypermutation

10.1101/218438 ◽

2017 ◽

Author(s):

Johanne T. Jacobsen ◽

Luka Mesin ◽

Styliani Markoulaki ◽

Cecília B. Cavazzoni ◽

Djenet Bousbaine ◽

...

Keyword(s):

B Cell ◽

Somatic Hypermutation ◽

Class Switch Recombination ◽

Cell Receptor ◽

Affinity Maturation ◽

B Cell Receptor ◽

Class Switch ◽

One Step ◽

Step Generation ◽

Rapid Generation

We developed a method for rapid generation of B cell receptor (BCR) monoclonal mice expressing pre-rearranged Igh and Igk chains monoallelically from the Igh locus by CRISPR/Cas9 injection into fertilized oocytes. B cells from these mice undergo somatic hypermutation (SHM), class switch recombination (CSR), and affinity-based selection in germinal centers. This method combines the practicality of BCR transgenes with the ability to study Ig SHM, CSR and affinity maturation.

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