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

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1448-1455 ◽  
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.

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 Regulation of class switch recombination and somatic mutation by AID phosphorylation

2008 ◽  
Vol 205 (11) ◽  
pp. 2585-2594 ◽  
Author(s):  
Kevin M. McBride ◽  
Anna Gazumyan ◽  
Eileen M. Woo ◽  
Tanja A. Schwickert ◽  
Brian T. Chait ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Point Mutations ◽  
Class Switch Recombination ◽  
Variable Region ◽  
Dna Breaks ◽  
Class Switching ◽  
Class Switch

Activation-induced cytidine deaminase (AID) is a mutator enzyme that initiates somatic mutation and class switch recombination in B lymphocytes by introducing uracil:guanine mismatches into DNA. Repair pathways process these mismatches to produce point mutations in the Ig variable region or double-stranded DNA breaks in the switch region DNA. However, AID can also produce off-target DNA damage, including mutations in oncogenes. Therefore, stringent regulation of AID is required for maintaining genomic stability during maturation of the antibody response. It has been proposed that AID phosphorylation at serine 38 (S38) regulates its activity, but this has not been tested in vivo. Using a combination of mass spectrometry and immunochemical approaches, we found that in addition to S38, AID is also phosphorylated at position threonine 140 (T140). Mutation of either S38 or T140 to alanine does not impact catalytic activity, but interferes with class switching and somatic hypermutation in vivo. This effect is particularly pronounced in haploinsufficient mice where AID levels are limited. Although S38 is equally important for both processes, T140 phosphorylation preferentially affects somatic mutation, suggesting that posttranslational modification might contribute to the choice between hypermutation and class switching.

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

2009 ◽  
Vol 182 (7) ◽  
pp. 4226-4236 ◽  
Author(s):  
Dina C. Nacionales ◽  
Jason S. Weinstein ◽  
Xiao-Jie Yan ◽  
Emilia Albesiano ◽  
Pui Y. Lee ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Lymphoid Tissue ◽  
Somatic Hypermutation ◽  
Class Switch Recombination ◽  
Murine Lupus ◽  
Autoantibody Production ◽  
Class Switch

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

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1421-1427 ◽  
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.

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

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.

scholarly journals In vivo and in vitro studies of immunoglobulin gene somatic hypermutation

2001 ◽  
Vol 356 (1405) ◽  
pp. 21-28 ◽  
Author(s):  
Julian E. Sale ◽  
Mats Bemark ◽  
Gareth T. Williams ◽  
Christopher J. Jolly ◽  
Michael R. Ehrenstein ◽  
...  
Keyword(s):  
Somatic Hypermutation ◽  
Class Switch Recombination ◽  
Variable Region ◽  
Immunoglobulin Gene ◽  
Immunoglobulin Genes ◽  
Class Switch ◽  
Immunoglobulin Repertoire ◽  
Genetic Events

Following antigen encounter, two distinct processes modify immunoglobulin genes. The variable region is diversified by somatic hypermutation while the constant region may be changed by class–switch recombination. Although both genetic events can occur concurrently within germinal centre B cells, there are examples of each occurring independently of the other. Here we compare the contributions of class–switch recombination and somatic hypermutation to the diversification of the serum immunoglobulin repertoire and review evidence that suggests that, despite clear differences, the two processes may share some aspects of their mechanism in common.

scholarly journals Polζ ablation in B cells impairs the germinal center reaction, class switch recombination, DNA break repair, and genome stability

2009 ◽  
Vol 206 (2) ◽  
pp. 477-490 ◽  
Author(s):  
Dominik Schenten ◽  
Sven Kracker ◽  
Gloria Esposito ◽  
Sonia Franco ◽  
Ulf Klein ◽  
...  
Keyword(s):  
B Cells ◽  
Genome Stability ◽  
Somatic Hypermutation ◽  
Class Switch Recombination ◽  
Dna Breaks ◽  
Dsb Repair ◽  
Direct Role ◽  
Class Switch

Polζ is an error-prone DNA polymerase that is critical for embryonic development and maintenance of genome stability. To analyze its suggested role in somatic hypermutation (SHM) and possible contribution to DNA double-strand break (DSB) repair in class switch recombination (CSR), we ablated Rev3, the catalytic subunit of Polζ, selectively in mature B cells in vivo. The frequency of somatic mutation was reduced in the mutant cells but the pattern of SHM was unaffected. Rev3-deficient B cells also exhibited pronounced chromosomal instability and impaired proliferation capacity. Although the data thus argue against a direct role of Polζ in SHM, Polζ deficiency directly interfered with CSR in that activated Rev3-deficient B cells exhibited a reduced efficiency of CSR and an increased frequency of DNA breaks in the immunoglobulin H locus. Based on our results, we suggest a nonredundant role of Polζ in DNA DSB repair through nonhomologous end joining.

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