scholarly journals IL-21 is a broad negative regulator of IgE class switch recombination in mouse and human B cells

2020 ◽  
Vol 217 (5) ◽  
Author(s):  
Zhiyong Yang ◽  
Chung-An M. Wu ◽  
Sasha Targ ◽  
Christopher D.C. Allen
Keyword(s):  
B Cells ◽  
Class Switch Recombination ◽  
Primary Source ◽  
Negative Regulator ◽  
Class Switch ◽  
Cellular Analysis ◽  
Follicular Helper ◽  
Human B Cells

IgE antibodies may elicit potent allergic reactions, and their production is tightly controlled. The tendency to generate IgE has been thought to reflect the balance between type 1 and type 2 cytokines, with the latter promoting IgE. Here, we reevaluated this paradigm by a direct cellular analysis, demonstrating that IgE production was not limited to type 2 immune responses yet was generally constrained in vivo. IL-21 was a critical negative regulator of IgE responses, whereas IFN-γ, IL-6, and IL-10 were dispensable. Follicular helper T cells were the primary source of IL-21 that inhibited IgE responses by directly engaging the IL-21 receptor on B cells and triggering STAT3-dependent signaling. We reconciled previous discordant results between mouse and human B cells and revealed that the inhibition of IgE class switch recombination by IL-21 was attenuated by CD40 signaling, whereas IgG1 class switch recombination was potentiated by IL-21 in the context of limited IL-4. These findings establish key features of the extrinsic regulation of IgE production by cytokines.

scholarly journals DNA-PKcs Is Involved in Ig Class Switch Recombination in Human B Cells

2015 ◽  
Vol 195 (12) ◽  
pp. 5608-5615 ◽  
Author(s):  
Andrea Björkman ◽  
Likun Du ◽  
Kerstin Felgentreff ◽  
Cornelia Rosner ◽  
Radhika Pankaj Kamdar ◽  
...  
Keyword(s):  
B Cells ◽  
Class Switch Recombination ◽  
Class Switch ◽  
Human B Cells

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.

Human CD5 promotes B-cell survival through stimulation of autocrine IL-10 production

Blood ◽  
2002 ◽  
Vol 100 (13) ◽  
pp. 4537-4543 ◽  
Author(s):  
Hélène Gary-Gouy ◽  
Julie Harriague ◽  
Georges Bismuth ◽  
Cornelia Platzer ◽  
Christian Schmitt ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Human Peripheral Blood ◽  
Cell Receptor ◽  
Interleukin 10 ◽  
Negative Regulator ◽  
B Cell Tolerance ◽  
Human B Cells ◽  
B Cell Survival

CD5 is a negative regulator of B-cell receptor (BCR) signaling that is up-regulated after BCR stimulation and likely contributes to B-cell tolerance in vivo. However, CD5 is constitutively expressed on the B-1 subset of B cells. Contrary to CD5− B-2 B cells, B-1 B cells are long-lived because of autocrine interleukin-10 (IL-10) production through unknown mechanisms. We demonstrate herein a direct relationship between CD5 expression and IL-10 production. Human peripheral blood CD5+ B cells produce more IL-10 than CD5− B cells after BCR activation. Introducing CD5 into CD5− B cells induces the production of IL-10 by activating its promoter and the synthesis of its mRNA. The cytoplasmic domain of CD5 is sufficient for this process. CD5 also protects normal human B cells from apoptosis after BCR stimulation while reducing the BCR-induced Ca2+ response. We conclude that CD5 supports the survival of B cells by stimulating IL-10 production and by concurrently exerting negative feedback on BCR-induced signaling events that can promote cell death.

scholarly journals KIAA1841, a novel SANT and BTB domain-containing protein, inhibits class switch recombination

2020 ◽  
Author(s):  
Simin Zheng ◽  
Allysia J. Matthews ◽  
Numa Rahman ◽  
Kayleigh Herrick-Reynolds ◽  
Jee Eun Choi ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Class Switch Recombination ◽  
Negative Regulator ◽  
Uncharacterized Protein ◽  
Btb Domain ◽  
Class Switch ◽  
Primary Mouse ◽  
Library Screen ◽  
Shrna Library

AbstractClass switch recombination (CSR) enables B cells to produce different immunoglobulin isotypes and mount an effective immune response against pathogens. Timely resolution of CSR prevents damage due to an uncontrolled and prolonged immune response. While many positive regulators of CSR have been described, negative regulators of CSR are relatively unknown. Using a shRNA library screen in a mouse B cell line, we have identified the novel protein KIAA1841 (NM_027860) as a negative regulator of CSR. KIAA1841 is an uncharacterized protein of 82kD containing SANT and BTB domains. The BTB domain of KIAA1841 exhibited characteristic properties such as self-dimerization and interaction with co-repressor proteins. Overexpression of KIAA1841 inhibited CSR in primary mouse splenic B cells, and inhibition of CSR is dependent on the BTB domain while the SANT domain is largely dispensable. Thus, we have identified a new member of the BTB family that serves as a negative regulator of CSR.

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.

scholarly journals Aberrant recombination and repair during immunoglobulin class switching in BRCA1-deficient human B cells

2015 ◽  
Vol 112 (7) ◽  
pp. 2157-2162 ◽  
Author(s):  
Andrea Björkman ◽  
Per Qvist ◽  
Likun Du ◽  
Margarita Bartish ◽  
Apostolos Zaravinos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
B Cells ◽  
Class Switch Recombination ◽  
Cancer Type ◽  
End Joining ◽  
Immunoglobulin Class ◽  
Class Switch ◽  
Human B Cells ◽  
Breast Cancer Type

Breast cancer type 1 susceptibility protein (BRCA1) has a multitude of functions that contribute to genome integrity and tumor suppression. Its participation in the repair of DNA double-strand breaks (DSBs) during homologous recombination (HR) is well recognized, whereas its involvement in the second major DSB repair pathway, nonhomologous end-joining (NHEJ), remains controversial. Here we have studied the role of BRCA1 in the repair of DSBs in switch (S) regions during immunoglobulin class switch recombination, a physiological, deletion/recombination process that relies on the classical NHEJ machinery. A shift to the use of microhomology-based, alternative end-joining (A-EJ) and increased frequencies of intra-S region deletions as well as insertions of inverted S sequences were observed at the recombination junctions amplified from BRCA1-deficient human B cells. Furthermore, increased use of long microhomologies was found at recombination junctions derived from E3 ubiquitin-protein ligase RNF168-deficient, Fanconi anemia group J protein (FACJ, BRIP1)-deficient, or DNA endonuclease RBBP8 (CtIP)-compromised cells, whereas an increased frequency of S-region inversions was observed in breast cancer type 2 susceptibility protein (BRCA2)-deficient cells. Thus, BRCA1, together with its interaction partners, seems to play an important role in repairing DSBs generated during class switch recombination by promoting the classical NHEJ pathway. This may not only provide a general mechanism underlying BRCA1’s function in maintaining genome stability and tumor suppression but may also point to a previously unrecognized role of BRCA1 in B-cell lymphomagenesis.

scholarly journals Immunoglobulin genes undergo legitimate repair in human B cells not only after cis- but also frequent trans-class switch recombination

2014 ◽  
Vol 15 (5) ◽  
pp. 341-346 ◽  
Author(s):  
B Laffleur ◽  
S M Bardet ◽  
A Garot ◽  
M Brousse ◽  
A Baylet ◽  
...  
Keyword(s):  
B Cells ◽  
Class Switch Recombination ◽  
Immunoglobulin Genes ◽  
Class Switch ◽  
Human B Cells
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