Notch1 is an important mediator for enhancing of B‐cell activation and antibody secretion by <scp>N</scp>otch ligand

Kang, Jung‐Ah; Kim, Woo-Seok; Park, Sung‐Gyoo

doi:10.1111/imm.12333

Cited by 28 publications

(24 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The LiHyp6 gene is predicted to encode a protein with a theoretical molecular weight of 21.4 kDa, while the HRF gene is predicted to encode a protein with 19.4 kDa. Interestingly, mammals´ HRF protein, has been described as having a stimulatory activity on the immune system of the hosts by activating both T and B cells [ 32 , 33 ]. Therefore, the first purpose of this study is to analyze the antigenicity of the three recombinant proteins using canine patients.…”

Section: Introductionmentioning

confidence: 99%

Antigenicity, Immunogenicity and Protective Efficacy of Three Proteins Expressed in the Promastigote and Amastigote Stages of Leishmania infantum against Visceral Leishmaniasis

et al. 2015

View full text Add to dashboard Cite

In the present study, two Leishmania infantum hypothetical proteins present in the amastigote stage, LiHyp1 and LiHyp6, were combined with a promastigote protein, IgE-dependent histamine-releasing factor (HRF); to compose a polyproteins vaccine to be evaluated against L. infantum infection. Also, the antigenicity of the three proteins was analyzed, and their use for the serodiagnosis of canine visceral leishmaniasis (CVL) was evaluated. The LiHyp1, LiHyp6, and HRF DNA coding sequences were cloned in prokaryotic expression vectors and the recombinant proteins were purified. When employed in ELISA assays, all proteins were recognized by sera from visceral leishmaniasis (VL) dogs, and presented no cross-reactivity with either sera from dogs vaccinated with a Brazilian commercial vaccine, or sera of Trypanosoma cruzi-infected or Ehrlichia canis-infected animals. In addition, the antigens were not recognized by antibodies from non-infected animals living in endemic or non-endemic areas for leishmaniasis. The immunogenicity and protective efficacy of the three proteins administered in the presence of saponin, individually or in combination (composing a polyproteins vaccine), were evaluated in a VL murine model: BALB/c mice infected with L. infantum. Spleen cells from mice inoculated with the individual proteins or with the polyproteins vaccine plus saponin showed a protein-specific production of IFN-γ, IL-12, and GM-CSF after an in vitro stimulation, which was maintained after infection. These animals presented significant reductions in the parasite burden in different evaluated organs, when compared to mice inoculated with saline or saponin. The decrease in parasite burden was associated with an IL-12-dependent production of IFN-γ against parasite total extracts (produced mainly by CD4+ T cells), correlated to the induction of parasite proteins-driven NO production. Mice inoculated with the recombinant protein-based vaccines showed also high levels of parasite-specific IgG2a antibodies. The polyproteins vaccine administration induced a more pronounced Th1 response before and after challenge infection than individual vaccines, which was correlated to a higher control of parasite dissemination to internal organs.

show abstract

Section: Introductionmentioning

confidence: 99%

Antigenicity, Immunogenicity and Protective Efficacy of Three Proteins Expressed in the Promastigote and Amastigote Stages of Leishmania infantum against Visceral Leishmaniasis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…4,5 Notch1 signaling has a major effect on T-cell lineage commitment and intrathymic T-cell development, 6,7 whereas Notch2 plays a key role in progression of transitional B cells to marginal zone B cells. 5,8 By contrast, Notch1 expression in mature B cells is increased markedly by activation of B-cell receptor signaling or lipopolysaccharide (LPS), 9,10 and Notch1 signaling plays a role in terminal differentiation of B cells. 10,11 Germinal center (GC) B cells express both Notch1 and Notch2, and Notch-signaling activity also protects GC B cells from apoptosis.…”

Section: Introductionmentioning

confidence: 99%

B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell–dominant T-cell responses via IL-33

et al. 2018

View full text Add to dashboard Cite

The Notch-signaling pathway in a variety of mature B-cell neoplasms is often activated by gene alterations, but its role remains unclear. Here, we show that B cells harboring dysregulated activation of Notch1 signaling have an immunomodulatory effect on T cells by amplifying regulatory T (Treg) and T helper 2 (Th2) cell responses in an interleukin-33 (IL-33)-dependent manner. A conditional mouse model, in which constitutive expression of an active form of Notch1 is induced in B cells by gene promoter-driven Cre recombinase, revealed no obvious phenotypic changes in B cells; however, mice demonstrated an expansion of Treg and Th2 cell subsets and a decrease in cytokine production by Th1 and CD8 T cells. The mice were susceptible to soft tissue sarcoma and defective production of CD8 T cells specific for inoculated tumor cells, suggesting impaired antitumor T-cell activity. Gene-expression microarray revealed that altered T-cell responses were due to increased IL-33 production by Notch1-activated B cells. Knockout of or blockade of IL-33 by a receptor-blocking antibody abrogated the Treg and Th2 cell-dominant T-cell response triggered by B cells. Gene-expression data derived from human diffuse large B-cell lymphoma (DLBCL) samples showed that an activated Notch-signaling signature correlates positively with expression and Treg cell-rich gene-expression signatures. These findings indicate that B cells harboring dysregulated Notch signaling alter T-cell responses via IL-33, and suggest that aberrant activation of Notch signaling plays a role in fostering immune privilege in mature B-cell neoplasms.

show abstract

“…The interaction between NOTCH and BCR has been previously described in murine primary B cells (35), in which NOTCH1 appeared as an important mediator of BCR-induced enhancement of B-cell activation. In this context, BCR stimulation increased NOTCH1 mRNA and protein expression, but not signaling activation, for which it was necessary the interaction of activated B cells with a NOTCH ligand.…”

Section: Discussionmentioning

confidence: 77%

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

Papa

Baldoni

Dorillo

et al. 2019

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), has improved the outcomes of chronic lymphocytic leukemia (CLL), but primary resistance or relapse are issues of increasing significance. While the predominant mechanism of action of BTKi is the B-cell receptor (BCR) blockade, many offtarget effects are unknown. We investigated potential interactions between BCR pathway and NOTCH1 activity in ibrutinib-treated CLL to identify new mechanisms of therapy resistance and markers to monitor disease response. Experimental Design: NOTCH activations was evaluated either in vitro and ex vivo in CLL samples after ibrutinib treatment by Western blotting. Confocal proximity ligation assay (PLA) experiments and analyses of down-targets of NOTCH1 by qRT-PCR were used to investigate the crosstalk between BTK and NOTCH1. Results: In vitro ibrutinib treatment of CLL significantly reduced activated NOTCH1/2 and induced dephosphory-lation of eIF4E, a NOTCH target in CLL. BCR stimulation increased the expression of activated NOTCH1 that accumulated in the nucleus leading to HES1, DTX1, and c-MYC transcription. Results of in situ PLA experiments revealed the presence of NOTCH1-ICD/BTK complexes, whose number was reduced after ibrutinib treatment. In ibrutinib-treated CLL patients, leukemic cells showed NOTCH1 activity downregulation that deepened over time. The NOTCH1 signaling was restored at relapse and remained activated in ibrutinib-resistant CLL cells. Conclusions: We demonstrated a strong clinical activity of ibrutinib in a real-life context. The ibrutinib clinical efficacy was associated with NOTCH1 activity downregulation that deepened over time. Our data point to NOTCH1 as a new molecular partner in BCR signaling with potential to further improve CLL-targeted treatments.

show abstract

Notch1 is an important mediator for enhancing of B‐cell activation and antibody secretion by Notch ligand

Cited by 28 publications

References 34 publications

Antigenicity, Immunogenicity and Protective Efficacy of Three Proteins Expressed in the Promastigote and Amastigote Stages of Leishmania infantum against Visceral Leishmaniasis

Antigenicity, Immunogenicity and Protective Efficacy of Three Proteins Expressed in the Promastigote and Amastigote Stages of Leishmania infantum against Visceral Leishmaniasis

B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell–dominant T-cell responses via IL-33

Decreased NOTCH1 Activation Correlates with Response to Ibrutinib in Chronic Lymphocytic Leukemia

Contact Info

Product

Resources

About