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Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus

OBJECTIVE: To evaluate the effects of targeting Ikaros and Aiolos by cereblon modulator iberdomide on the activation and differentiation of B-cells from patients with systemic lupus erythematosus (SLE). METHODS: CD19(+) B-cells isolated from the peripheral blood of patients with SLE (n=41) were cult...

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Autores principales: Rivellese, Felice, Manou-Stathopoulou, Sotiria, Mauro, Daniele, Goldmann, Katriona, Pyne, Debasish, Rajakariar, Ravindra, Gordon, Patrick, Schafer, Peter, Bombardieri, Michele, Pitzalis, Costantino, Lewis, Myles J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2021
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970264/
https://www.ncbi.nlm.nih.gov/pubmed/33727237
http://dx.doi.org/10.1136/lupus-2020-000445
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author Rivellese, Felice
Manou-Stathopoulou, Sotiria
Mauro, Daniele
Goldmann, Katriona
Pyne, Debasish
Rajakariar, Ravindra
Gordon, Patrick
Schafer, Peter
Bombardieri, Michele
Pitzalis, Costantino
Lewis, Myles J
author_facet Rivellese, Felice
Manou-Stathopoulou, Sotiria
Mauro, Daniele
Goldmann, Katriona
Pyne, Debasish
Rajakariar, Ravindra
Gordon, Patrick
Schafer, Peter
Bombardieri, Michele
Pitzalis, Costantino
Lewis, Myles J
author_sort Rivellese, Felice
collection PubMed
description OBJECTIVE: To evaluate the effects of targeting Ikaros and Aiolos by cereblon modulator iberdomide on the activation and differentiation of B-cells from patients with systemic lupus erythematosus (SLE). METHODS: CD19(+) B-cells isolated from the peripheral blood of patients with SLE (n=41) were cultured with TLR7 ligand resiquimod ±IFNα together with iberdomide or control from day 0 (n=16). Additionally, in vitro B-cell differentiation was induced by stimulation with IL-2/IL-10/IL-15/CD40L/resiquimod with iberdomide or control, given at day 0 or at day 4. At day 5, immunoglobulins were measured by ELISA and cells analysed by flow cytometry. RNA-Seq was performed on fluorescence-activated cell-sorted CD27(-)IgD(+) naïve-B-cells and CD20(low)CD27(+)CD38(+) plasmablasts to investigate the transcriptional consequences of iberdomide. RESULTS: Iberdomide significantly inhibited the TLR7 and IFNα-mediated production of immunoglobulins from SLE B-cells and the production of antinuclear antibodies as well as significantly reducing the number of CD27(+)CD38(+) plasmablasts (0.3±0.18, vehicle 1.01±0.56, p=0.011) and CD138(+) plasma cells (0.12±0.06, vehicle 0.28±0.02, p=0.03). Additionally, treatment with iberdomide from day 0 significantly inhibited the differentiation of SLE B-cells into plasmablasts (6.4±13.5 vs vehicle 34.9±20.1, p=0.013) and antibody production. When given at later stages of differentiation, iberdomide did not affect the numbers of plasmablasts or the production of antibodies; however, it induced a significant modulation of gene expression involving IKZF1 and IKZF3 transcriptional programmes in both naïve B-cells and plasmablasts (400 and 461 differentially modulated genes, respectively, false discovery rate<0.05). CONCLUSION: These results demonstrate the relevance of Ikaros and Aiolos as therapeutic targets in SLE due to their ability to modulate B cell activation and differentiation downstream of TLR7.
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spelling pubmed-79702642021-04-01 Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus Rivellese, Felice Manou-Stathopoulou, Sotiria Mauro, Daniele Goldmann, Katriona Pyne, Debasish Rajakariar, Ravindra Gordon, Patrick Schafer, Peter Bombardieri, Michele Pitzalis, Costantino Lewis, Myles J Lupus Sci Med Immunology and Inflammation OBJECTIVE: To evaluate the effects of targeting Ikaros and Aiolos by cereblon modulator iberdomide on the activation and differentiation of B-cells from patients with systemic lupus erythematosus (SLE). METHODS: CD19(+) B-cells isolated from the peripheral blood of patients with SLE (n=41) were cultured with TLR7 ligand resiquimod ±IFNα together with iberdomide or control from day 0 (n=16). Additionally, in vitro B-cell differentiation was induced by stimulation with IL-2/IL-10/IL-15/CD40L/resiquimod with iberdomide or control, given at day 0 or at day 4. At day 5, immunoglobulins were measured by ELISA and cells analysed by flow cytometry. RNA-Seq was performed on fluorescence-activated cell-sorted CD27(-)IgD(+) naïve-B-cells and CD20(low)CD27(+)CD38(+) plasmablasts to investigate the transcriptional consequences of iberdomide. RESULTS: Iberdomide significantly inhibited the TLR7 and IFNα-mediated production of immunoglobulins from SLE B-cells and the production of antinuclear antibodies as well as significantly reducing the number of CD27(+)CD38(+) plasmablasts (0.3±0.18, vehicle 1.01±0.56, p=0.011) and CD138(+) plasma cells (0.12±0.06, vehicle 0.28±0.02, p=0.03). Additionally, treatment with iberdomide from day 0 significantly inhibited the differentiation of SLE B-cells into plasmablasts (6.4±13.5 vs vehicle 34.9±20.1, p=0.013) and antibody production. When given at later stages of differentiation, iberdomide did not affect the numbers of plasmablasts or the production of antibodies; however, it induced a significant modulation of gene expression involving IKZF1 and IKZF3 transcriptional programmes in both naïve B-cells and plasmablasts (400 and 461 differentially modulated genes, respectively, false discovery rate<0.05). CONCLUSION: These results demonstrate the relevance of Ikaros and Aiolos as therapeutic targets in SLE due to their ability to modulate B cell activation and differentiation downstream of TLR7. BMJ Publishing Group 2021-03-16 /pmc/articles/PMC7970264/ /pubmed/33727237 http://dx.doi.org/10.1136/lupus-2020-000445 Text en © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/ https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.
spellingShingle Immunology and Inflammation
Rivellese, Felice
Manou-Stathopoulou, Sotiria
Mauro, Daniele
Goldmann, Katriona
Pyne, Debasish
Rajakariar, Ravindra
Gordon, Patrick
Schafer, Peter
Bombardieri, Michele
Pitzalis, Costantino
Lewis, Myles J
Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus
title Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus
title_full Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus
title_fullStr Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus
title_full_unstemmed Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus
title_short Effects of targeting the transcription factors Ikaros and Aiolos on B cell activation and differentiation in systemic lupus erythematosus
title_sort effects of targeting the transcription factors ikaros and aiolos on b cell activation and differentiation in systemic lupus erythematosus
topic Immunology and Inflammation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970264/
https://www.ncbi.nlm.nih.gov/pubmed/33727237
http://dx.doi.org/10.1136/lupus-2020-000445
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