Cargando…
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...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2021
|
Materias: | |
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 |
_version_ | 1783666401621311488 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7970264 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT rivellesefelice effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT manoustathopoulousotiria effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT maurodaniele effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT goldmannkatriona effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT pynedebasish effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT rajakariarravindra effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT gordonpatrick effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT schaferpeter effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT bombardierimichele effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT pitzaliscostantino effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus AT lewismylesj effectsoftargetingthetranscriptionfactorsikarosandaiolosonbcellactivationanddifferentiationinsystemiclupuserythematosus |