Deletion of a rheumatoid arthritis risk enhancer in mouse disrupts Bim expression and immune homeostasis
5 affiliations
- 1Arthritis UK Centre for Genetics and Genomics, The University of Manchester, Manchester, UK
- 2NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- 3Genome Editing Unit, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 4Division of Immunology, Immunity to Infection and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- 5Lydia Becker Institute of Immunology and Inflammation, University of Manchester, Manchester, UK
Abstract
Objectives: This study aimed to characterise the in vivo function of a murine regulatory region syntenic to the human rheumatoid arthritis (RA)-associated enhancer at the ACOXL locus and its role in immunity.
Methods: Using CRISPR-Cas9, we generated the Bim-eΔ mouse model by excising a 15 kb genomic region syntenic to the human RA-associated locus tagged by rs13401811 from C57BL/6J zygotes. Bim expression was assessed by quantitative polymerase chain reaction. Thymocytes and splenocytes were profiled by flow cytometry, and whole-spleen RNA-seq was used to define transcriptional changes. Immune responses were tested using a Trichuris muris infection model and an antigen-induced arthritis (AIA) protocol.
Results: Bim-eΔ mice show reduced Bim expression vs wild-type counterparts. This indicates that Bim is a transcriptional target of this region. Enhancer loss was correlated with differences in T cell proportions across age- and sex-stratified cohorts consistent with altered thymic selection. Splenic T and B cells were altered, and the transcriptome skewed toward inflammation. Bim-eΔ and wild-type mice mounted comparable responses to T. muris, whereas Bim-eΔ mice developed a severe adverse response during the sensitisation phase of the AIA protocol.
Conclusions: A murine noncoding regulatory region modulates Bim expression and immunity in vivo. Enhancer deletion altered the splenic transcriptional profile and lymphocyte composition while revealing a context-dependent phenotype upon inflammatory in vivo challenge. These findings support a role for RA-associated regulatory architecture in shaping immunity and point to BIM regulation as a potential therapeutic lever for restoring immune balance.
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BibTeX
@article{rossi2026deletion,
title = {{Deletion of a rheumatoid arthritis risk enhancer in mouse disrupts Bim expression and immune homeostasis}},
author = {Stefano Rossi and Kelly S. Hayes and Jake Butler and James Ding and Ellie L. Richards and Antonios Frantzeskos and Gareth J. Howell and Richard K. Grencis and Antony D. Adamson and Stephen Eyre and Gisela Orozco},
journal = {EULAR Rheumatology Open},
year = {2026},
month = oct,
doi = {10.1016/j.ero.2026.100260},
url = {https://doi.org/10.1016/j.ero.2026.100260},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Deletion of a rheumatoid arthritis risk enhancer in mouse disrupts Bim expression and immune homeostasis
AU - Stefano Rossi
AU - Kelly S. Hayes
AU - Jake Butler
AU - James Ding
AU - Ellie L. Richards
AU - Antonios Frantzeskos
AU - Gareth J. Howell
AU - Richard K. Grencis
AU - Antony D. Adamson
AU - Stephen Eyre
AU - Gisela Orozco
PY - 2026
DA - 2026/10/17
JO - EULAR Rheumatology Open
DO - 10.1016/j.ero.2026.100260
UR - https://doi.org/10.1016/j.ero.2026.100260
AB - Objectives: This study aimed to characterise the in vivo function of a murine regulatory region syntenic to the human rheumatoid arthritis (RA)-associated enhancer at the ACOXL locus and its role in immunity. Methods: Using CRISPR-Cas9, we generated the Bim-eΔ mouse model by excising a 15 kb genomic region syntenic to the human RA-associated locus tagged by rs13401811 from C57BL/6J zygotes. Bim expression was assessed by quantitative polymerase chain reaction. Thymocytes and splenocytes were profiled by flow cytometry, and whole-spleen RNA-seq was used to define transcriptional changes. Immune responses were tested using a Trichuris muris infection model and an antigen-induced arthritis (AIA) protocol. Results: Bim-eΔ mice show reduced Bim expression vs wild-type counterparts. This indicates that Bim is a transcriptional target of this region. Enhancer loss was correlated with differences in T cell proportions across age- and sex-stratified cohorts consistent with altered thymic selection. Splenic T and B cells were altered, and the transcriptome skewed toward inflammation. Bim-eΔ and wild-type mice mounted comparable responses to T. muris, whereas Bim-eΔ mice developed a severe adverse response during the sensitisation phase of the AIA protocol. Conclusions: A murine noncoding regulatory region modulates Bim expression and immunity in vivo. Enhancer deletion altered the splenic transcriptional profile and lymphocyte composition while revealing a context-dependent phenotype upon inflammatory in vivo challenge. These findings support a role for RA-associated regulatory architecture in shaping immunity and point to BIM regulation as a potential therapeutic lever for restoring immune balance.
SN - 3050-7081
ER -