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Targeting the MICA-mediated oxidative stress-immune axis: a novel therapeutic strategy for ankylosing spondylitis
Rongqing He1, Zuyuan Huang1, Xiaopeng Qin1
1The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
Objectives:
Ankylosing spondylitis (AS) involves a complex interplay between oxidative stress (OS) and immune dysregulation, yet the precise molecular links involved remain unclear.
Methods:
OS-related genes were obtained from the GeneCards database. Differential expression analysis was performed on mRNA microarray (MA) data to identify OS-associated differentially expressed genes (DEGs). A two-sample Mendelian randomisation analysis was conducted to assess the causal relationships between OS-related genes and AS risk at the protein level. Immune cell mediation was further examined using genetic information from 731 immune phenotypes. Additionally, Logistic regression was used to examine the association between immune cell profiles and AS risk. The findings were further validated via experimental study using western blotting (WB) and single-cell RNA-seq (scRNA-seq) data.
Results:
We found that the MICA protein is a key AS risk modulator via integrative omics analyses, with protein abundance showing a positive association (OR=1.89; PFDR=3.6×10-4). Mediation analyses revealed that the genetic effects of these genes were partially transmitted through specific T cell subsets, particularly CD28+ resting Tregs. The mediated proportion was 82.3%. Clinical validations confirmed lymphocyte-associated protection (OR: 0.64, 95%CI: 0.54-0.76). scRNA-seq analyses demonstrated significant MICA upregulation in AS-drived T cells, confirmed by Western blot analysis.
Conclusions:
This integrative multiomics analysis revealed OS-related genes as causal drivers of AS through immune dysregulation pathways. Targeting OS-related immune mechanisms may offer novel precision therapeutic strategies for AS.
Insights
Oxidative stress (OS) drives ankylosing spondylitis (AS) through immune dysregulation. MICA protein modulates AS risk, with T cells mediating effects, suggesting new therapeutic targets.
Area of Science:
- Immunology
- Genetics
- Systems Biology
Background:
- Ankylosing spondylitis (AS) pathogenesis involves oxidative stress (OS) and immune system dysfunction.
- The specific molecular mechanisms linking OS and immune dysregulation in AS are not fully understood.
Purpose of the Study:
- To elucidate the molecular links between OS-related genes and AS risk.
- To investigate the role of immune cell mediation in AS development.
- To identify potential therapeutic targets for AS.
Main Methods:
- Acquired OS-related genes from GeneCards database.
- Performed differential expression analysis on mRNA microarray data.
- Conducted two-sample Mendelian randomization to assess causal relationships.
- Examined immune cell mediation using genetic data from 731 immune phenotypes.
- Validated findings using Western blotting and single-cell RNA sequencing.
Main Results:
- Identified MICA protein as a key modulator of AS risk (OR=1.89).
- Demonstrated partial genetic transmission through T cell subsets, notably CD28+ resting Tregs (82.3% mediated).
- Confirmed lymphocyte-associated protection (OR=0.64).
- Observed MICA upregulation in AS-derived T cells via scRNA-seq and Western blot.
Conclusions:
- OS-related genes causally drive AS through immune dysregulation pathways.
- Targeting OS-related immune mechanisms presents novel precision therapeutic strategies for AS.
