Lupus & antiphospholipid syndrome
Down‐Regulation–Resistant STAT4 Risk Haplotype Contributes to Lupus Nephritis Through CD4+ T Cell Interferon‐γ Production
Authors' conclusion
The SLE-associated STAT4 haplotype correlates with an abnormal IL-12-mediated STAT4 transcriptional regulation. Carriers of the risk variant exhibit exaggerated CD4+ proinflammatory capacities that, in the context of SLE, contribute to more severe disease.
Study context
- Population
- Naive CD4+ T cells from healthy donors; mice; patients with lupus nephritis
- Comparison
- Healthy donors homozygous for STAT4 risk vs nonrisk alleles
- Outcome
- STAT4 regulation in naive CD4+ T cells in response to IL-12
Methodological detailsgenetic editing, in vivo mouse overexpression model
- Genetic editing
- In vivo mouse overexpression model
Main finding
As reported in the abstract
- NR/NR cells down-regulated STAT4 in response to IL-12; R/R cells maintained high levels
- R/R cells: higher abundance of transcriptionally active STAT4 and increased interferon-γ production
- R/R donors: stronger induction of local active enhancer marks
- Genetic editing confirmed a negative regulatory region in the STAT4 third intron, where most systemic lupus erythematosus (SLE)-associated STAT4 single-nucleotide polymorphisms (SNPs) are located
- Increased Stat4 levels in T cells enhanced glomerulonephritis in mice
Further findings
Treatment response and clinical outcomes in proliferative LN
- R/R genotype associated with suboptimal response to treatment and worse clinical outcomes
Original publication
Down‐Regulation–Resistant STAT4 Risk Haplotype Contributes to Lupus Nephritis Through CD4+ T Cell Interferon‐γ Production. Arthritis Rheumatol. Published 22 March 2023. doi:10.
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