Elucidating monocyte-specific disease mechanisms in systemic lupus erythematosus

Year of award: 2024

Grantholders

  • Dr Tabitha Turner-Stokes

    Imperial College London, United Kingdom

Project summary

Systemic lupus erythematosus (SLE) is a devastating autoimmune disease that disproportionally affects young women, particularly those from ethnic minority groups. Lupus nephritis (LN), the commonest organ-threatening manifestation of SLE, develops in 50% of patients and, without effective treatment, frequently leads to kidney failure. Current treatments (typically targeting autoantibody-producing B-cells) are inadequate, achieving sustained remission in fewer than 50% of patients. Targeting monocytes/macrophages, the key effector cells that drive kidney damage in LN, may represent a more effective strategy. Genome-wide association studies (GWAS) can help identify molecular pathways that contribute to human diseases, providing better therapeutic targets than those without genetic support. GWAS have identified ~170 genetic loci that predispose to SLE, several of which I have shown are specifically functional in monocytes/macrophages. I will investigate the SLE-associated haplotype on chr6p21, which is robustly associated with SLE across ancestries, and which increases expression of an uncharacterised gene, UHRF1BP1, in monocytes/macrophages. My preliminary work suggests that UHRF1BP1 regulates the type-I interferon(IFN-I) response in monocytes, a pathway important in SLE pathogenesis. Using clinically-relevant experimental conditions and epigenetic analysis/genome editing technologies in primary human monocytes, I will characterise the role of UHRF1BP1 and assess whether this represents a target for monocyte-directed LN treatment.