Title: From human genetics to monocyte-specific disease mechanisms in systemic lupus erythematosus
Funder: The Academy of Medical Sciences

Abstract: Lupus nephritis (LN) is a common and serious complication of SLE that can lead to irreversible renal failure. It occurs due to immune complex deposition within glomerular capillaries which interact with intravascular monocytes to generate a severe inflammatory response. Treatment with potent immunosuppressive agents is often ineffective and no monocyte-directed therapies are available, in part because the specific pathways by which monocytes contribute to LN are poorly understood. In preliminary work examining SLE-associated GWAS loci for cell-type specific activity, I identified two uncharacterised genes, TMEM187 and UHRF1BP1, that are directly implicated in the pathogenesis of SLE via effects in monocytes; providing an opportunity to better understand how monocytes contribute to SLE pathogenesis. In the proposed work: Firstly, I aim to characterise the biological functions of TMEM187 and UHRF1BP1 in primary human monocytes. Using protocols that facilitate efficient genome editing, I will assess the effect of deletion of these genes on cytokine and reactive oxygen species production, migration and phagocytosis; processes all known to contribute to organ damage in SLE. Secondly, I will characterise the molecular mechanisms of disease risk at these loci. Using an adapted massively-parallel reporter assay(MPRA) optimised for use in primary macrophages, I will identify expression-modulating causal variants within each haplotype and follow these up to investigate how genetic variation at these loci may regulate expression of these candidate genes to alter SLE disease risk. This work should provide important insights into the molecular mechanisms by which monocytes contribute to inflammation in SLE and may reveal therapeutic opportunities.

Lay abstract: Systemic lupus erythematosus (SLE) is a disease in which the immune system attacks the body’s tissues and organs, causing inflammation and damage. The kidney is affected in ~40% of patients with SLE. Antibodies (special proteins), produced abnormally by the immune system against the body’s own cells, become stuck within small blood vessels in the filtering units of the kidney (glomeruli), triggering severe inflammation that results in life-threatening kidney failure. Early treatment with medications that suppress the immune system are essential to avoid irreversible kidney damage; but are not always effective. Monocytes (type of white blood cell) are very important in driving kidney inflammation in SLE. Therefore, monocyte-directed treatments, although not yet developed, may be more effective. The genetic makeup of individuals contributes to the development of SLE. Specific changes (variants) in more than 150 different areas of our genetic code (genome) are found more commonly in patients with SLE compared to the general population. Genetic studies to explore how these variations lead to SLE provide a unique opportunity to better understand disease mechanisms. By analysing SLE-associated variants, I identified two genes we currently know little about (TMEM187 and UHRF1BP1), which are implicated in SLE development through effects in monocytes. I will investigate how these genes affect the function of monocytes and determine the mechanisms by which SLE-associated variants affect gene activity, and thus monocyte function. This may reveal important pathways used by monocytes to drive kidney inflammation in SLE. This will allow us to design more effective treatments for patients.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM