The role of CD8+ T-cells and type-I IFN in juvenile-SLE and accelerated atherosclerosis

Juvenile-onset systemic lupus erythematosus (JSLE) is an autoimmune disorder characterised by chronic inflammation and pro-inflammatory type-I interferon (IFN) signatures.

Patients with JSLE have an increased risk of developing cardiovascular disease (CVD) through atherosclerosis, chronic inflammation of the larger arteries, compared to healthy individuals, a leading cause of patient mortality. JSLE patients also have a more severe disease phenotype, increased CVD-risk and mortality compared to adult-SLE.

Investigating early developments of atherosclerosis in these younger patients could allow for early intervention to improve long-term prognosis.

No guidelines exist for CVD-risk management in JSLE and it is not possible to predict CVD-risk using traditional biomarkers; the precise mechanism is yet to be elucidated.

CD8+ T-cells were recently shown to be extremely abundant in atherosclerotic plaques (>30% of immune cells) and circulating type-I IFN levels are associated with sub-clinical markers of CVD in JSLE.

In support, my preliminary data suggests a key role for CD8+ T-cells and type-I IFNs in JSLE-associated atherosclerosis.

In world-leading research environments specialised in CVD and adolescent rheumatology, I now aim to: Define how type-I IFN-signalling associated with JSLE influences CD8+ T-cell metabolism/function.

Investigate IFN-signatures in JSLE patients with sub-clinical atherosclerosis (collaboration with 2 clinical trial sponsors) and compare matched CD8+ T-cell transcriptomic signatures to experimental models of atherosclerosis (1-year placement at New York University).

Investigate therapeutic strategies to mitigate atherosclerosis-associated CD8+ T-cell activation by inhibition of IFN-signalling.

This will generate novel mechanistic knowledge regarding CD8+ T-cell-mediated inflammation in atherosclerosis and could identify new predictive biomarkers and therapeutic targets for CVD in young patients with JSLE to improve disease prognosis and quality-of-life, an unmet clinical need.

Patients have been involved in the development of this project and these aims will run in parallel with frequent patient engagement events to maximise the translational potential of the research outputs.