Radziszewska, Anna; (2023) Investigating cytotoxic cell phenotype and function in juvenile systemic lupus erythematosus. Doctoral thesis (Ph.D), UCL (University College London).

Text PhD Thesis Anna Radziszewska FINAL.pdf - Other Access restricted to UCL open access staff until 1 January 2025. Download (15MB)

Abstract

Juvenile systemic lupus erythematosus (JSLE) is an autoimmune condition which causes significant morbidity in children and young adults. It is a complex, systemic disease, characterized by autoantibody production against nuclear antigens. While many aspects of immune dysfunction have been studied extensively in adult-onset SLE, there is limited and contradictory evidence of how cytotoxic CD8+ T cells and natural killer (NK) cells contribute to disease pathology and studies exploring cytotoxicity in JSLE are very rare. To address this, this work examined cytotoxic cell immunophenotype in the peripheral blood of a large cohort of JSLE patients and age and sex-matched controls. The results revealed a reduction in CD8+ T cells expressing the cytotoxic mediators, perforin and CD107a, and effector cytokines IFN-γ and TNF-α in JSLE compared to controls. This reduction was present regardless of treatment or disease activity, suggesting it was an underlying feature of disease. Transcriptomic analysis identified potential metabolic disturbances, including mitochondrial dysfunction, as a possible mechanism underpinning these observations. The results also revealed that NK cells as a whole and perforin and granzyme A producing NK cells were markedly reduced in JSLE versus controls, which was associated with a decrease in NK functionality. Unlike CD8+ T cells, the reduction in overall NK cell frequencies was associated with increasing disease activity, with transcriptomic analysis revealing upregulation of IFN-α responses and apoptotic pathways in active JSLE. Notably, both JSLE CD8+ T cell and NK cell apoptosis was markedly increased in the presence of IFN-α suggesting the numerical deficiency in cytotoxic cell frequencies could be attributed, at least in part, to increased apoptosis. Altogether these results identify a global deficiency in cytotoxicity in JSLE. However further characterization of the role of cytotoxic cells is necessary to understand the contribution of cytotoxic cells to disease pathology enabling the development of new therapeutic avenues.

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