Sex and gender differences in lupus - intersection between immunometabolism, epigenetic remodeling and cardiac involvement

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Lupus is predominantly a female disease, however men with lupus frequently have more severe symptoms and organ involvement including cardiovascular disease, a leading cause of death in lupus. Environmental and gender differences such as sunlight exposure and vitamin D levels have also been shown to play a role in lupus progression and cardiovascular disease. Differences in metabolic activity have also been suggested to contribute to sexually dimorphic immune responses and autoimmunity. Our recent data in female lupus combining cardiac imaging with metabolomic profiling has shown potential links between cardiac involvement and metabolic reprogramming of lupus monocytes. This proposal investigates the hypothesis that sex biases in metabolic activity of monocytes drives epigenetic reprogramming of monocytes, driving functional differences. Secondly, it will address how sexually dimorphic responses to vitamin D contribute to monocytic reprogramming. As epigenetic changes in monocytes is linked with cardiovascular disease (CVD), and given the prevalence of CVD in both male and female lupus, this proposal will address whether sex-specific changes in metabolic and genetic reprogramming drive phenotypic differences in lupus monocytes and ask how this relates to prevalence of CMD and CVD using state of the art cardiac imaging. Aim 1: Determine whether metabolic pathways differ in monocytes from male and female lupus patients. We will address how sexual dimorphism in immune responses and immunometabolism in monocytes integrate to affect outcome between male and female patients using metabolic, proteomic and flow cytometry approaches. Aim 2: Determine how genetic reprogramming drives sexually dimorphic monocytic function in lupus. Single cell next generation sequencing will be used to determine chromatin accessibility in monocyte subsets and ask how this influences gene expression programs and functional differences in male and female lupus. Aim 3: Assess relative risk of CVD in male lupus using non-invasive cardiac imaging techniques. Cardiac imaging will determine prevalence of CVD in male and female lupus and correlated with metabolic changes or gene expression patterns to determine sexually dimorphic responses that determine risk. Impact: Determining whether metabolic reprograming and epigenetic remodeling are sexually dimorphic in lupus monocytes will potentially impact treatment approaches as we enter an era where drugs targeting immunometabolism as being trialed in lupus.