Pathogenesis of chronic cutaneous lupus erythematosus

Systemic lupus erythematosus (SLE, lupus) is characterized by loss of immune tolerance with production of pathogenic autoantibodies and immune cell infiltration into multiple tissues, with resultant damage and organ injury. The spatial-temporal interactions between infiltrating immune cell subsets and target tissues that dictate severity of local and systemic inflammation with progression to long term damage in lupus has not been defined. The skin is an interface of host immune responses and parenchymal tissue, with its inflammation often the first manifestation of lupus. Skin involvement is often chronic and disfiguring, hence its designation as chronic cutaneous lupus erythematosus (CCLE), with its pathogenesis ill-defined and therapies ineffective. As it is clinically accessible via biopsy, lupus skin offers a window into dissection of the cell-cell interactions in the inflammatory microenvironment and the immune response that leads to chronic injury. Understanding these interactions will potentially lead to new therapeutic targets for this chronic and disfiguring condition. We propose to combine novel single cell spatial-transcriptomics to examine tissue at high resolution with single-cell multi-omics profiling to describe cell types in affected and unaffected skin of patients with CCLE, to be compared with the immune cells in the blood. If successful, this platform can be applied to analysis of other tissues in lupus and tissues in other autoimmune diseases