Research

Type I interferons are the canonical vertebrate antiviral signaling program and are pathologically elevated in autoimmune diseases including systemic lupus erythematosus and dermatomyositis. Although the receptors for type I interferons are expressed broadly across nearly all cell types, the inflammation in these diseases is often restricted to certain organ systems, particularly the skin. We use single-cell RNA sequencing and spatial transcriptomics of human cutaneous lupus tissue to map the cell-type-specific effects of interferon signaling. Our recent work, published in the Journal of Investigative Dermatology (2025), revealed that cutaneous lupus features specialized stromal niches—including unique fibroblast populations involved in inflammatory cell recruitment and fibrosis—and a dominant interferon signature that pervades all cell types. We identified key chemokine axes (CXCR3, CXCR4, CCR7) mediating plasmacytoid dendritic cell–stromal interactions, suggesting new therapeutic targets. We further showed that treatment with anifrolumab reduces RIG-I and cGAS-STING pathway activation alongside retroelement expression, providing mechanistic insight into this emerging biologic therapy.

While elevated antiviral signaling is well-established in autoimmune diseases like lupus, the proximal origins of this signaling remain unclear. Endogenous retroelements—highly repetitive DNA sequences comprising up to 50% of the human genome—have been implicated as potential inducers of type I interferons and as autoantigens in autoimmune disorders. Our single-cell and spatial analyses of human cutaneous lupus skin revealed increased retroelement expression that correlated with interferon-stimulated genes across multiple cell types, alongside elevated expression of innate nucleic acid sensing pathways (RIG-I and cGAS-STING). We are actively investigating whether retroelements serve as a proximal trigger of the interferon cascade in lupus and evaluating their potential as therapeutic targets. Defining the relationship between retroelement activation and interferon-driven immunopathology could fundamentally reshape our understanding of how autoimmune inflammation initiates and persists in the skin.