Next-generation technologies for autoantigen detection in sex-biased autoimmunity

Stanford University, Stanford CA

Investigators

Abstract

Project Summary Autoimmune diseases disproportionately affect women, who represent four out of five of ~50 million Americans living with these diseases. In part, this is due to an RNA named Xist that is expressed in every cell in a woman’s body, which performs important functions but also can drive autoimmunity associated with anti-Xist RNP antibodies (AXA) against the proteins bound to Xist. However, the spatial expression patterns of the proteins bound to Xist in the tissues affected by autoimmunity are still unknown, and population-level profiling for AXA in women is currently a cost-prohibitive endeavor. We will use spatial proteomics to identify the spatial patterns of expression of the Xist RNP complex in five human tissues targeted by XIST-driven autoimmunity: skin (affected by SSc), kidney (affected by SLE), skeletal muscle (affected by DM), lung, and heart. We will also correlate the patterns of AXA staining in HEp-2 male laryngeal carcinoma cells that are typically used for testing for autoimmunity but may miss AXAs, as well as U-2 OS female osteosarcoma cells that express Xist and are used for staining all human proteins in the Human Protein Atlas (HPA) subcellular atlas. This will enable us to apply advanced computational models, such as self-supervised classification of protein localizations using vision transformer models, as well as building multiscale integrated cell (MuSIC) models, to better interpret the biology underlying AXA staining patterns. Finally, we will streamline antigen discovery in female-biased immunity by leveraging the proteome-wide antigen and antibody resources of the Human Protein Atlas. With a new high- throughput method to profile AXA for women, we can make a potentially transformative advance in women’s health by better identifying Xist-biased autoimmunity and laying the groundwork to develop better treatments for sex-biased autoimmunity.