(A) Binding profile for XAPs. XIST secondary structure was determined by psoralen cross-linking in living cells and deep sequencing (3); each arc on top represents an RNA duplex along XIST RNA. Clusters of XAP are indicated by bars that are color coded to XIST functional domains. Frequency of autoreactivity (MFI > 100) to XAP-derived autoantigens in patients with autoimmune disease is indicated by orange bars. Hotspots that are significantly elevated in any autoimmune disease are indicated by purple bars; others are indicated by white bars. (B) Cell of origin for antigenic proteins. Proportions for each cell type are displayed as a pie chart. (C) dHL-60 cells were stimulated with ionomycin to induce NETosis and stained with DAPI (blue), anti-SPEN (green), and XIST FISH probe (red). Scale bars: 10 μm. (D) Distribution of MFI values for sera reactivity against SPEN in the Stanford scleroderma cohort. (E) Calculated ORs for categorical variables of interest in the Stanford scleroderma cohort as defined by Stanford investigators, with horizontal lines indicating the 95% CIs, and a dotted vertical line at 1.0 signifying no association. *P < 0.05. P values were calculated using Barnard’s unconditional exact test. (F) Representative clinical photos of severe digital ulceration and gangrene in 3 patients with high anti-SPEN sera reactivity. (G) Model of the XIST RNP complex acting as an immunogenic scaffold. Created in BioRender.