A new study partially funded by the SRF offers a potential explanation for why autoimmune disease, including scleroderma, affects women at far higher rates than men. The researchers focused on XIST, a molecule found only in women that forms large complexes with proteins inside cells. Coauthors include SRF funded investigators Jinwoo Lee, PhD; Diana Dou, PhD; Ami Shah, MD; David Fiorentino, MD, PhD; Lorinda Chung, MD; and SRF Scientific Advisor Howard Chang, MD, PhD
They found that the immune system can mistakenly target these complexes, producing autoantibodies, and identified specific “hotspots” within them that are particularly prone to triggering this response. A process called NETosis, where immune cells release their contents into surrounding tissue, appears to be the mechanism that initially exposes these complexes to the immune system.
The findings are directly relevant to scleroderma. In two patient cohorts, individuals with high levels of autoantibodies against a key XIST-associated protein were significantly more likely to experience severe manifestations of Raynaud’s phenomenon, including digital ulcers and gangrene.
These results point to a new potential biomarker for identifying scleroderma patients at risk for severe vascular disease, and suggest new answers as to why women experience a disproportionate burden of autoimmune disorders.
