Abstract
Systemic sclerosis (SSc) is an autoimmune disease marked by fibrosis and extensive autoantibody production. Although B-cell depletion with rituximab (RTX) has shown clinical benefit, predictive biomarkers of response remain elusive. Here, we apply proteome-wide autoantibody screening using wet protein arrays covering 13,455 human antigens in serum samples from participants of the randomized trial of RTX. We identify a significant elevation in the total autoantibody levels in SSc compared to healthy controls, with greater reductions post-treatment observed in RTX high responders than in low responders. A stepwise selection highlights 88 clinically relevant autoantibodies, including those targeting G protein-coupled receptors. Among them, anti-C-C motif chemokine receptor 8 (CCR8) autoantibodies are functionally validated by cell-based assays using CCR8-overexpressing HEK293 cells. Furthermore, in a bleomycin-induced mouse model, anti-CCR8 antibody administration exacerbates dermal fibrosis and modifies immune cell infiltration. Although external validation with multiple comparison adjustment is further required, these findings reveal an autoantibody signature associated with therapeutic response and pathogenic potential in SSc, providing a foundation for precision immunotherapy and mechanistic insights into disease progression.