Psoriasis (Pso) is a chronic inflammatory skin disease driven by T helper 17 (TH17) cells, with several clinical subtypes. While self-reactive immune responses have been observed, the role of autoantigens in Pso remains unclear. Using immunopeptidomics, we identified serpin family B member 3 (SERPINB3) and SERPINB4 as candidate autoantigens in Pso skin. In a mouse model, the SERPINB3 ortholog Serpinb3b enhanced inflammation, promoted tissue-resident memory T cells, and skewed immunity toward a TH2 phenotype. In humans, SERPINB3 reactivity was specifically associated with "eczematized psoriasis" (EczPso), a subtype marked by TH2/TH17 immune signatures. SERPINB3 protein was enriched in EczPso lesions and highly secreted by keratinocytes under combined TH2/TH17 stimulation. Lesional T cells from EczPso-but not from eczema or classical plaque Pso-proliferated in response to SERPINB3 and induced EczPso-like features in a skin model. Our findings identify SERPINB3 as an autoantigen driving a distinct Pso subtype, supporting more precise diagnosis and therapy.
