Transcobalamin 1 is a keratinocyte-derived autoantigen driving psoriasis through T helper 17 cell activation

Autoantigens play a critical role in triggering autoimmunity in autoimmune diseases. Psoriasis, a systemic autoimmune skin disease, has an incompletely defined spectrum of autoantigens in terms of both identity and function. Here, through integrated analysis of bulk transcriptomic, DNA methylomic, and immunopeptidomic datasets, we identify 10 psoriasis-associated autoantigens that are reactivated by DNA hypomethylation. Among them, transcobalamin 1 (TCN1) is a keratinocyte-secreted autoantigen that is internalized by antigen-presenting cells and presented via human leukocyte antigen class II molecules to CD4 + T cells. Accordingly, TCN1 expression tracks with keratinocyte hyperproliferation and interleukin-17 (IL-17) signaling intensity in psoriatic lesions. In vitro coculture assays confirm that keratinocyte-derived TCN1 promotes T helper 17 cell (T H 17 cell) differentiation and concurrently activates IL-17 signaling in keratinocytes. The absence of TCN1 in mice precludes further functional investigation using murine psoriasis models. Thus, DNA hypomethylation–reactivated TCN1 acts both as an autoantigen that amplifies T H 17 cell/IL-17 immunity and as a driver of keratinocyte hyperproliferation, making it a promising therapeutic target and biomarker for psoriasis.