A two-hit mechanism triggers autoimmune hair loss

Autoimmune diseases arise from a breakdown of immune tolerance, yet the mechanisms that initiate tissue-specific autoimmunity remain poorly understood 1 , 2 , 3 , 4 . Here we identify a two-hit mechanism in which immune dysregulation and physiological neural activation converge to trigger autoimmune alopecia. We show that transient depletion of regulatory T (T reg ) cells during the anagen phase of the hair cycle, but not during telogen, induces CD8 + T-cell-mediated destruction of immune-privileged hair follicle stem cells (HFSCs), resulting in hair loss. This anagen-restricted susceptibility depends on sympathetic nerve activity, which is physiologically elevated during anagen: sympathetic denervation prevents disease, whereas psychological stress or optogenetic activation of sympathetic nerves renders otherwise resistant telogen skin susceptible to autoimmune attack after T reg cell depletion. Mechanistically, sympathetic noradrenaline signalling through HFSC-intrinsic ADRB2 promotes physiological reactivation of endogenous retroviruses (ERVs) in anagen HFSCs. Under conditions of T reg cell depletion, this ERV-associated state drives autoimmune pathology by engaging AIM2-dependent innate immune activation and pathogenic CD8 + T cell responses. Accordingly, genetic ablation of Aim2 or pharmacological inhibition of ERV reverse transcription protects against disease development. Together, these findings show that physiological sympathetic activity establishes a transiently vulnerable epithelial state, whereas T reg cells prevent this state from progressing to tissue-specific autoimmunity. This neuro–epithelial–immune circuit links hair-cycle state to the breach of HFSC immune privilege and the initiation of autoimmune alopecia.