Autoimmune skin disease pathogenesis: a chronological immune cascade and multi-hit model

Abstract Autoimmune skin diseases share core immune dysregulation principles but exhibit distinct spatiotemporal dynamics. This review leverages vitiligo, a model of melanocyte-targeted autoimmunity, to establish a comprehensive chronological framework spanning disease onset, progression, and recurrence. Central to this framework is a "stochastic multi-hit model", where disease arises from the cumulative breach of immunological checkpoints due to genetic and environmental hits. Within this model, we discussed the immune “self” and “nonself” of target cells in antigen exposure, dendritic cells and Langerhans cells activation and T cell priming. Sequentially, the cellular events around T cells migrating to skin, including the formation of tertiary lymphoid structure and the interaction between T cells and macrophages, Tregs, and extracellular matrix were reviewed. We also depicted new insights into inflammation resolution and the recurrence instigated by adaptive immunity, trained immunity, and inflammatory memory. Extending the framework to other main autoimmune skin diseases, such as alopecia areata, pemphigus vulgaris, and psoriasis, also allowed us to identify unexplored mechanistic gaps. This integrated chronological and multi-hit perspective explains the profound heterogeneity in disease manifestation and response. We hope that the review will provide potential future directions of immunological studies in autoimmune skin diseases and new ideas for clinical practice.