Antigen-specific immune responses and microbiota interactions in skin: Insights into autoimmune skin diseases and emerging therapeutic strategies

The skin plays a vital role in serving as a physical and immunologic barrier against external insults while orchestrating complex immune responses. Autoimmune skin diseases including pemphigus, vitiligo, and alopecia areata illustrate the intricate interplay between antigen-specific immunity and tissue-specific pathologies. Pemphigus serves as a model to understand the dynamics of peripheral immune tolerance and the interplay between humoral and cellular autoimmunity, emphasizing the role of regulatory T cells in controlling autoreactive responses. Similarly, vitiligo and alopecia areata highlight the pathological contribution of resident memory CD8⁺ T cells and IFN-γ signaling, identifying potential therapeutic targets such as the IL-15 signaling pathway to address disease intractability. In addition to autoimmune mechanisms, the skin microbiota profoundly influences local and systemic immune responses. Commensals such as Staphylococcus epidermidis promote homeostasis by regulating barrier integrity, T-cell activation, and wound repair, while dysbiosis exacerbates immune dysregulation. Innovative strategies, including the use of genetically modified microorganisms to stimulate antigen-specific immunity, hold promise for next-generation therapies. This review underscores the significance of antigen-specific immunity in skin diseases and the emerging role of microbiota in modulating immune responses. Future research into these areas is pivotal for advancing targeted therapies and understanding the interconnectedness of skin health and systemic immunity.