A skin colonizer disrupts inflammatory and humoral immune defenses in hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease associated with a polybacterial dysbiosis devoid of a known pathogen. Here, we report that HS patients mount IgA and IgG responses against skin colonizers, notably Porphyromonas uenonis (Pu), a rare species selectively enriched in severe disease. In these patients, Pu foci are detected in the epidermis, surrounded by IgA deposits, and anti-Pu IgGs cross-react with self-antigens expressed by healthy keratinocytes. Using healthy human skin explants, we demonstrate that patient-derived Pu can cross an intact epidermal barrier, infect and persist within keratinocytes, triggering their expression of pro-inflammatory mediators. In contrast, topical application of Pu on immunocompetent mice elicit cutaneous and systemic humoral immune responses without tissue infection. These findings uncover an impaired innate immune control of Pu in HS patients, linking keratinocyte infection to skin inflammation and humoral autoimmunity. They underscore the potential of targeting cutaneous dysbiosis as a strategy to limit HS progression.