Auto-inflammatory / Follicular Occlusion in HS
The primary defect in HS pathophysiology involves occlusion and subsequent inflammation of the hair follicle; and innate immune dysregulation, together initiate the development of clinical HS. Bacterial infection and colonization are considered a secondary pathogenic factor that can worsen HS. Follicular occlusion leads to dilation followed by rupture, resulting in the follicular contents, including keratin and bacteria, spilling into the surrounding dermis and inducing a vigorous chemotactic response from neutrophils and lymphocytes. The inflammatory cellular infiltrate causes abscess formation, leading to the destruction of the pilosebaceous unit and eventually of other adjacent adnexal structures. Other factors that may contribute to HS include abnormal invaginations of the epidermis leading to sinus tract formation, and deficient numbers of sebaceous glands.
The basis for follicular occlusion in HS is yet to be fully defined. Recently proposed the concept of HS as an auto-inflammatory disease characterized by dysregulation of the gamma-secretase/Notch pathway.
Appropriate Notch signaling is of pivotal importance for maintaining the inner and outer root sheath of the hair follicle and skin appendages. Deficiency in the Notch signaling pathway results in conversion of hair follicles to keratin-enriched epidermal cysts, leads to the stimulation of toll-like receptor (TLR)-mediated innate immunity, supporting and maintaining chronic inflammation. In support of this hypothesis, elevated levels of several pro-inflammatory cytokines, most notably tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-17, have been observed in HS lesions.
Altered TLRs signaling on macrophages and dendritic cells (DCs), the most abundant cells in HS lesions, produces increased amounts of these cytokines, leading to activation of DCs, which secrete IL-23 promoting Th17 cell polarization (IL-17-producing T helper cells were found to infiltrate the dermis in chronic HS lesions).35–40 In particular, one of the major actors in HS pathogenesis is TNF-α, whose overexpression has been observed in lesional and perilesional skin of HS, together with a positive correlation with disease severity. Hence, it is clear that HS is a follicular disease showing some defect in keratin clearance, with resultant follicular occlusion, where defective innate cellular immunity, and autoinflammatory process plays an important role.