Hidradenitis suppurativa: TLSs take the center stage

Abstract

Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease with limited response to therapy. In this issue of Immunity, Yu et al.¹ identify skin tertiary lymphoid structures (TLSs) as primary sites for lymphocyte clonal expansion and autoantibody production, driving disease progression, and provide insight into how formation and maintenance of TLS impact therapeutic outcomes.

Fig 1.. Tertiary lymphoid structure (TLS) formation and function in Hidradenitis Suppurativa (HS).

Top left: HS induces inflammatory, keratinized epithelial tunnels (ETs) that penetrate deep into the dermis. Yu et al. identified TLSs forming around ETs at HS lesion sites, consisting of fibroblast/stromal cells (brown), B cells (blue), T cells (green), and plasma cells (purple). Bottom: TNFα (orange) initiates early TLS formation by activating reticular fibroblasts to produce CXCL13 and papillary fibroblasts to make CCL19, attracting CXCR5⁺ B cells and CCR7⁺ T cells, respectively. Chemokine signals further enhance lymphocyte TNFα production, which activates fibroblasts in a positive feedback loop that amplifies lymphocyte aggregation and TLS formation. Top right: Established TLSs serve as the primary sites for the proliferation of Ki67⁺ effector T cells (dark green), B cells (dark blue), and CD38⁺ plasma cells (purple). Plasma cells produce autoantibodies targeting unknown antigen(s) (red) associated with lesional ET keratinocytes, inducing the formation of pathogenic immune complexes to support neutrophil recruitment and function in the ET lumen. Created in BioRender.