Spatial transcriptomics maps early B-cell and T-cell activation in hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease that progresses from superficial nodules in early stages to dermal tunnels, tertiary lymphoid structures (TLSs), and fibrosis in advanced lesions. Interplays between dermal tunnel keratinocytes, TLSs, and fibroblasts promote pathogenic T-cell and B-cell inflammation in late-stage disease. However, whether these immune activations sequentially precede or follow late-stage structure formation is unclear. To delineate the temporal sequence of immune activation, we integrated spatial and single-cell transcriptomic analyses of early- and late-stage HS and compared them with acne conglobata and psoriasis. Spatial transcriptomics of 156 regions of interest revealed robust dermal immune activation in early-stage HS, including B-cell enrichment, type 17 T-cell (T17) pathway activation, and neutrophilic infiltration, occurring prior to tunnel or TLS formation. Single-cell RNA sequencing confirmed early plasma cell expansion and identified multifunctional B-cells expressing pro-inflammatory cytokines, antigen-presentation machinery, and immunoglobulins. Notably, T-cells, rather than fibroblasts, were the predominant producers of the B-cell chemoattractant CXCL13 in early lesions. Together, these findings demonstrate that HS exhibits early and sustained immune activation that precedes dermal remodeling, underscoring the aggressive nature from its onset and suggesting that early therapeutic targeting of the T17 axis and B-cell-mediated inflammation may help prevent disease progression.