Skin immune-mesenchymal interplay within tertiary lymphoid structures promotes autoimmune pathogenesis in hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (IL17A+ and IFNG+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. HS fibroblasts express CXCL13 or CCL19 in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-α)-CXCL13 and TNF-α-CCL19 feedback loops with B and T cells, respectively; early TNF-α blockade suppressed aggregate initiation. Our findings provide insights into TLS formation in the skin, suggest therapeutic avenues for HS, and reveal mechanisms that may apply to other autoimmune settings, including Crohn’s disease. [Display omitted] •TLSs near tunnel epithelium of HS lesional skin support local immune cell proliferation•Extensive clonal expansion of plasma cells producing antibodies against keratinocytes•HS fibroblasts promote lymphocyte aggregation through TNF-α-CXCL13 and TNF-α-CCL19 loops•TNF-α blockade is more effective at the initiation of lymphocyte aggregation Hidradenitis suppurativa (HS) is a severe chronic inflammatory disease without effective treatment options. Yu et al. identify and characterize tertiary lymphoid structures (TLSs) in HS, highlighting fibroblast-driven TLS formation via cytokine feedback loops with immune cells and lymphocyte clonal expansion and antibody production against keratinocytes. Their findings have implications for autoimmune pathogenesis and treatment options.