Dynamic Immune-mesenchymal interplay within the tertiary lymphoid structures promotes autoimmune pathogenesis in Hidradenitis Suppurativa

Tertiary lymphoid structures (TLS) play a pivotal role in sustaining chronic inflammation within autoimmune diseases and tumors by fostering crucial immune cell interactions. While much is known about TLS linked to mucosal epithelium, their formation in the skin epithelium and the supporting microenvironment remains unclear. Using multiomics, we uncovered the presence of TLSs in a severe chronic inflammatory skin disease, Hidradenitis Suppurativa (HS), and showed that lymphocyte proliferation exclusively occurs in TLSs, predominantly located in adjacent to the unique epithelialized tunnels in lesional skin. Notably, we found extensive clonal expansion of plasma cells generating antibodies specific to HS lesional keratinocytes across different patients, alongside the proliferation of Tfh, Treg, and pathogenic T cells (IL17A+ and IFNG+). Additionally, we identified two distinct skin fibroblast populations with transcriptional signatures resembling stromal cells in secondary lymphoid organs (SLO), expressing CXCL13 or CCL19, in response to immune cytokines. Employing a microfluidic system to mimic TLSs-on-a-chip, we demonstrated that HS lesional fibroblasts are critical in orchestrating lymphocyte aggregation and proliferation, which involve TNFα-CXCL13 and TNFα-CCL19 feedback loops with B and T cells, respectively. Furthermore, our study revealed that early TNFα blockade effectively suppresses lymphocyte aggregation, but not after aggregates are formed, underscoring the critical role of TNFα during the initiation of the lymphoid aggregation. Through dissecting the intricate network interactions between immune and mesenchymal cells within the HS lesion, our work revealed the crucial mechanism sustaining chronicity in Hidradenitis Suppurativa and potentially other autoimmune diseases.