Immune-mesenchymal crosstalk contribute to the expansion of autoreactive plasma cells in the tertiary lymphoid structures in Hidradenitis Suppurativa

Tertiary lymphoid structures (TLSs) are formed in the lesions of various autoimmune diseases and tumors, and provide critical microenvironment to sustain chronic inflammation. In Hidradenitis suppurativa (HS), a severe chronic inflammatory skin disease that still lacks effective therapeutics, we demonstrated that lymphocyte proliferation occursexclusively in the TLSs adjacent to the dermal tunnels in the lesional skin. Combining spatial transcriptomics, single-cell RNA and V(D)J- sequencing, we showed extensive clonal expansion of plasma cells sharing VHJHusage across patients, as well as proliferating IL17A+ and IFNG+ T cells, are enriched in TLS. We further identified two distinctpopulations of fibroblasts resembling stromal cells in secondary lymphoid organs (SLOs), and they secret inflammatory cytokines in response to TNFa and IL7 from the immune cells. Employing microfluidic system to reconstruct the HS TLS on a chip, we showed that HS lesional fibroblasts is critical in orchestrating the lymphocyte aggregation and activation. Importantly, antibodies generated from the expanded plasma cell clones exhibit reactivity to lesional skin across patients, supporting the existence of common autoantigens amongst HS patients. Altogether, our data bolster the complex interacting network between immune and mesenchymal cells within TLSs underlying HS pathogenesis.