Abstract Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with complex immune dysregulation. While previous studies have reported tertiary lymphoid structures (TLS) and IgA-producing B cells in HS skin lesions, the pathogenic role of IgA autoantibodies remains insufficiently characterized. Here, we demonstrate that lesional skin from patients with HS exhibits elevated expression of IGHA1, IGHA2, and J chain, as confirmed by qPCR, immunofluorescence, and Western blot analyses. Single-cell RNA sequencing identified local plasma cells and B cells as the primary source of IgA. Autoantigen profiling revealed a diverse repertoire of IgA autoantibodies targeting nuclear, cytoplasmic, and membrane antigens, with levels correlating with disease severity and other clinical manifestations. We identified IgA autoantibodies binding to CD68⁺ macrophages, which induced secretion of TNF, IL-6, and IL-1β and upregulated inflammasome and profibrotic pathways. Anti-neutrophil extracellular trap (NET) IgA was elevated in HS and promoted NET formation, establishing a pathogenic feedback loop. NET–IgA immune complexes induced macrophages to secrete CCL18, driving collagen production by fibroblasts and promoting a type I interferon (IFN) gene signature. IgA immune complexes presented by myeloid dendritic cells activated CD4⁺ T cells, triggering IFN-γ production and further amplifying local inflammation. Notably, supernatants from macrophages exposed to IgA were able to polarize naïve CD4⁺ T cells toward a Th17 phenotype, linking innate immune activation to the expansion of pathogenic adaptive immune responses. Direct exposure of fibroblasts to NET–IgA complexes triggered expression of adhesion molecules, chemokines, and regulators of adaptive immunity. Together, these findings uncover a role for IgA autoantibodies in HS, implicating them as central drivers of chronic inflammation, fibrosis, and immune crosstalk across neutrophils, macrophages, fibroblasts, and T cells.
Carmona-Rivera et al. (Tue,) studied this question.