IgA autoantibodies trigger pro-inflammatory, pro-fibrotic and type I interferon responses in Hidradenitis suppurativa skin lesion

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 lesions, the pathogenic role of IgA autoantibodies remains poorly understood. Here, we demonstrate that lesional HS skin 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 and B cells as the primary source of IgA. Autoantigen profiling revealed a diverse repertoire of IgA autoantibodies targeting nuclear, cytoplasmic, and membrane antigens, including MDA5, complement C3/C4, NLRP1, and ACE, with levels correlating with disease severity. We identified IgA autoantibodies targeting CD68⁺ macrophages, which induced secretion of TNF, IL-6, and IL-1β, and upregulated inflammasome and fibrotic pathways. Anti-NET IgA was elevated in HS and promoted NET formation, establishing a pathogenic feedback loop. NET–IgA immune complexes activated M2 macrophages to secrete CCL18, driving collagen production by fibroblasts and promoting a type I IFN signature. IgA immune complexes presented by myeloid dendritic cells activated CD4⁺ T cells, triggering IFN-γ production, further amplifying local inflammation. Direct exposure of fibroblasts to NET–IgA complexes triggered expression of adhesion molecules, chemokines, and regulators of adaptive immunity. Together, these findings uncover a novel 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.