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

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.