This study investigated autoantibody internalisation as a mechanism of tissue injury across autoimmune diseases, using anti-Mi2 dermatomyositis and anti-PM/Scl scleromyositis as model diseases. It combined bulk RNA-seq of 814 muscle biopsies (+ 41 external validation samples), in vitro IgG electroporation into primary human cells, immunofluorescence, and spatial transcriptomics.
Autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction were reproducible across cohorts; purified patient IgG electroporated into healthy cells recapitulated disease-associated transcriptional programmes. Spatial transcriptomics identified distinct downstream signalling (type I IFN and TGFβ in anti-Mi2 DM; type II IFN in anti-PM/Scl), affected multiple cell types (muscle fibres, macrophages, endothelial cells, fibroblasts/FAPs), and revealed immunoglobulin RNA transfer from antibody-secreting cells to adjacent target cells. Antibody internalisation was also confirmed in skin (anti-Mi2, anti-PM/Scl) and in anti-U1RNP MCTD, anti-Ku overlap syndrome, and anti-Scl70 systemic sclerosis.
The bulk RNA-seq dataset is heavily weighted toward muscle biopsies, limiting conclusions about other tissue types. In vitro electroporation of IgG may not fully replicate physiological autoantibody internalisation kinetics. Causal directionality between autoantibody internalisation and observed transcriptional injury programmes cannot be definitively established from these data.
Internalised autoantibodies appear to drive distinct, disease-specific transcriptional injury programmes in multiple cell types and tissues beyond muscle, suggesting autoantibody internalisation is a broadly relevant pathogenic mechanism across autoantibody-mediated diseases. Clinicians should consider this mechanism when evaluating tissue damage in patients with anti-Mi2, anti-PM/Scl, anti-U1RNP, anti-Ku, or anti-Scl70 antibodies.
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