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Updated: Aug 6, 2026
Interrogating Individual Autoreactive Germinal Centers by Photoactivation in a Mixed Chimeric Model of Autoimmunity
Published on: April 11, 2019
Spatial transcriptomics reveals mechanism of autoimmunity driven by internalised autoantibodies
Iago Pinal-Fernandez1, Katherine Pak2, Maria Casal-Dominguez1
1Muscle Disease Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Objectives:
Autoantibody internalisation has been implicated in autoimmune disease pathogenesis, yet its mechanisms and generalisability across diseases, cell types, and tissues remain poorly defined. We sought to address these gaps.
Methods:
Bulk RNA sequencing was performed on 814 muscle biopsies from patients with autoimmune diseases and healthy controls, including an external validation cohort of 41 additional samples. Purified patient immunoglobulin (Ig) G was electroporated into primary human cells to assess functional effects in vitro. Immunofluorescence evaluated localisation of immunoglobulins across diseases and tissues. Spatial transcriptomics assessed disease-specific gene expression, cellular injury, and inflammatory responses.
Results:
Using anti-Mi2 dermatomyositis and anti-PM/Scl scleromyositis as model diseases, we validated reproducible, autoantibody-specific transcriptomic signatures consistent with autoantigen dysfunction across cohorts and confirmed that electroporation of purified patient IgG into healthy primary cells recapitulates these disease-associated transcriptional programmes. Spatial transcriptomics linked these signatures to cellular injury and distinct inflammatory responses, including activation of type I interferon and TGFβ signalling in anti-Mi2 dermatomyositis and type II interferon signalling in anti-PM/Scl scleromyositis. These programmes were observed predominantly not only in muscle fibres but also in macrophages, endothelial cells, and fibroblasts/fibroadipogenic progenitors. Spatial transcriptomics further revealed transfer of immunoglobulin RNA from antibody-secreting cells to adjacent target cells expressing disease-specific transcriptional programmes. Antibody internalisation, previously described in myositis muscle, was also observed in skin from patients with anti-Mi2 and anti-PM/Scl and in tissues from anti-U1RNP mixed connective tissue disease, anti-Ku overlap syndrome, and anti-Scl70 systemic sclerosis.
Conclusions:
Together, these findings establish autoantibody internalisation as a mechanism of tissue injury in autoimmunity, suggesting its broader relevance across autoantibody-mediated diseases.
