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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.
Autoantibody internalization is a key mechanism driving tissue damage in autoimmune diseases. This study demonstrates its broad relevance across various conditions and cell types, revealing specific molecular signatures.
Area of Science:
- Immunology
- Molecular Biology
- Autoimmune Diseases
Background:
- Autoantibody internalization is implicated in autoimmune disease pathogenesis.
- Mechanisms and generalizability across diseases, cell types, and tissues remain poorly defined.
Purpose of the Study:
- To investigate the mechanisms and generalizability of autoantibody internalization in autoimmune diseases.
- To identify autoantibody-specific transcriptomic signatures and their functional consequences.
Main Methods:
- Bulk RNA sequencing of 814 muscle biopsies and 41 validation samples.
- In vitro electroporation of patient immunoglobulin (Ig) G into primary human cells.
- Immunofluorescence and spatial transcriptomics to assess immunoglobulin localization, gene expression, and cellular responses.
Main Results:
- Reproducible, autoantibody-specific transcriptomic signatures linked to autoantigen dysfunction were validated.
- Electroporation of patient IgG recapitulated disease-associated transcriptional programs in healthy cells.
- Spatial transcriptomics revealed distinct inflammatory responses (e.g., interferon, TGFβ signaling) and immunoglobulin RNA transfer between cells.
- Autoantibody internalization was observed across multiple autoimmune diseases and tissues, including skin and connective tissues.
Conclusions:
- Autoantibody internalization is established as a mechanism of tissue injury in autoimmunity.
- Findings suggest broader relevance of this mechanism across various autoantibody-mediated diseases.
