Spatial transcriptomics reveals mechanism of autoimmunity driven by internalized autoantibodies

Area of Science:

• Immunology
• Molecular Biology
• Genomics

Background:

• Autoantibody internalization is implicated in autoimmune disease pathogenesis but poorly understood.
• Mechanisms and scope across diseases, cell types, and tissues require clarification.

Purpose of the Study:

• To investigate the mechanisms and generality of autoantibody internalization in autoimmune diseases.
• To identify autoantibody-specific transcriptomic signatures and associated cellular responses.

Main Methods:

• Bulk and spatial RNA sequencing of patient biopsies.
• Purified patient IgG electroporation into healthy cells in vitro.
• Direct immunofluorescence for immunoglobulin localization.

Main Results:

• Identified reproducible, autoantibody-specific transcriptomic signatures linked to autoantigen dysfunction.
• Demonstrated IgG internalization induces disease-specific transcriptomic programs.
• Observed antibody-secreting cells transferring RNA to adjacent cells.
• Found disease-specific transcripts in various cell types, associated with inflammation and cell damage.
• Confirmed antibody internalization in diverse autoimmune diseases.

Conclusions:

• Autoantibody internalization is a shared pathogenic mechanism across various autoimmune diseases.
• This provides a unifying framework for understanding diseases driven by autoantibodies against intracellular antigens.