Pathological autoantibody internalisation in myositis.

Area of Science:

• Immunology
• Molecular Biology
• Muscle Biology

Background:

• Autoantibodies targeting intracellular proteins are prevalent in autoimmune diseases.
• The role of these autoantibodies in myositis has been debated due to the belief that they cannot penetrate muscle cells.

Purpose of the Study:

• To investigate whether autoantibodies can enter living muscle cells in myositis.
• To determine if internalised autoantibodies cause functional changes in muscle cells.

Main Methods:

• Confocal immunofluorescence microscopy to localize antibodies in muscle biopsies.
• Bulk RNA sequencing of 669 muscle samples (myositis, controls).
• Electroporation of patient antibodies into cultured myoblasts followed by RNA sequencing.

Main Results:

• Myositis autoantibodies were found within muscle fibers, co-localizing with their autoantigens.
• Muscle biopsies with autoantibodies targeting transcriptional regulators showed transcriptomic changes indicating autoantigen dysfunction.
• Specific examples include altered RNA processing in patients with anti-PM/Scl antibodies.
• In vitro experiments confirmed that patient antibodies induce similar transcriptomic changes in muscle cells.

Conclusions:

• Autoantibodies are internalized into living muscle cells in myositis.
• Internalized autoantibodies disrupt the function of their target autoantigens, leading to observable biological effects.