NEW research into how antisynthetase autoantibodies disrupt critical enzymatic functions in muscle cells was presented as part of a plenary abstract session at ACR Convergence 2024 in Washington, D.C. This research advances current understanding of antisynthetase syndrome (AS), a rare form of myositis characterized by autoantibodies targeting aminoacyl-transfer tRNA synthetases (aaRSs).
Researchers used bulk RNA sequencing on 669 frozen human muscle biopsies from patients with different AS autoantibodies, other inflammatory myopathies, and controls. Cultured human skeletal muscle myoblasts (HSMM) were electroporated to internalize AS autoantibodies or treated with histidinol. Transcriptomic profiles were compared between AS muscle biopsies and human HSMM after antibody internalization and inhibition of histidyl-tRNA synthetase. Specific gene sets were defined by intersecting differentially overexpressed gene between groups.
The researchers identified a unique gene signature, including CAMK1G, EGR4, PROK2, ALOXE3, and CXCL8, that was most prominent in anti-Jo1-positive patients. These genes correlated strongly with markers of disease activity, underscoring their potential role in AS pathology.
The study also demonstrated that antibodies internalized into HSMM activated the NFKB pathway, a driver of inflammation, and induced gene expression changes seen in AS patient muscle biopsies. Similarly, inhibiting histidyl-tRNA synthetase with histidinol replicated these effects, highlighting a shared mechanism of dysfunction.
This research underscores the pathogenic role of AS autoantibodies in disrupting aaRS functions, triggering inflammation through the NFKB pathway, and altering gene expression. Understanding these mechanisms offers potential therapeutic targets, particularly for anti-Jo1-positive patients with AS, who exhibited the most pronounced effects.
Reference: Casal-Dominguez M et al. Antisynthetase Autoantibodies Disrupt the Function of Their Target Aminoacyl-tRNA Synthetases in Muscle Cells. Abstract 1645. ACR Convergence 2024, November 16-19, 2024.
