Pathogenic drivers of lupus myocarditis and potential therapeutic targets.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organs simultaneously, complicating diagnosis and treatment. Despite extensive research, tissue-specific autoantigens and precise disease mechanisms remain unclear. Hallmark SLE autoantibodies primarily target nuclear antigens ubiquitously expressed across all tissues, limiting their diagnostic and therapeutic specificity. Myocarditis is a severe cardiovascular complication of SLE with a high mortality. However, not all patients with lupus myocarditis test positive for hallmark SLE antibodies, and their titers show no significant differences between patients with SLE with and without myocarditis, suggesting the involvement of additional, unidentified mechanisms. Autoimmunity against cardiac myosin heavy chain (MyHC) is a well-established driver of various forms of autoimmune myocarditis. However, the role of autoreactive T cells and autoantibodies targeting MyHC or other cardiac antigens in lupus myocarditis remains largely unknown. Here, in this Review, we offer an overview of the current knowledge on autoreactive T cells and autoantibodies identified in primary SLE or autoimmune myocarditis conditions from both clinical and preclinical studies. We also propose a novel two-stage model for lupus myocarditis pathogenesis, integrating both nuclear and cardiac antigen targets. Finally, we discuss antigen-specific regulatory T cells and chimeric antigen receptor T cells as promising therapeutic strategies for future research and clinical applications.