Anti-TFAM antibodies link mitochondrial damage with antiphospholipid syndrome and thrombosis in SLE

Mitochondria are a source of autoantigens and damage-associated molecular patterns (DAMPs) in systemic lupus erythematosus (SLE). Nucleoids carrying TFAM (transcription factor A, mitochondrial) and mitochondrial DNA (mtDNA) are important DAMPs in SLE. While mtDNA has been associated with anti-double-stranded (ds)DNA antibodies and type I interferon (IFN-I), the immunogenic role of TFAM in SLE pathogenesis is unknown. Here, we characterised the clinical and transcriptional phenotypes linked to anti-TFAM antibodies in SLE. Anti-TFAM antibodies were discovered in an exploratory sample of 22 SLE patients and 9 healthy controls. To define the prevalence, clinical significance, and associations with transcriptional profiles and IFN levels, anti-TFAM antibodies were detected using enzyme-linked immunosorbent assay (ELISA) in 98 healthy controls and 158 SLE patients. Sera from patients with dermatomyositis, rheumatoid arthritis, and primary antiphospholipid syndrome (PAPS) were also tested. Anti-TFAM antibodies were discovered in patients with SLE while analysing neutrophil autoantigens and confirmed by ELISA and immunoblotting. One-third of SLE patients (48/158) were positive for anti-TFAM antibodies. Unlike anti-dsDNA antibodies, anti-TFAM antibodies were not associated with disease activity or the IFN signature. Instead, anti-TFAM antibodies were associated with thrombosis, antiphospholipid syndrome (APS) (odds ratio [OR], 2.9 and 5.4, respectively), thrombosis-associated transcriptional profiles, and elevated IFN-III. Anti-TFAM antibodies were also found in PAPS, supporting their role in APS but not SLE pathogenesis. Lupus anticoagulant increased the risk of thrombosis associated with anti-TFAM antibodies (OR, 8.71), indicating they are markers of independent prothrombotic pathways. Anti-TFAM antibodies identify a distinct clinical and transcriptional disease subset associated with mitochondrial damage, thrombosis, and APS in SLE.