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Anti-TFAM antibodies link mitochondrial damage with antiphospholipid syndrome and thrombosis in SLE
Eduardo Gómez-Bañuelos1, Alessandra Ida Celia2, Maria Isabel Trejo-Zambrano1
1Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Objectives:
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.
Methods:
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.
Results:
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.
Conclusions:
Anti-TFAM antibodies identify a distinct clinical and transcriptional disease subset associated with mitochondrial damage, thrombosis, and APS in SLE.
Insights
Anti-TFAM antibodies in systemic lupus erythematosus (SLE) are linked to thrombosis and antiphospholipid syndrome (APS), not disease activity. These antibodies identify a distinct subset of SLE patients with mitochondrial damage and prothrombotic pathways.
Area of Science:
- Immunology
- Rheumatology
- Molecular Biology
Background:
- Mitochondria release autoantigens and damage-associated molecular patterns (DAMPs) in systemic lupus erythematosus (SLE).
- Mitochondrial nucleoids, including transcription factor A, mitochondrial (TFAM) and mitochondrial DNA (mtDNA), are implicated as DAMPs in SLE.
- While mtDNA's role in SLE is linked to anti-double-stranded (ds)DNA antibodies and type I interferon (IFN-I), TFAM's immunogenic role remains unclear.
Purpose of the Study:
- To investigate the clinical and transcriptional phenotypes associated with anti-TFAM antibodies in SLE patients.
- To determine the prevalence and clinical significance of anti-TFAM antibodies in SLE.
- To explore the association of anti-TFAM antibodies with interferon levels and transcriptional profiles.
Main Methods:
- Anti-TFAM antibodies were detected using enzyme-linked immunosorbent assay (ELISA) and immunoblotting.
- Prevalence was assessed in 158 SLE patients, 98 healthy controls, and patients with other autoimmune diseases.
- Clinical data, transcriptional profiles, and interferon levels were analyzed in relation to anti-TFAM antibody status.
Main Results:
- Anti-TFAM antibodies were found in one-third of SLE patients (48/158).
- These antibodies were not associated with SLE disease activity or the type I IFN signature.
- Anti-TFAM antibodies correlated with thrombosis, antiphospholipid syndrome (APS), thrombosis-associated transcriptional profiles, and elevated IFN-III, and were also present in primary antiphospholipid syndrome (PAPS).
Conclusions:
- Anti-TFAM antibodies identify a distinct subset of SLE patients.
- This subset is characterized by mitochondrial damage, thrombosis, and APS.
- Anti-TFAM antibodies may indicate independent prothrombotic pathways, particularly when lupus anticoagulant is present.
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