Confirmation of anti-TERF1 autoantibodies in systemic sclerosis and fibrotic lung disease using a novel particle-based immunoassay

Anti-TERF1 autoantibodies were previously identified in systemic sclerosis (SSc) sera and were associated with severe lung involvement, adding to earlier evidence that telomere dysregulation may contribute to disease pathogenesis. Nevertheless, the report of anti-TERF1 autoantibodies in SSc has not been confirmed in an independent cohort. We sought to confirm the presence of anti-TERF1 autoantibodies in patients with SSc using a novel particle-based multi-analyte technology (PMAT) and to characterize antibody specificity by epitope mapping. A comparability study assessing agreement between a research-use only (RUO) enzyme-linked immunosorbent assay (ELISA) and a RUO PMAT assay developed for detection of anti-TERF1 autoantibodies was performed on sera from 42 individuals, including 32 with SSc and 5 healthy controls. Anti-TERF1 autoantibodies were subsequently measured in a cross-sectional cohort of 381 patients, including 133 with SSc, 28 with idiopathic pulmonary fibrosis/interstitial pneumonia with autoimmune features (IPF/IPAF), 198 with other autoimmune or infectious diseases, and 22 healthy controls. Exploratory epitope mapping of the TERF1 autoantigen was performed using pooled sera to probe a custom peptide microarray. A strong correlation was observed between ELISA and PMAT assays (Spearman rho = 0.805 [95% CI 0.658–0.893]), with good discriminatory performance (AUC 0.852 [95% CI 0.745–0.960]). In the cross-sectional cohort, anti-TERF1 autoantibodies were identified in 6/133 (4.5%) with SSc, 3/28 (10.7%) with IPF/IPAF, 6/198 (3.0%) in other conditions, and 0/22 (0%) healthy controls. Exploratory epitope mapping identified five immunoreactive regions within TERF1, with the highest signal intensity observed for peptides containing the SAVTESSE octapeptide. Anti-TERF1 autoantibodies were detected in an independent cohort of SSc and IPF/IPAF patients using an automated PMAT assay, with strong cross-platform correlation with ELISA. Epitope mapping suggested amino acid sequence-specific antibody recognition of TERF1. Further studies are warranted to define the clinical and mechanistic relevance of these autoantibodies in SSc and fibrotic lung disease.