Objectives Systemic sclerosis (SSc) is an autoimmune fibrotic disease affecting multiple tissues including the lung. A subset of patients with SSc with lung disease exhibit short telomeres in circulating lymphocytes, but the mechanisms underlying this observation are unclear.
Methods Sera from the Johns Hopkins and University of California, San Francisco (UCSF) Scleroderma Centers were screened for autoantibodies targeting telomerase and the shelterin proteins using immunoprecipitation and ELISA. We determined the relationship between autoantibodies targeting the shelterin protein TERF1 and telomere length in peripheral leucocytes measured by qPCR and flow cytometry and fluorescent in situ hybridisation (Flow-FISH). We also explored clinical associations of these autoantibodies.
Results In a subset of patients with SSc, we identified autoantibodies targeting telomerase and the shelterin proteins that were rarely present in rheumatoid arthritis, myositis and healthy controls. TERF1 autoantibodies were present in 40/442 (9.0%) patients with SSc and were associated with severe lung disease (OR 2.4, p=0.04, Fisher’s exact test) and short lymphocyte telomere length. 6/6 (100%) patients with TERF1 autoantibodies in the Hopkins cohort and 14/18 (78%) patients in the UCSF cohort had a shorter telomere length in lymphocytes or leukocytes, respectively, relative to the expected age-adjusted telomere length. TERF1 autoantibodies were present in 11/152 (7.2%) patients with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disease believed to be mediated by telomere dysfunction.
Conclusions Autoantibodies targeting telomere-associated proteins in a subset of patients with SSc are associated with short lymphocyte telomere length and lung disease. The specificity of these autoantibodies for SSc and IPF suggests that telomere dysfunction may have a distinct role in the pathogenesis of SSc and pulmonary fibrosis.
- pulmonary fibrosis
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Handling editor Josef S Smolen
Contributors BLA: contributed to the conception of the work and the data acquisition and interpretation, wrote manuscript. FB: contributed to data acquisition and revising the manuscript critically. PJW: contributed to data acquisition and revising the manuscript critically. COB: contributed to data acquisition and revising the manuscript critically. AAS: contributed to data acquisition and revising the manuscript critically. CG: contributed to revising the manuscript critically. LC-R: contributed to the conception of the work and the data acquisition and interpretation, revised the manuscript critically. AR: contributed to the conception of the work and the data acquisition and interpretation, revised the manuscript critically.
Funding BLA was supported by the Jerome L. Greene Foundation, Scleroderma Research Foundation and T32 AR048522. LC-R and AAS were supported in part by the Donald B. and Dorothy L. Stabler Foundation. The UCSF Scleroderma Cohort was supported by the Lennox Foundation and the Scleroderma Research Foundation. The UCSF ILD Cohort was funded by the Nina Ireland Program for Lung Health. The Johns Hopkins Scleroderma Center Research Registry receives support from the Johns Hopkins inHealth Precision Medicine Initiative, the Scleroderma Research Foundation and the Chresanthe Staurulakis Memorial Discovery Fund. Samples from the Rheumatoid Arthritis Cohort were obtained through a pilot project supported by the Patient Centered Outcomes Research Institute (PCORI), IP2-PI000737 and additionally supported by the Camille Julia Morgan Arthritis Research and Educational Fund. This study was additionally supported by P30-AR053503 and P30-AR070254. Funding of the Myositis Cohort is from the Huayi and Siuling Zhang Discovery Fund and the Peter Buck Foundation.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the Hopkins IRB (IRB00239503). The Institutional Review Boards at Johns Hopkins and UCSF approved the different components of this study.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. The data are stored as deidentified participant data which are available on request to BLA (firstname.lastname@example.org)
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