Diversity and Epitope Spreading of Anti–RNA Polymerase III Antibodies in Systemic Sclerosis: A Potential Biomarker for Skin and Lung Involvement

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Abstract
Objective: Epitope spreading (ES), involving autoantibodies, plays a crucial role in the development and persistence of autoimmune reactions in various autoimmune diseases. This study aimed to investigate the relationship between ES of anti–RNA polymerase III (RNAP III) antibodies (ARAs) and the clinical manifestations of systemic sclerosis (SSc).Methods: We investigated whether intermolecular ES occurs in the subunits of the RNAP III complex and whether intramolecular ES targets the major antigen, RNA polymerase III subunit A (RPC1), in patients with SSc. To achieve this, we synthesized 17 full‐length subunit proteins of the RNAP III complex and 5 truncated forms of RPC1 in vitro using a wheat germ cell‐free translation system. Subsequently, we prepared antigen‐binding plates and measured autoantibodies in the serum of patients with SSc.Results: Autoantibodies against different RNAP III complex subunits were found in patients who were ARA‐positive with SSc. The intermolecular ES indicators significantly correlated with the modified Rodnan skin thickness score (mRSS) and surfactant protein‐D, a biomarker of interstitial lung disease. However, the extent of disease on high‐resolution computed tomography or pulmonary function tests did not show any significant correlation. Intramolecular ES indicator against RPC1 were significantly correlated with mRSS and renal crisis. Furthermore, longitudinal assessment of ES in RNAP III complex subunits correlated with mRSS and exhibited potential as a disease activity biomarker.Conclusion: Our findings indicate a correlation between ES levels and the severity of skin sclerosis or the risk of other complications in SSc. This study suggests that measuring ES in SSc serves as a novel biomarker for disease activity. image

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