Autoantibody reactome analysis reveals novel biomarkers for idiopathic retroperitoneal fibrosis

Idiopathic retroperitoneal fibrosis (iRPF) is a rare disease frequently misdiagnosed due to the lack of reliable biomarkers. This study aimed to identify novel autoantibodies to improve the diagnosis and differential diagnosis of iRPF.

A total of 33 patients with iRPF, 100 healthy controls, 11 with retroperitoneal sarcoma (RPS) and 74 with other autoimmune diseases were recruited from Renji Hospital from January 2018 to April 2025. Autoantibodies were screened using the Sengenics Immunome Protein Array. Their expression and particularly their IgG4 subclass were then validated by enzyme-linked immunosorbent assay (ELISA) and dot blot assays. Pearson correlation and receiver operating characteristic (ROC) curve analyses were performed with clinical parameters to evaluate their diagnostic performance.

Plasma levels of autoantibodies targeting recombination signal binding protein for immunoglobulin kappa J region (RBPJ), tropomyosin alpha-1 (TPM1), nuclear nucleic acid-binding protein (C1D), nucleophosmin 1 (NPM1) and interleukin-1α (IL-1A) were significantly elevated in iRPF patients compared with healthy controls. Among these, anti-TPM1 antibody levels positively correlated with hydronephrosis severity (P < 0.05) and serum creatinine concentrations (P < 0.01), and declined after treatment, suggesting their potential as biomarkers of renal injury and disease activity. Anti-RBPJ antibodies increased after treatment (P < 0.01) and showed a negative correlation with IL-6 (P < 0.05), suggesting the potential for protective antibodies. Anti-C1D antibodies distinguished iRPF from RPS (P < 0.01, AUC = 0.718), and their IgG4 subclass was associated with a Th1/Th2 imbalance and renal impairment. Anti-NPM1 IgG4/IgG ratio was positively correlated with renal injury markers and Th2-type cytokines.

This study identified five autoantibodies with diagnostic potential for iRPF, providing a novel basis for early detection, disease monitoring and further mechanistic investigations.