Identification EXOSC4 as a novel autoantigen of interstitial lung disease in rheumatoid arthritis.

BACKGROUND

Interstitial lung disease (ILD) is a common and severe comorbidity of rheumatoid arthritis (RA), yet reliable diagnostic biomarkers remain lacking. Alveolar type II (ATII) cells are widely recognized to play a key role in the pathogenesis of ILD. This study first aimed to screen and validate potential autoantigens involved in RA-ILD using ATII cells.

METHODS

Sera from multiple patient groups were subjected to immunoprecipitation with ATII cells and analyzed for candidate autoantigens related to RA-ILD through proteomic methods. Antibody concentrations in the sera were subsequently measured using protein chips and ELISA. Expression levels of target antigens in the lung tissues of collagen-induced arthritis-bleomycin (CIA-BLM) mice were evaluated via immunohistochemistry, while their expression in ATII-BLM cells was assessed using indirect immunofluorescence. The diagnostic value of these antibodies was further examined by ROC curve analysis. Preliminary studies also explored the cellular mechanisms involved.

RESULTS

We identified exosome component 4 (EXOSC4) as a potential autoantigen in RA-ILD, with significantly higher levels of EXOSC4 antibodies found in the sera of RA-ILD patients. Moreover, EXOSC4 expression was elevated in the lung tissues of CIA-BLM mice and in ATII-BLM cells. Clinical assessments showed that the area under the curve (AUC) for EXOSC4 antibody in diagnosing RA-ILD was 0.809, increasing to 0.890 (95% CI:0.812–0.967) when combined with other clinical indicators. Notably, EXOSC4, Wnt 3a, and β-catenin expression were significantly upregulated in ATII-BLM cells as compared to ATII cells. Additionally, we found a significant interaction between naïve CD4 + T cells and ATII cells within the Wnt/β-catenin signaling pathway, suggesting a possible mechanistic role of EXOSC4 in RA-ILD pathogenesis.

CONCLUSION

We identified EXOSC4 as a novel autoantigen associated with RA-ILD, which may assist in its clinical diagnosis.