(215) Neutrophil Activation Signature Associated with Pulmonary Fibrosis in Hermansky–Pudlak Syndrome Type 1

Introduction/Rationale: Hermansky–Pudlak Syndrome type 1 (HPS-1) is a rare lysosomal disorder in which all patients develop progressive pulmonary fibrosis. Neutrophils are increasingly recognized as drivers of epithelial injury and aberrant repair, but the systemic inflammatory signatures that distinguish fibrotic from non-fibrotic HPS remain unclear. We quantified plasma immune mediators to derive pathway-based neutrophil activation and fibrosis remodeling scores, aiming to determine whether circulating profiles reflect HPS disease phenotype and clinical severity.

Methods: Plasma from HPS-Fibrotic (HPS-F), HPS-Nonfibrotic (HPS-NF), Nonfibrotic Lung Disease (NFLD), and Healthy Controls (HC) was analyzed using NULISAseq™. A Neutrophil Activation Score (NAS-10) with 10 markers and a Fibrosis Remodeling Score with 8 markers for epithelial injury and profibrotic injury was computed. Group comparisons used nonparametric testing; clinical associations were assessed using Spearman correlations.

Results: NAS-10 was significantly higher in HPS-F compared with HPS-NF (p = 0.034) and HC (p = 0.034), indicating increased neutrophil activation in fibrotic disease. The Fibrosis Score was also significantly elevated in HPS-F relative to HC (p < 0.0001). Both indices were associated with pulmonary function, showing inverse correlations with FVC% (Fibrosis Score: r = –0.74, p = 0.046; NAS-10: r = –0.72, p = 0.037). In addition, NAS-10 correlated positively with the Fibrosis Score (r = 0.80, p = 0.014), linking neutrophil-driven inflammation with fibrotic remodeling in HPS-associated lung disease.

Conclusion: High-dimensional immune profiling enables the development of composite scores that discriminate fibrotic from non-fibrotic HPS and show strong associations with pulmonary function decline. Together, these findings support the use of immune signatures as tools for disease monitoring and for guiding therapeutic studies in HPS-associated pulmonary fibrosis.