Platelet-Derived Growth Factor Isoform Imbalance Is Associated with Innate Inflammation and Corneal Epitheliopathy in Dry Eye Disease.

Abstract

Introduction: Tear-deficient dry eye disease (DED), including Sjögren's syndrome and ocular graft-versus-host disease (oGVHD), is often refractory to therapy. We tested whether platelet-derived growth factor (PDGF) isoform imbalance, quantified as a PDGF-AB/BB: PDGF-AA ratio ("PDGF Ratio"), is associated with innate activation and corneal epitheliopathy.

Methods: Tear samples from 151 participants were profiled across two independent assay runs: discovery (n = 79) and replication (n = 72). Data were harmonized as within-plate rank percentiles. Plate-adjusted mediation tested whether the PDGF Ratio mediated associations between tear-deficient status and an innate NF-κB composite (IL-18/IL-6/IL-8/TNF-α) and National Eye Institute (NEI) scale graded corneal staining. A parallel model for staining included Schirmer scores to distinguish trophic from aqueous volume deficiency.

Results: The PDGF Ratio differed significantly across diagnostic groups (Kruskal-Wallis p < 0.001), driven by concurrent PDGF-AA depletion (median rank 0.69 healthy vs. 0.19 oGVHD) and PDGF-AB/BB enrichment (0.18 vs. 0.62; both p < 0.001). High ratio co-occurred with higher innate cytokine ranks and lower EGF and IFN-γ. In pooled mediation, the ratio accounted for 62.8% of the tear-deficient association with innate inflammation (indirect 0.168; 95% CI 0.118-0.225) and 34.2% of the association with corneal staining (indirect 0.117; 95% CI 0.055-0.190). The staining pathway remained significant after accounting for Schirmer (indirect 0.113; 95% CI 0.050-0.185).

Conclusion: Tear-deficient DED exhibits a reproducible PDGF isoform imbalance that statistically accounts for substantial portions of innate activation and corneal staining. These findings support the PDGF Ratio as a coherent candidate biomarker and therapeutic axis for isoform-selective rebalancing.