Abstract / Summary
Abstract Background Drug-induced immune-mediated retinal vasculopathy and choroiditis (DIRVAC) is a rare complication following pegcetacoplan injection. Histopathology of two previously reported enucleated eyes with DIRVAC suggests a delayed hypersensitivity response, but the pathologic mechanism remains elusive. FS-7-associated cell surface antigen (Fas) and Fas ligand (FasL) binding causes apoptosis, yet studies of Fas/FasL in ocular inflammation are limited. This study evaluated Fas and FasL immunohistochemical expression in the retina, choroid, and optic nerve of an eye with DIRVAC and compared these patterns to eyes with exogenous endophthalmitis and non-inflamed controls. Methods In this retrospective clinical-pathologic study, subjects were one enucleated eye with DIRVAC, one eviscerated eye with acute exogenous endophthalmitis, one with chronic exogenous endophthalmitis, and two control autopsy eyes. Multiplex double immunohistochemical stains for Fas and FasL were performed on paraffin-embedded sections and correlated with histopathology. Staining intensity and distribution in posterior segment tissues were the main outcomes, and results were compared with Fas and FasL mRNA and protein expression in public databases. Results Compared with controls, in exogenous endophthalmitis Fas expression increased in the retina and RPE adjacent to Fas/FasL-positive inflammatory infiltrates and ischemic damage. The DIRVAC eye showed a distinct pattern: absence of retinal inflammatory infiltrate, prominent choroidal Fas/FasL-rich inflammation, and upregulation of Fas in the retina and optic nerve head, with an inflammatory infiltrate surrounding partially thrombosed vessels at the optic disc. FasL expression in study-eye posterior segment tissues resembled controls. Low-level Fas in the neurosensory retina was concordant with databases, whereas broad FasL protein staining in the control eye substantially exceeded the low FasL transcription reported in databases. Conclusions Upregulation of Fas in inflamed eyes may reflect heightened tissue vulnerability to cell death or a localized strategy to contain inflammation at the expense of affected tissue. In DIRVAC, immune infiltration of the optic disc and juxtapapillary retina may activate the Fas/FasL pathway, contributing to retinal vascular endothelial apoptosis, vascular occlusion, and inflammatory containment. These findings support a role for the Fas-FasL system in ocular immune privilege and warrant further investigation.