Characterization of ocular lesions in gp91phox-/- and p47phox-/- mice with ocular pathological features of human chronic granulomatous disease

Abstract

Purpose: Chronic granulomatous disease (CGD) is caused by deficiencies in any one of the 5 subunits of the NADPH oxidase complex and is characterized by recurrent life-threatening bacterial and fungal infections. Sixty-five percent of CGD cases are due to gp91phox deficiency, while 30% are due to p47phox deficiency. In a previous cross-sectional study, we found that patients with both gp91phox and p47phox-deficient CGD develop chorioretinal lesions, most of which are associated with bacterial DNA. In this study, we evaluated the ocular pathological changes in gp91phox-/- and p47phox-/- mice to characterize the pathogenesis in CGD-associated ocular lesions.

Methods: We performed fundoscopy on age (12-15 months old) and gender-matched gp91phox-/-, p47phox-/- , and WT mice. After fundoscopy, eyes were enucleated from euthanized mice for ocular histopathology and transmission electron microscopy (TEM) examination.

Results: On fundoscopy, 1 of 5 gp91phox-/- mouse showed bilateral yellow-white chorioretinal lesions and hypopigmentary retinal pigment epithelium (RPE) changes. The ocular lesions in 7 p47phox-/- mice were bilateral in 6 mice and unilateral in 1 mouse. These lesions included vitreous opacity, yellow-white chorioretinal lesions, hypopigmentary RPE changes or retinal vasculitis, at various degrees of severity. Histological examination showed bilateral inflammatory lesions in all mice with clinical disease ranging from mild to moderate choroiditis and RPE degeneration. Additionally, 4 p47phox-/- mice showed chorioretinal scars and/or marked choroiditis. Two of these 4 mice also disclosed unilateral lesions of corneal scarring/neovascularization, keratitis, iris synechiae, and retinal detachment. TEM confirmed photoreceptor atrophy and RPE degeneration in the scar area. By comparison, fundoscopy and histopathology of age-matched WT mice did not show the CGD-associated lesions seen in gp91phox-/- and p47phox-/- mice.

Conclusions: Our study shows that old gp91phox-/- and p47phox-/- mice develop ocular lesions similar those found in patients with CGD, while WT mice, even at >12 months of age, do not. Moreover, the ocular presentation was more severe in p47phox-/- than gp91phox-/- mice. Together these findings support the use of gp91phox-/- and p47phox-/- mice as models to further investigate the pathogenesis of CGD chorioretinal lesions.

Keywords: 451 chorioretinitis • 637 pathology: experimental • 746 uveitis-clinical/animal model