Early Dry Eye Disease Onset in a NOD.H-2^h4 Mouse Model of Sjögren's Syndrome

Abstract

Purpose To develop a mouse model of human dry eye disease (DED) for investigation of sex differences in autoimmune-associated dry eye pathology. Methods Ocular surface disease was assessed by quantifying corneal epithelial damage with lissamine green stain in the NOD.H-2 h4 ,IFNγ − / − ,CD28 − / − (NOD.H-2 h4 DKO) mouse model of Sjögren's syndrome (SS). Lacrimal gland function was assessed by tear volume quantification with phenol red thread and lacrimal gland inflammation (i.e., dacryoadenitis) was assessed by quantification of immune cell foci, flow cytometric analysis of immune cell composition, and expression of proinflammatory markers. Results The NOD.H-2 h4 DKO mouse model of SS exhibits greater age-dependent increases in corneal damage than in NOD.H-2 h4 parental mice and demonstrates an earlier disease onset in females compared to males. The severity of ocular surface disease correlates with loss of goblet cell density, increased conjunctivitis, and dacryoadenitis that is more pronounced in NOD.H-2 h4 DKO than NOD.H-2 h4 mice. B cells dominate lacrimal infiltrates in 16-week-old NOD.H-2 h4 and NOD.H-2 h4 DKO mice, but T helper cells and macrophages are also present. Lacrimal gland expression of proinflammatory genes, including the P2X7 and P2Y 2 purinergic receptors, is greater in NOD.H-2 h4 DKO than NOD.H-2 h4 mice and correlates with dacryoadenitis. Conclusions Our results demonstrate for the first time that autoimmune dry eye disease occurs in both sexes of NOD.H-2 h4 DKO and NOD.H-2 h4 mice, with earlier onset in female NOD.H-2 h4 DKO mice when compared to males of the same strain. This study demonstrates that both NOD.H-2 h4 and NOD.H-2 h4 DKO mice are novel models that closely resemble SS-related and sex-dependent DED.