By Altering Ocular Immune Privilege, Bone Marrow–derived Cells Pathogenically Contribute to DBA/2J Pigmentary Glaucoma

Abstract

Pigment dispersion syndrome causes iris pigment release and often progresses to elevated intraocular pressure and pigmentary glaucoma (PG). Because melanin pigment can have adjuvant like properties and because the Gpnmb gene, which contributes to pigment dispersion in DBA/2J (D2) mice, is expressed in dendritic cells, we tested the hypothesis that ocular immune abnormalities participate in PG phenotypes. Strikingly, we show that D2 eyes exhibit defects of the normally immunosuppressive ocular microenvironment including inability of aqueous humor to inhibit T cell activation, failure to support anterior chamber (AC)-associated immune deviation, and loss of ocular immune privilege. Histologic analysis demonstrates infiltration of inflammatory leukocytes into the AC and their accumulation within the iris, whereas clinical indications of inflammation are typically very mild to undetectable. Importantly, some of these abnormalities precede clinical indications of pigment dispersal, suggesting an early role in disease etiology. Using bone marrow chimeras, we show that lymphohematopoietic cell lineages largely dictate the progression of pigment dispersion, the ability of the eye to support induction of AC-associated immune deviation, and the integrity of the blood/ocular barrier. These results suggest previously unsuspected roles for bone marrow–derived cells and ocular immune privilege in the pathogenesis of PG.

Gpnmb Is Induced in Macrophages by IFN-γ and Lipopolysaccharide and Acts as a Feedback Regulator of Proinflammatory Responses

“…Subsequent evidence indicated that there is a bone marrow-dependent contribution to eye-associated inflammation (35,36). We confirmed that DBA/2J mice have a point mutation resulting in a premature truncated GPNMB protein (data not shown).…”

GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients

“…The source of this secreted GDF15 may be the GCL, since GCL was the only cell population in the eye to exhibit increased gene expression after ONC. We also showed increased Gdf15 expression in the retina and increased GDF15 levels in AH of DBA/2J mice, a well-characterized murine chronic glaucoma model (17)(18)(19). Based on these results, we concluded that GDF15 secreted in to the AH by GCL may be a quantifiable measure of glaucomatous neurodegeneration.…”

“…The ONC model is an acute axonal injury model, whereas the majority of human glaucoma have chronic features. Although DBA/2J mouse strain is a model of chronic glaucoma, it is considered as pigmentary glaucoma model, in which DCs are known to phagocytose pigment granules in the AS of DBA/2J mice (19). Thus, when we analyze the AH of DBA/2J mice, we have to consider confounding features, including the effect of phagocytic DCs in the AS and inflammation in this model of glaucoma.…”

“…DBA/2J mouse strain is considered to be a model of chronic, pigmentary glaucoma that is characterized by pigment liberation throughout the AS (17)(18)(19). Iris pigment dispersion and subsequent iris stromal atrophy in DBA/2J mice are caused by mutations in the Gpnmb and Tyrp1 genes, respectively (18,20).…”

Eye-Directed Overpressure Airwave-Induced Trauma Causes Lasting Damage to the Anterior and Posterior Globe: A Model for Testing Cell-Based Therapies

“…10 The DBA/2J lacks a fully functional anterior chamber-associated immune deviation, possibly explaining the greater injury response. 11 The immune response in the DBA/2J may be similar to an open-globe trauma without the additional complication of bacterial pathogens since the eye was intact.…”