Abstract
BackgroundThe molecular mechanisms causing pigment dispersion syndrome (PDS) and the pathway(s) by which it progresses to pigmentary glaucoma are not known. Mutations in two melanosomal protein genes (Tyrp1 b and Gpnmb R150X ) are responsible for pigment dispersing iris disease, which progresses to intraocular pressure (IOP) elevation and subsequent glaucoma in DBA/2J mice. Melanosomal defects along with ocular immune abnormalities play a role in the propagation of pigment dispersion and progression to IOP elevation. Here, we tested the role of specific immune components in the progression of the iris disease and high IOP.ResultsWe tested the role of NK cells in disease etiology by genetically modifying the B6.D2-Gpnmb R150X Tyrp1 b strain, which develops the same iris disease as DBA/2J mice. Our findings demonstrate that neither diminishing NK mediated cytotoxic activity (Prf1 mutation) nor NK cell depletion (Il2rg mutation) has any influence on the severity or timing of Gpnmb R150X Tyrp1 b mediated iris disease. Since DBA/2J mice are deficient in CD94, an important immune modulator that often acts as an immune suppressor, we generated DBA/2J mice sufficient in CD94. Sufficiency of CD94 failed to alter either the iris disease or the subsequent IOP elevation. Additionally CD94 status had no detected effect on glaucomatous optic nerve damage.ConclusionOur previous data implicate immune components in the manifestation of pigment dispersion and/or IOP elevation in DBA/2J mice. The current study eliminates important immune components, specifically NK cells and CD94 deficiency, as critical in the progression of iris disease and glaucoma. This narrows the field of possible immune components responsible for disease progression.
Highlights
The molecular mechanisms causing pigment dispersion syndrome (PDS) and the pathway(s) by which it progresses to pigmentary glaucoma are not known
Because NK cells are an important component of the innate immune system, we assessed if altered NK cell activity participates in the propagation of Tyrp1b GpnmbR150X driven iris disease
Since many immune mutations are available on the C57BL/6J strain background, this strain is valuable for determining the roles of specific immune processes in the pigment dispersing iris disease
Summary
The molecular mechanisms causing pigment dispersion syndrome (PDS) and the pathway(s) by which it progresses to pigmentary glaucoma are not known. Mutations in two melanosomal protein genes (Tyrp1b and GpnmbR150X) are responsible for pigment dispersing iris disease, which progresses to intraocular pressure (IOP) elevation and subsequent glaucoma in DBA/2J mice. The dispersed pigment accumulates within the ocular drainage structures, resulting in IOP elevation and glaucoma in some but not all individuals with PDS [4,5,6,7,8]. DBA/2J (D2) mice provide a model of inherited glaucoma They develop a pigmentary form of glaucoma characterized by a pigment-dispersing iris disease, increased IOP, and optic nerve degeneration [9,10,11,12]. The Gpnmb mutation induces prominent pigment dispersion (PD) with a radial slit-like pattern of transillumination defects and atrophy of the iris pigment epithelium, all of which are hallmarks of human PDS [14]
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