Title

GpnmbR150X allele must be present in bone marrow derived cells to mediate DBA/2J glaucoma.

Document Type

Article

Publication Date

2008

Keywords

Animals, Antigen-Presenting-Cells, Aqueous-Humor, Bone-Marrow-Cells, Disease-Susceptibility, Eye-Proteins, Genotype, Glaucoma, Interleukin-18, Intraocular-Pressure, Membrane-Glycoproteins, Mice-Congenic, Mice-Inbred-C57BL, Mice-Inbred-DBA, Mutation

JAX Source

BMC Genet 2008; 9:30.

Abstract

BACKGROUND: The Gpnmb gene encodes a transmembrane protein whose function(s) remain largely unknown. Here, we assess if a mutant allele of Gpnmb confers susceptibility to glaucoma by altering immune functions. DBA/2J mice have a mutant Gpnmb gene and they develop a form of glaucoma preceded by a pigment dispersing iris disease and abnormalities of the immunosuppressive ocular microenvironment. RESULTS: We find that the Gpnmb genotype of bone-marrow derived cell lineages significantly influences the iris disease and the elevation of intraocular pressure. GPNMB localizes to multiple cell types, including pigment producing cells, bone marrow derived F4/80 positive antigen-presenting cells (APCs) of the iris and dendritic cells. We show that APCs of DBA/2J mice fail to induce antigen induced immune deviation (a form of tolerance) when treated with TGFbeta2. This demonstrates that some of the immune abnormalities previously identified in DBA/2J mice result from intrinsic defects in APCs. However, the tested APC defects are not dependent on a mutant Gpnmb gene. Finally, we show that the Gpnmb mediated iris disease does not require elevated IL18 or mature B or T lymphocytes. CONCLUSION: These results establish a role for Gpnmb in bone marrow derived lineages. They suggest that affects of Gpnmb on innate immunity influence susceptibility to glaucoma in DBA/2J mice.