GpnmbR 150Xallele must be present in bone marrow derived cells to mediate DBA/2J glaucoma

Abstract

Background: TheGpnmbgene encodes a transmembrane protein whose function(s) remain largely unknown. Here, we assess if a mutant allele ofGpnmbconfers susceptibility to glaucoma by altering immune functions. DBA/2J mice have a mutantGpnmbgene 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 theGpnmbgenotype 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 TGFβ2. 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 mutantGpnmbgene. Finally, we show that theGpnmbmediated iris disease does not require elevated IL18 or mature B or T lymphocytes.Conclusion: These results establish a role forGpnmbin bone marrow derived lineages. They suggest that affects ofGpnmbon innate immunity influence susceptibility to glaucoma in DBA/2J mice.