Research article

Gpnmb^R150X allele must be present in bone marrow derived cells to mediate DBA/2J glaucoma

Michael G Anderson^{* 1,2} , K Saidas Nair^{* 3} , Leslie A Amonoo¹ , Adrienne Mehalow³ , Colleen M Trantow¹ , Sharmila Masli⁴ and Simon WM John^3,5,6

¹Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa USA

²Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa, USA

³The Jackson Laboratory, Bar Harbor, Maine, USA

⁴Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA

⁵Howard Hughes Medical Institute, Bar Harbor, Maine, USA

⁶Tufts University School of Medicine, Boston, Massachusetts, USA

author email corresponding author email* Contributed equally

BMC Genetics 2008, 9:30doi:10.1186/1471-2156-9-30

Published:	10 April 2008

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 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 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.