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


CONCLUSIONS
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.
Anderson
Michael G
MG
Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa USA. michael-g-anderson@uiowa.edu
Nair
K Saidas
KS
Amonoo
Leslie A
LA
Mehalow
Adrienne
A
Trantow
Colleen M
CM
Masli
Sharmila
S
John
Simon W M
SW
D000483:Alleles; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D001082:Aqueous Humor / Q000276:immunology; D001854:Bone Marrow Cells / Q000276:immunology / Q000502:physiology*; D004198:Disease Susceptibility; D005136:Eye Proteins / Q000235:genetics*; D005838:Genotype; D005901:Glaucoma / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D020382:Interleukin-18 / Q000276:immunology; D007429:Intraocular Pressure / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009154:Mutation
D005136:Eye Proteins; C445671:Gpnmb protein, mouse; D020382:Interleukin-18; D008562:Membrane Glycoproteins