Fas ligand (FasL) is produced as a membrane-bound and soluble protein and both forms are expressed within the immune privileged eye. In our previous studies we used an ocular tumor model to demonstrate that the different forms of FasL regulate innate immunity in the eye: (i) membrane FasL (mFasL) induces inflammation and terminates immune privilege, while (ii) soluble FasL (sFasL) prevents inflammation and maintains immune privilege. Therefore, given that FasL is constitutively expressed within the eye, and the membrane form of FasL is pro-inflammatory, we propose that in a normal eye either: (i) the pro-inflammatory function of mFasL is blocked, and/or (ii) FasL is expressed primarily in the soluble (anti-inflammatory) form. Our experimental data support the latter. Western blot analysis of FasL was performed on normal, FasL knockout, and chronically inflamed eyes. A high ratio of soluble (27 kDa) to membrane (38 kDa) FasL (10:1) was detected in normal eyes. Three additional bands (28-31 kDa) of modified sFasL were detected that were completely absent in the eyes of FasL knockout mice. The modified sFasL was unique to the eye and not found in other immune privileged sites, such as the testis. ? Finally, the 27kD and 31kD sFasL bands were completely absent from eyes that lacked immune privilege and displayed chronic inflammation secondary to pigment dispersion syndrome. ? ? We hypothesize that modified sFasL is expressed within the eye and plays a central role in ? maintaining immune privilege. This hypothesis will be tested in three Specific Aims (i) determine where sFasL is expressed in the eye and how it is modified, (ii) determine how modified sFasL stimulates innate immunity, and (iii) determine if modified sFasL controls immune privilege. We believe this study will advance not only our understanding of immune privilege, but help explain the controversy over the physiological role of FasL in transplants and tumors. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY016145-03
Application #
7171789
Study Section
Special Emphasis Panel (ZRG1-AED (01))
Program Officer
Shen, Grace L
Project Start
2004-12-01
Project End
2009-11-30
Budget Start
2006-12-01
Budget End
2007-11-30
Support Year
3
Fiscal Year
2007
Total Cost
$380,644
Indirect Cost
Name
Schepens Eye Research Institute
Department
Type
DUNS #
073826000
City
Boston
State
MA
Country
United States
Zip Code
02114
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Wu, Jian; Du, Yiqin; Watkins, Simon C et al. (2012) The engineering of organized human corneal tissue through the spatial guidance of corneal stromal stem cells. Biomaterials 33:1343-52
Gregory, Meredith S; Hackett, Caroline G; Abernathy, Emma F et al. (2011) Opposing roles for membrane bound and soluble Fas ligand in glaucoma-associated retinal ganglion cell death. PLoS One 6:e17659
Whiston, Emily A; Sugi, Norito; Kamradt, Merideth C et al. (2008) alphaB-crystallin protects retinal tissue during Staphylococcus aureus-induced endophthalmitis. Infect Immun 76:1781-90
Gregory, Meredith S; Saff, Rebecca R; Marshak-Rothstein, Ann et al. (2007) Control of ocular tumor growth and metastatic spread by soluble and membrane Fas ligand. Cancer Res 67:11951-8