The open environment of the ocular surface is continuously subject to the entry of pathogens and other foreign agents. The molecular mechanisms which provide for protection of ocular surface cells from bystander injury resulting from host responses that may be elicited by these agents are incompletely understood. Unexpectedly, it was found that corneal and conjuctival epithelia express high levels of the decay-accelerating factor (DAF or CD55), the membrane cofactor protein (MCP or CD46), and a membrane inhibitor of reactive lysis (MIRL or CD59), three surface regulatory proteins that play critical roles in protecting blood cells from autologous complement-mediated damage. Remarkably, the expression levels of the three proteins on the corneal and conjuctival surfaces are higher that those on blood cells or measured elsewhere in the body. In previous work, the investigators have shown that 1) DAF is synthesized by both ocular surface and lacrimal glandular-cells, 2) a glycoinositol phospholipid anchor-cleaved and previously underdescribed form of the protein is secreted into tears, 3) all of the C3 regulatory activity in tear fluid resides in these molecules, and 4) surface DAF molecules are shed onto contact lenses and can be depleted by certain bacteria. In this application they propose to 1) fully characterize DAF, CD59, and MCP proteins in ocular tissues structurally, functionally, metabolically, 2) develop an experimental animal model to investigate the importance of the ocular surface regulatory proteins in protecting the corneal and conjuctival surface from injury physiologically, and 3) examine ocular infections, ocular complications of contact lens wear, ocular tumors, and other clinical settings in which immune and inflammatory processes lead to ocular surface damage for abnormalities of the three proteins. The studies should provide new insights concerning the manner in which the ocular surface circumvents attack by host effector responses and could yield new information regarding pathogenic mechanisms underlying ocular diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY011288-02
Application #
2545880
Study Section
Visual Sciences A Study Section (VISA)
Project Start
1996-09-30
Project End
1999-09-29
Budget Start
1997-09-30
Budget End
1998-09-29
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Flückiger, Rudolf; Cocuzzi, Enzo; Nagaraj, Ram H et al. (2018) DAF in diabetic patients is subject to glycation/inactivation at its active site residues. Mol Immunol 93:246-252
Strainic, Michael G; Shevach, Ethan M; An, Fengqi et al. (2013) Absence of signaling into CD4? cells via C3aR and C5aR enables autoinductive TGF-?1 signaling and induction of Foxp3? regulatory T cells. Nat Immunol 14:162-71
Esposito, A; Suedekum, B; Liu, J et al. (2010) Decay accelerating factor is essential for successful corneal engraftment. Am J Transplant 10:527-34
Plevka, Pavel; Hafenstein, Susan; Harris, Katherine G et al. (2010) Interaction of decay-accelerating factor with echovirus 7. J Virol 84:12665-74
Lin, Marvin; Yin, Na; Murphy, Barbara et al. (2010) Immune cell-derived c3 is required for autoimmune diabetes induced by multiple low doses of streptozotocin. Diabetes 59:2247-52
Liu, Jinbo; Lin, Feng; Strainic, Michael G et al. (2008) IFN-gamma and IL-17 production in experimental autoimmune encephalomyelitis depends on local APC-T cell complement production. J Immunol 180:5882-9
Lalli, Peter N; Strainic, Michael G; Yang, Min et al. (2008) Locally produced C5a binds to T cell-expressed C5aR to enhance effector T-cell expansion by limiting antigen-induced apoptosis. Blood 112:1759-66
Strainic, Michael G; Liu, Jinbo; Huang, Danping et al. (2008) Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity 28:425-35
Fukuoka, Y; Strainic, M; Medof, M E (2003) Differential cytokine expression of human retinal pigment epithelial cells in response to stimulation by C5a. Clin Exp Immunol 131:248-53
Lin, Feng; Kaminski, Henry J; Conti-Fine, Bianca M et al. (2002) Markedly enhanced susceptibility to experimental autoimmune myasthenia gravis in the absence of decay-accelerating factor protection. J Clin Invest 110:1269-74

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