This project was initiated in FY 2006, as a component of project EY000069-29. In FY 2007 the study focused mainly on the expression in the eye of two families of molecules, complement components and DAP-12/TREM-2. ? ? Studies of recent years revealed the important role played by complement in eye diseases such as age-related macular degeneration, or diabetic retinopathy. Complement deposition was noted in damaged tissues of these chronic diseases and to learn about the deposition process we analyzed mouse eyes affected by various damaging processes. Using immunofluorescent methods we identified complement accumulation in damaged tissues of eyes with experimental autoimmune uveitis (EAU), or local expression of interleukin (IL)-1 or IL-7. On the other hand, no complement was observed in eyes damaged by exposure to light. Surprisingly, we also found complement deposition on apparently un-damaged corneal tissues and lens capsule in eyes affected by inflammation, suggesting that the inflammatory environment renders healthy tissues to become more accessible to complement deposition.? ? To further learn about the role of complement in ocular inflammation, we compared wild type (WT) mice with mice deficient in their C3, a key component of complement, for their susceptibility to development of inflammatory processes induced by various procedures. The procedures included (i) induction of experimental autoimmune uveitis (EAU), by immunization of mice with a retinal antigen (IRBP); (ii) induction of intraocular inflammation by injection of interleukin (IL)-1 and (iii) selective damage to retinal pigment epithelium by injection of sodium iodate. In all these experimental systems, no differences could be detected between C3-- mice and their C3 controls, thus indicating that complement plays a minor role, if any, in the pathogenic processes.? ? DAP-12 is a transmembrane-anchored signaling adapter that conveys activating properties to surface receptors on various myeloid cells. One of DAP12 receptors is TREM-2, a molecule we found previously to be increased in inflamed eyes (FY 2006, project EY000069-29). A deficiency of functional DAP12 in human results in a syndrome named Nasu-Hakola Disease. We examined the involvement of DAP12 in immune-mediated ocular inflammation. DAP12 could not be detected by immunostaining in normal mouse eye, but was expressed by a portion of inflammatory cells that infiltrate eyes with experimental autoimmune uveitis (EAU), induced by immunization with IRBP, or by local transgenic expression of IL-1 or IL-7. The biological function(s) of DAP12 in ocular inflammation was further investigated by comparing DAP12 deficient mice and their wild type controls for certain immunological capacities. When immunized with IRBP, DAP12 deficient mice developed more severe EAU than did DAP12 controls. Moreover, draining lymph nodes from the DAP12 deficient mice secreted remarkably higher levels of all tested cytokines, IL-1, IL-4, IL-5, IL-6, IL-17, IFN-gamma and TNF-alpha than did DAP12 mice. These data thus show that DAP12 exerts anti-inflammatory activity in the system tested here.
| Tan, Cuiyan; Wandu, Wambui S; Lee, R Steven et al. (2017) Shedding New Light on the Process of ""Licensing"" for Pathogenicity by Th Lymphocytes. J Immunol 198:681-690 |
| Montalvo, Vanessa; Gery, Igal (2009) Constitutive pro-apoptotic molecules are differentially expressed in the fetal and adult mouse eye. Curr Eye Res 34:328-32 |
| Montalvo, Vanessa; Campos, Maria M; Chan, Chi-Chao et al. (2007) Complement deposits on ocular tissues adjacent to sites of inflammation. Curr Eye Res 32:917-22 |
