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C. Fujimoto, D.M. Klinman, B.P. Vistica, E.F. Wawrousek, C.C. Chan, I. Gery; Toll–Like Receptor (TLR) Ligands Trigger Pathogenic Ocular Autoimmunity . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1135.
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Purpose: Lymphocytes that recognize tissue–specific self–antigens are present in healthy individuals in a "resting" state. If activated, however, such cells invade the target tissue and cause pathogenic autoimmunity. Microbial infection has been considered a crucial mechanism for activation of pathogenic autoimmunity, but little is known about the actual mechanism. Here, we examined the capacity of different TLR ligands to stimulate naïve CD4 cells and convert them into inflammation–inducing effector cells in vivo. Methods: Naïve CD4 cells specific against hen egg lysozyme (HEL) were adoptively transferred into transgenic mice expressing HEL in their eyes. The tested TLR ligands were injected later, with or without HEL. The development of pathogenic autoimmunity was assessed by histological examination of the recipient eyes. The transferred cells were traced by clonotypic antibody, and their surface markers were analyzed by flow cytometry. The tested TLR ligands included CpG motif–containing oligodeoxynucleotides (ODNs) which mimic bacterial DNA (recognized via TLR9), lipopolysaccharide (LPS) which represents bacterial walls (via TLR4), and poly (I:C) which is a synthetic dsRNA and mimics viral products (via TLR3). Results: Little or no inflammation was found in the eyes of recipient mice following injection with PBS, HEL, or with any of the ligands. On the other hand, ocular inflammation characterized with iritis, vitritis and retinal vasculitis was induced when HEL was injected in combination with CpG ODNs, poly(I:C), or LPS. Flow cytometric analysis revealed that the injected cells in recipients treated with HEL and the ligands proliferated more vigorously than their controls and exhibited elevated expression of CD49d and reduced levels of CD62L, changes that facilitate invasion into non–lymphoid target tissues. Conclusions: These results suggest that certain ligands for different TLRs can stimulate antigen–specific resting CD4 cells and convert them into effector cells that induce ocular inflammation. The data provide new supporting evidence to the notion that bacterial and viral components may serve as a major co–activator of initiation of inflammatory eye disease.
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