Acute anterior uveitis (AAU) is the most common form of intraocular inflammatory disease and an important cause of visual impairment. Microbial triggers to the development of AAU have been strongly implicated, however the pathogenesis and molecular mechanisms for this are unclear. Toll-like receptors (TLR) and nucleotide oligomerisation domain receptors (NOD) are pattern recognition receptors (PRR) of the innate immune system that facilitate immediate recognition and immunostimulatory responses to unique molecular patterns of microbial components, including the production of chemoattractant cytokines called chemokines. The major aim of this study was to investigate the role of PRRs, namely TLRs and NODs, in the pathogenesis of human AAU. The mRNA and protein expressions of TLR4 and NOD2 in the normal human eye were determined by RT-PCR and immunohistochemistry. Resident antigen presenting cells of the normal human uvea expressed TLR4 protein. NOD2 protein expression was highly restricted to a subpopulation of retinal cells. A selective perturbation in the expression and function of TLRs were demonstrated in active human AAU by flow cytometry and in vitro stimulation with selective TLR agonists. These changes were not due to any polymorphisms in the TLR genes. Elevated plasma levels of lipopolysaccharide (LPS), an agonist for TLR4, were not detected in patients with active AAU by the limulus amebocyte lysate assay. New information regarding the complex in vivo network of cytokines in active human AAU were provided by multiplex cytokine bead immunoassay on aqueous humor samples, including a Th1-polarised pattern of aqueous humor cytokines, the intraocular expression of multiple LPS-inducible cytokines, and the aqueous humor expression of cytokines such as IL-17 in AAU. Expressions of the respective chemokine receptors on peripheral blood leukocytes were also determined. The findings of this study provides several lines of evidence to support the hypothesis that PRRs, namely TLRs and NODs, are of pathogenic importance in the development of clinical AAU. The results of this study provide significant new information regarding the role of PRRs in ocular immunity and immune privilege, their role in the pathogenesis of AAU, and it provides a molecular mechanism whereby microbial triggers could initiate the development of uveitis.
| Identifer | oai:union.ndltd.org:ADTP/187133 |
| Date | January 2006 |
| Creators | Chang, John Hyun-Min, Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. School of Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright John Hyun-Min Chang, http://unsworks.unsw.edu.au/copyright |
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