Ellen J. Lee, OD, PhD, a research assistant professor of ophthalmology at the Oregon Health and Science University in Portland, and colleagues published the results of their study of the pathogenesis of uveitis in the April 1 issue of the Journal of Immunology. The investigators used knockout mice to tease apart the receptors responsible for the induction of EAU. They began their study by focusing on the caspase-associated recruitment domain adaptor 9 (Card9) protein, which mincle uses for signaling.
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The researchers attempted to induce EAU via immunization of wild type and Card9 knockout mice with the interphotoreceptor retinoid binding protein (IRBP). They found the immunized Card9 knockout mice had a diminished proportion of CD4+ cells in the eye when compared with the wild type mice. Specifically, they noted that the lack of EAU in Card9 knockout mice correlated with a decreased ratio of IRBP-specific Th17 vs. IRBP-specific Th1 cells. They explained this finding by documenting that Card9 regulates IRBP-specific production of IL-17A.
Further investigation revealed that, in addition to differences in IRBP-specific T cells, vaccinated Card9 knockout mice had reduced Th1 and Th17 populations in their eyes relative to vaccinated wild type mice. The Card9 knockout mice did, however, have an intact peripheral-associated Th1 response. The authors proposed that this difference was the result of altered T cell trafficking mechanisms. The team concluded from these experiments that Card9 is required for the inflammatory pathway leading to EAU and that Card9 has the ability to influence the development of Th1 vs. Th17 T cell effector responses in EAU.
The researchers next turned their attention to the early/acute phase of the ocular inflammatory response. They found this phase of the response reflected the Card9 transcriptional profile in the retina. Moreover, activation of the proximal CLR mincle appeared to initiate the induction of EAU. The investigators confirmed this with mincle knockout mice, which they found to have decreased severity of EAU relative to wild type mice.