JOURNAL ARTICLE
REVIEW

Ocular surface inflammation mediated by innate immunity

Mayumi Ueta, Shigeru Kinoshita
Eye & Contact Lens 2010, 36 (5): 269-81
20703156
This review addresses three subjects: the innate immunity of the ocular surface epithelium, innate immunity and ocular surface inflammation, and Stevens-Johnson syndrome (SJS) and abnormality of innate immunity. In innate immunity of the ocular surface epithelium, ocular surface epithelial cells respond selectively to microbial components and induce limited inflammation, whereas immune-competent cells such as macrophages can recognize various microbial components through Toll-like receptors (TLRs) and induce inflammation to exclude the microbes. The difference between macrophages and ocular surface epithelial cells may be caused by the dissimilarity in the degree of coexistence with commensal bacteria. The unique innate immune response of ocular surface epithelium might contribute to coexistence with commensal bacteria. In innate immunity and ocular surface inflammation, we speculate that an abnormality in the proper innate immunity of the ocular surface may result in ocular surface inflammation. Our investigation shows that TLR3 positively regulates the late-phase reaction of experimental allergic conjunctivitis, which causes reduced eosinophilic conjunctival inflammation in TLR3KO (knockout) mice and pronounced eosinophilic conjunctival inflammation in TLR3Tg mice. We also demonstrate that human ocular surface epithelial cells can be induced to express many transcripts, including antiviral innate immune response-related genes and allergy-related genes, through polyI:C stimulation. Furthermore, we show that IkappaBzeta KO mice exhibit severe, spontaneous ocular surface inflammation accompanied by the eventual loss of almost all goblet cells and spontaneous perioral inflammation. IkappaBzeta is induced by diverse pathogen-associated molecular patterns and regulates nuclear factor-kappaB activity, possibly to prevent excessive inflammation in the presence of bacterial components. The spontaneous ocular surface inflammation observed in IkappaBzeta KO mice suggested that dysfunction/abnormality of innate immunity can play a role in ocular surface inflammation. In SJS and abnormality of innate immunity, we considered the possibility that there may be an association between SJS and a disordered innate immune response. In gene expression analysis of CD14 cells, we found that IL4R gene expression was different in patients with SJS/toxic epidermal necrolysis (TEN) and controls on lipopolysaccharide stimulation, being downregulated in patients with SJS/TEN and slightly upregulated in the controls. The expression of IkappaBzeta- and interleukin (IL)-1alpha-specific mRNA in patients with SJS/TEN was lower than in normal controls after 1-hour culture. Although SJS/TEN can be induced by drugs, not all individuals treated with these drugs developed SJS/TEN. Because the incidence of SJS/TEN is very low, we suspected a genetic predisposition and performed single-nucleotide polymorphism (SNP) association analysis using candidate genes associated with innate immunity, apoptosis, or allergy. We found that TLR3 SNP rs.3775296 and IL4R SNP rs.1801275 (Gln551Arg) were strongly associated (P<0.0005) with SJS/TEN with ocular surface complications, FasL rs.3830150 SNP was mildly associated (P<0.005), and IL13 rs.20541 (Arg110Gln) and IkappaBzeta SNP rs.595788G/A exhibited a weak association (P<0.05). Genetic and environmental factors may play a role in an integrated cause of SJS, and there is the possibility of an association between SJS and a disordered innate immunity.

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