Innate Immunity of the Ocular Surface and Ocular Surface Inflammatory Disorders

Abstract

Ocular surface epithelial cells selectively respond to microbial components and induce limited inflammation, whereas immune competent cells such as macrophages can recognize various microbial components through Toll-like receptors (TLRs), induce inflammation, and, thereby, exclude microbes. The difference between macrophages and ocular surface epithelial cells could be due to their dissimilarity in coexistence with commensal bacteria. The unique innate immune response of the ocular surface epithelium might contribute to its coexistence with commensal bacteria. Moreover, we suspect that some ocular surface inflammatory disorders might be caused by abnormality of the mucosal innate immunity. We considered the possibility that there is an association between Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)--a severe variant of SJS--and a disordered innate immune response. In gene expression analysis of CD14 cells, we found that interleukin-4 receptor (IL-4R) gene expression was different between patients with SJS/TEN and normal control subjects upon lipopolysaccharide (LPS) stimulation: it was downregulated in the former and slightly upregulated in the latter. Furthermore, expression of mRNA specific for IkappaBzeta and interleukin (IL)-1alpha was lower in patients with SJS/TEN than in normal controls after 1-hour culture. We next performed single nucleotide polymorphism (SNP) association analysis of IL-4R, IkappaBzeta, and IL1alpha genes and TLR2 and TLR3--genes associated with innate immunity--in 80 Japanese patients with SJS/TEN and 160 Japanese healthy volunteers. IL4R SNP Gln551Arg (rs.1801275) (P = 0.0004), TLR3 rs.3775296T/G SNP (P = 0.0001) and TLR3 rs.3775290A/G SNP (P = 0.009) showed a significant association with SJS/TEN. IkappaBzeta SNP rs.595788G/A showed a weak inverse association (P = 0.04). Genetic and environmental factors may play a role in an integrated etiology of SJS/TEN, and there is possibly an association between SJS/TEN and a disordered innate immunity.