Pathogenesis of Non-Infectious Uveitis Elucidated by Recent Genetic Findings

Abstract

Uveitis is a generic term for inflammation of the uvea, which includes the iris, ciliary body, and choroid. Prevalence of underlying non-infectious uveitis varies by race and region and is a major cause of legal blindness in developed countries. Although the etiology remains unclear, the involvement of both genetic and environmental factors is considered important for the onset of many forms of non-infectious uveitis. Major histocompatibility complex (MHC) genes, which play a major role in human immune response, have been reported to be strongly associated as genetic risk factors in several forms of non-infectious uveitis. Behçet's disease, acute anterior uveitis (AAU), and chorioretinopathy are strongly correlated with MHC class I-specific alleles. Moreover, sarcoidosis and Vogt-Koyanagi-Harada (VKH) disease are associated with MHC class II-specific alleles. These correlations can help immunogenetically classify the immune pathway involved in each form of non-infectious uveitis. Genetic studies, including recent genome-wide association studies, have identified several susceptibility genes apart from those in the MHC region. These genetic findings help define the common or specific pathogenesis of ocular inflammatory diseases by comparing the susceptibility genes of each form of non-infectious uveitis. Interestingly, genome-wide association of the interleukin (IL)23R region has been identified in many of the major forms of non-infectious uveitis, such as Behçet's disease, ocular sarcoidosis, VKH disease, and AAU. The interleukin-23 (IL-23) receptor, encoded by IL23R, is expressed on the cell surface of Th17 cells. IL-23 is involved in the homeostasis of Th17 cells and the production of IL-17, which is an inflammatory cytokine, indicating that a Th17 immune response is a common key in the pathogenesis of non-infectious uveitis. Based on the findings from the immunogenetics of non-infectious uveitis, a personalized treatment approach based on the patient's genetic make-up is expected.

Keywords: Behcet’s disease; GWAS - genome-wide association study; Vogt-Koyanagi-Harada disease; acute anterior uveitis; birdshot chorioretinopathy; immunogenetics; ocular sarcoidosis; uveitis.

Figure 1

Pathogenesis of non-infectious non-infectious uveitis elucidated by immunogenetic findings. Susceptibility genes of Behçet’s disease (red boxes), sarcoidosis (green boxes), Vogt-Koyanagi-Harada disease (purple boxes), acute anterior uveitis (yellow boxes), birdshot chorioretinopathy (orange boxes), and tubulointerstitial nephritis and uveitis syndrome (light blue boxes) are indicated in the figure. The direction on gene expression or function of risk alleles are described with arrows, where identified. APC, antigen presenting cell; CTL, cytotoxic T cell; NK, natural killer cell; Treg, regulatory T cell.