Common Genetic Determinants of Uveitis Shared with Other Autoimmune Disorders

Abstract

*Uveitis is a complex multifactorial autoimmune disease of the eye characterized by inflammation of the uvea and retina, degeneration of the retina, and blindness in genetically predisposed patients. Using the rat model of experimental autoimmune uveitis (EAU), we previously identified three quantitative trait loci (QTL) associated with EAU on rat chromosomes 4, 12, and 10 (Eau1, Eau2, and Eau3). The primary goal of the current study is to delineate additional non-MHC chromosomal regions that control susceptibility to EAU, and to identify any QTLs that overlap with the QTLs of other autoimmune diseases. Using a set of informative microsatellite markers and F 2 generations of resistant and susceptible MHC class II-matched rat strains (F344 and LEW), we have identified several new significant or suggestive QTLs on rat chromosomes 2, 3, 7, 10, and 19 that control susceptibility to EAU. A protective allele was identified in the susceptible LEW strain in the Eau5 locus at D7Wox18, and epistatic interactions between QTLs were found to influence the severity of disease. The newly identified regions (Eau4 through Eau9) colocalize with the genetic determinants of other autoimmune disease models, and to disease-regulating syntenic regions identified in autoimmune patients on human chromosomes 4q21-31, 5q31-33, 16q22-24, 17p11-q12, 20q11-13, and 22q12-13. Our results suggest that uveitis shares some of the pathogenic mechanisms associated with other autoimmune diseases, and lends support to the "common gene, common pathway" hypothesis for autoimmune disorders.

Direct identification of rat iNKT cells reveals remarkable similarities to human iNKT cells and a profound deficiency in LEW rats

“…Apart from F344 inbred rats, we also examined the widely used LEW inbred rat strain. The LEW strain is well known for its susceptibility to induced organ-specific autoimmunity, which is not to be found in F344 rats [24][25][26]. As shown in Figure 2F LEW rats lack the PLZF + NKR-P1A/B-intermediate T-cell population found in F344 and show no specific binding of α-GalCer-CD1d dimers ( Fig.…”

Understanding Autoimmune Uveitis through Animal Models The Friedenwald Lecture

“…16 This humanized model is now making possible the study of the retinal antigens and their fragments that are pathogenic in the context of the human MHC molecules. In parallel, the developing rat genetics and genomics permitted an increasing level of analysis of the contribution of background genes to disease susceptibility, demonstrating that many non-MHC uveitis susceptibility loci are common to other autoimmune diseases and are shared between animals and humans, 17,18 further supporting the usefulness of these models for the study of basic disease mechanisms.…”

Evaluation of the IL2/IL21, IL2RA and IL2RB genetic variants influence on the endogenous non-anterior uveitis genetic predisposition

“…This fact has suggested that these disorders may be influenced by both disease-specific and common molecular mechanisms [4]. Indeed, the autoimmune uveitis also seems to share common genetic factors with other autoimmune disorders [5]. To date, different studies have been conducted in order to identify the uveitis genetic component [6-9], although results have been inconclusive.…”