Uveitis is an intraocular inflammatory disorder mediated by a wide range of causes, including exogenous and endogenous agents. This condition is considered a major source of visual impairment being the fourth cause of blindness worldwide [1, 2]. Endogenous uveitis is an inflammatory response mediated by immune system driven for a loss of tolerance against ocular antigens .
A shared genetic component among different autoimmune diseases is well established. This fact has suggested that these disorders may be influenced by both disease-specific and common molecular mechanisms . Indeed, the autoimmune uveitis also seems to share common genetic factors with other autoimmune disorders . To date, different studies have been conducted in order to identify the uveitis genetic component [6–9], although results have been inconclusive. It is important to note that the majority of studies on uveitis susceptibility have been focused on anterior uveitis and few studies have been carried out to determine the non-anterior uveitis genetic background.
Interleukin 2 (IL-2) was initially identified as an autocrine product from activated T cells, although later was found that IL-2 plays a crucial role in the maintenance of immune system homeostasis and self-tolerance . The main non-redundant function of this cytokine seems to be the regulation of peripheral tolerance by supporting the survival and function of regulatory T cells. In fact, mice deficient in IL-2, IL-2Rα, and IL-2Rβ exhibit autoimmunity [11, 12]. In uveitis condition, IL-2 induces the expansion of Th17 cells, which were found to be elevated in uveitis patients . Moreover, Daclizumab therapy, a monoclonal antibody against alpha subunit of the IL-2 receptor, reduces the active uveitis inflammation .
On the other hand, interleukin 21 (IL-21) is a potent immunomodulatory cytokine with pleiotropic effects on both innate and adaptive immune responses. IL-21 is produced mainly by CD4+ T cells and promotes the effector CD8+ T cells and NK cells function and expansion. In addition, it is also critical for B-cell differentiation into plasma cells and negatively regulates the function of dendritic cells . Recently, it has been suggested that the dendritic cells maduration seems play a role in the pathogenesis of endogenous uveitis . Furthermore, IL-21 seems to be involved in the Behçet’s disease (BD)  as well as in the Vogt-Koyanagi-Harada (VKH) syndrome pathogenesis , both disorders strongly characterized by the presence of uveitis condition, probably by promoting IL-17 secretion.
Different studies with animal models have clearly supported the involvement of IL-21 as well as IL2/IL2R pathway as potential drivers of autoimmunity [19–24]. Additionally, genetic associations between different polymorphisms located within the IL2/IL21 region as well as within both IL2RA and IL2RB loci and several autoimmune diseases have also been reported [25–34].
Regarding the IL2RA gene, different independent signals on this gene were identified by fine mapping of the region, and their minor alleles were related to inherited lower circulating levels of the soluble IL-2RA protein, [25–27, 29]. IL-2RA is expressed constitutively on regulatory T cells, a population of T cells that has been shown to have a potent ability to suppress autoreactive T cells .
Taking into account all of the above, we herein aimed to investigate whether the previously most associated polymorphisms with different autoimmune disorders located in the IL2/IL21, IL2RA and IL2RB loci are involved in the genetic predisposition to autoimmune uveitis. For this purpose, we studied three SNPs located within the IL2/IL21 region (rs907715, located within the IL21 gene and most associated SNP with SLE in a recent fine mapping, rs2069762 situated within the IL2 gene and rs6822844 positioned in the IL2/IL21 inter-genic region), three functional independent Single Nucleotide Polymorphisms (SNPs) related with lower circulating levels of the soluble IL-2RA (rs11594656, rs2104286 and rs12722495) and one SNP in the IL2RB locus (rs743777), all of them previously associated to multiple autoimmune conditions through genome-wide association studies [28, 30–34].