As the main finding of our study, the IL2RA (rs2104286) gene polymorphism was shown to confer susceptibility to intermediate uveitis risk, with the G allele having a protective effect. This recapitulates what has been shown in MS and other autoimmune-mediated diseases.
3,4,16,17,28 Together these findings suggest that the IL2RA/CD25 locus may act as a general susceptibility region for autoimmune diseases. The rs2104286 polymorphism has recently been associated with a lower expression of CD25 on CD4
+ naïve T cells and on CD14
+CD16
+ monocytes.
28 Because CD25-positive naïve CD4
+ T cells expressing the high affinity IL-2 receptor can simultaneously be activated by IL-2 and engagement of the T cell receptor, the reduction of CD25 expression by the protective phenotype of the rs2104286 allele may reduce the likelihood of naïve CD4
+ T cells being activated under proinflammatory conditions. The notion that the polymorphism at rs2104286 confers susceptibility to intermediate uveitis risk is further supported by the fact that in individuals carrying the protective G allele even on T cell activation, a lower proportion of CD69
+CD4
+ naïve T cells upregulate CD25 when compared with fully susceptible donors.
28 This is concordant with the fact that in active intermediate uveitis an increased frequency of CD69
+CD4
+ T cells is seen and that CD69
+ expression of CD4
+ T cells parallels disease activity in intermediate uveitis.
29 Thus our findings that the IL2RA (rs2104286) polymorphism is associated with intermediate uveitis risk, is biologically plausible.
Aside from its expression on T cells, IL2RA is also seen on other immune cells including matured dendritic cells (DC). Dentritic cell surface expression of IL2RA, depending on the overall phenotype, has been correlated with enhanced T cell stimulatory capacity.
30 Thus one might speculate that a genotype related reduction of IL2RA might thereby affect T cell proliferation, but this still remains to be determined.
Soluble IL2RA serum levels have been demonstrated to be elevated in MS as well as in intermediate uveitis.
31 –33 In healthy individuals 18% of the variance of soluble IL2RA levels is due to the rs2104286 polymorphism compared to 5% in MS patients.
31 Therefore under inflammatory conditions other factors like proteolytic cleavage at the cell surface become more relevant for soluble IL2RA levels. Rs2104286 does not reside in a protein-coding sequence, so the genetic variant might not affect the cleavage. Matrix metalloproteinases have been demonstrated to exert proteolytic cleavage of IL2R.
33 Because these enzymes are elevated in patients with uveitis,
34 they might account for heightened serum levels of soluble IL2RA.
We found about one third of patients with intermediate uveitis carrying the protective G allele. This illustrates that intermediate uveitis as well as MS are multifactorial diseases, which are not caused by a defect in a single gene. Rather, polymorphic variants that also occur in the normal population contribute to the risk of the disease. Thus, the identified polymorphism explains only a small proportion of the variance in the risk to develop intermediate uveitis.
Interestingly, we did not find any significant differences in the genotype distributions of investigated gene polymorphisms between patients with HLA-B27–associated uveitis and control subjects. This may indicate variances in the immune mechanisms leading either to intermediate uveitis or HLA-B27–associated uveitis. It may further indicate possible parallel pathways between intermediate uveitis and multiple sclerosis and could possibly explain the predominance of intermediate uveitis among MS patients, whereas unilateral AAU is rarely seen. Immunopathogenetic similarities may also explain the different responses to therapeutic regimens. For instance, interferon beta (IFN-β), one of the mainstay drugs in MS, is also very effective in intermediate uveitis.
35 This is in contrast to spondylarthropathies, which are most likely associated with acute anterior HLA-B27–associated uveitis. In these patients IFN-β therapy has been shown to lead to an exacerbation of the disease.
36,37
The following potential limitations should be kept in mind, when interpreting our results. First, only a small number of SNPs were investigated in the present study. For example, sequencing of the IL2RA gene may reveal further associations of other IL2RA gene variants and intermediate uveitis risk. Second, as prevalence of genetic polymorphisms has been shown to vary between populations of different ethnic origin, our findings do not necessarily apply to populations other than Caucasian.
In conclusion, our data suggest an association between the rs2104286 polymorphism and intermediate uveitis risk.
The authors thank Eveline Elschatti and Helga Spitzenberger for their skillful technical assistance.