An amino acid motif in HLA-DRß1 distinguishes patients with uveitis in juvenile idiopathic arthritis

A.J.W. Haasnoot; M.W. Schilham; S.S.M. Kamphuis; P.C.E. Hissink Muller; A. Heiligenhaus; D. Foell; R.A. Ophoff; T.R.D.J. Radstake; A.I. Den Hollander; T.H.C.M. Reinards; S. Hiddingh; N. Schalij-Delfos; E.P.A.H. Hoppenreijs; M.A.J. van Rossum; C. Wouters; R.K. Saurenmann; N. Wulffraat; R. ten Cate; J.H. de Boer; S.L. Pulit; J.J.W. Kuiper

In-depth data on sex-specific epidemiology of uveitis associated with JIA are sparse, however, the typical bilateral chronic anterior uveitis has been reported to occur more frequently in females. 37, 47 This genotype-by-sex interaction informs an exciting field of future research that aims to elucidate how the uveitis risk mechanisms underlying the HLA-DRB1 signal may be mediated by sex-specific factors, such as hormone regulation. Further, the sex-specific pattern of genetic association may help to resolve previously reported evidence of sexual dimorphism with respect to severity or disease course in children with JIA-associated uveitis. 48 Lastly, the finding indicates that sex stratification may be beneficial for future clinical trials, as some therapeutic agents may be more efficacious in females or males only. 49, 50 HLA-DRβ1, like other MHC class II molecules, is essential to immunity and orchestrates downstream immune responses by presenting a dynamic cargo of thousands of different peptides for scrutiny by T helper cells. 51 Both JIA and uveitis are considered diseases mediated by T helper cell subsets. 4 The strong association of an amino acid motif (tagged by serine-11) in HLA-DRB1 suggests that predetermined peptide preferences may affect the regulation of T helper cells. To investigate the immunological impact of the motif in HLA-DRB1, we used a "reverse immunology" approach 38 (Materials and Methods), performed using data from proteins experimentally observed in human iris. 52 Since JIA-uveitis patients frequently have circulating ANAs directed to iris tissues, we specifically focused on nuclear proteins to provide a disease-relevant dataset for modelling. Although the large panel of putative antigens that we tested was by no means exhaustive (Supplementary Table 4) , the experiment demonstrated that the presence of a serine-11 motif in HLA-DRB1 is accompanied by distinguished changes in binding affinity in the resulting protein (Supplementary Table 5, Supplementary Figures 7) , suggesting that antigen presentation by the HLA-DRβ1 protein may underpin the uveitis susceptibility. Risk alleles of HLA-DRB1 that encode serine-11 (e.g. HLA-DRB1*11, Supplementary Table 2) may communicate distinct 'peptidomes' that influence T helper cells and significantly increase the likelihood of downstream immune responses (e.g., ANA) to the eye. Further, ANA-positivity is modestly correlated with presence of serine-11 in the cases studied here (Pearson's r= 0.26, P = 4.9 ✕ 10 -4 ). Functional studies using HLA-proteomic approaches will be necessary to experimentally validate and systematically dissect the complex downstream effects of serine-11 on tissue-specific antigen presentation by HLA-DRβ1 in uveitis.