Next-Generation HLA Sequence Analysis Uncovers Shared Risk Alleles Between Clinically Distinct Forms of Childhood Uveitis.

Purpose: Classical alleles of the human leukocyte antigen (HLA) complex have been linked to specific entities of pediatric noninfectious uveitis, yet genetic predisposition encoded by the HLA super-locus across the patient population remains understudied. Methods: We performed next-generation full-length sequencing of HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQB1, and HLA-DRB1 in 280 cases. Dense genotype data from 499 Dutch controls from Genome of the Netherlands were imputed using an HLA-specific reference panel (n = 5225 samples from European ancestry). Cases and controls were compared using logistic regression models adjusting for sex. Results: In total, 179 common and rare alleles were detected. Considering all cases and controls, HLA-DQB1*04:02 and HLA-DRB1*08:01 were identified as the principal HLA association, which was mainly driven by 92 cases with juvenile idiopathic arthritis-associated uveitis (JIA-U). The HLA-DQB1*04:02-HLA-DRB1*08:01 haplotype was also the primary association for the phenotypically similar idiopathic chronic anterior uveitis without arthritis (CAU). Also, HLA-DQB1*05:03 was an independent risk allele for CAU, but not in JIA-U. Analysis of 185 cases with other forms of uveitis revealed HLA-wide associations (P < 2.79 × 10-4) for HLA-DRB1*01:02, HLA-DRB1*04:03, and HLA-DQB1*05:03, which could be primarily attributed to cases with panuveitis. Finally, amino acid substitution modeling revealed that aspartic acid at position 57 that distinguishes the risk allele HLA-DQB1*05:03 (for CAU and panuveitis) from nonrisk alleles, significantly increased the binding capacity of naturally presented ligands to HLA-DQ. Conclusions: These results uncovered novel shared HLA associations among clinically distinct phenotypes of pediatric uveitis and highlight genetic predisposition affecting the antigen presentation pathway.

Whole Transcriptome Analysis Reveals Heterogeneity in B Cell Memory Populations in Patients With Juvenile Idiopathic Arthritis-Associated Uveitis.

Purpose: Patients with juvenile idiopathic arthritis (JIA) are prone to developing chronic anterior uveitis (JIA-U+). Although several risk factors for JIA-U+ have been identified, the underlying etiology is poorly understood. Histopathological studies demonstrate B cell infiltrates in eye tissues of patients with JIA-U+. Methods: We performed transcriptome profiling of peripheral blood CD19-positive B cells taken from 14 cases with JIA-U+, 13 JIA cases without uveitis (JIA-U-), and five healthy controls. Deconvolution-based estimation was used to determine the immune cell fractions for each sample. Results: Deconvolution results revealed that naive B cells made up on average 71% of the CD19-positive cell fractions analyzed. Differential expression analysis identified 614 differentially expressed genes (DEGs) between the groups at nominal significance and six genes at a false discovery rate of 5% (FDR < 0.05). Head-to-head comparison of all JIA-U- versus JIA-U+ revealed no DEGs in the CD19+ B cell pool (FDR < 0.05). However, principal component analysis based on a panel of key genes for B cell subsets revealed that JIA-U+ cases bifurcate into distinct clusters, characterized by markedly disparate expression for genes associated with specific memory B cell populations. CIBERSORT analysis of the overall transcriptome of the new uveitis cluster identified an increased proportion of memory B cells. Conclusion: These data show that JIA-U- and JIA-U+ have a globally similar transcriptome considering the global peripheral CD19-positive B cell pool. However, heterogeneity in B cell memory genes among cases with uveitis suggests a role for specific memory B cell subsets in the etiology of JIA-U+.

Predicting uveitis in juvenile idiopathic arthritis: from biomarkers to clinical practice.

INTRODUCTION: Uveitis is a sight-threatening eye inflammation and common manifestation of juvenile idiopathic arthritis (JIA). New biomarkers that can predict uveitis are needed to alleviate personalized clinical screening. In this review, we outline clinical and molecular risk factors for uveitis and discuss their putative biology and value for clinical practice. Areas covered: The recent discovery of the YST-amino acid motif in the Human Leukocyte Antigen DRB1 gene exposed a strong genetic predisposition for uveitis in females and can be used to identify low-risk cases and redefine screening policies. The established predictor 'young age at arthritis onset' appeared to only hold true for females, emphasizing the importance of sex-stratification in biomarker applications. Aqueous humor profiling studies have shown unique mediator changes. Finally, erythrocyte sedimentation rate and S100A12 levels can be used to stratify patients at high risk for uveitis. Expert commentary: Various markers have been identified and may significantly improve risk assessment for uveitis in JIA. However, there remains an unmet need to better predict uveitis in advance. Here, we propose a set of markers with high potential for prospective studies, which subsequently can be integrated to develop optimal prediction tools that complement improved screening guidelines for early disease detection and personalized care strategies.

Identification of an Amino Acid Motif in HLA-DRß1 That Distinguishes Uveitis in Patients With Juvenile Idiopathic Arthritis.

OBJECTIVE: Uveitis is a visually debilitating disorder that affects up to 30% of children with the most common forms of juvenile idiopathic arthritis (JIA). The disease mechanisms predisposing only a subgroup of children to uveitis are unknown. This study was undertaken to identify genetic susceptibility loci for uveitis in JIA, using a genome-wide association study in 522 children with JIA. METHODS: Two cohorts of JIA patients with ophthalmologic follow-up data were genotyped. Data were then imputed using a genome-wide imputation reference panel, and an HLA-specific reference panel was used for imputing amino acids and HLA types in the major histocompatibility complex (MHC). After imputation, genome-wide and MHC-specific analyses were performed, and a reverse immunology approach was utilized to model antigen presentation at 13 common HLA-DRß1 alleles. RESULTS: Presence of the amino acid serine at position 11 (serine 11) in HLA-DRß1 was associated with an increased risk of uveitis in JIA patients (odds ratio [OR] 2.60, P = 5.43 × 10-10 ) and was specific to girls (Pfemales = 7.61 × 10-10 versus Pmales = 0.18). Serine 11 resides in the YST motif in the peptide-binding groove of HLA-DRß1; all 3 amino acids in this motif are in perfect linkage disequilibrium and show identical association with disease. Quantitative prediction of binding affinity revealed that HLA-DRß1 alleles with the YST motif could be distinguished on the basis of discernable peptide-binding preferences. CONCLUSION: These findings highlight a genetically distinct, sexually dimorphic feature of JIA with uveitis as compared to JIA without uveitis. The association could be indicative of the potential involvement of antigen presentation by HLA-DRß1 in the development of uveitis in JIA. The results of this study may advance our progress toward improved treatments for, and possible prevention of, the sight-threatening complications of uveitis in children with JIA.

Impact of Uveitis on Quality of Life in Adult Patients With Juvenile Idiopathic Arthritis.

OBJECTIVE: To establish the impact of uveitis on the quality of life (QoL) in adult patients with juvenile idiopathic arthritis (JIA). METHODS: Adult patients with a history of JIA, both with (n = 31) or without (n = 51) chronic anterior uveitis, were included. Their scores on 3 validated QoL questionnaires (National Eye Institute Visual Functioning Questionnaire [NEI VFQ-25], Medical Outcomes Study 36-Item Short Form health survey [SF-36], and EuroQol 5-domain questionnaire [EQ-5D]) were analyzed to find factors that could influence QoL. RESULTS: The median overall composite score (OCS) of the NEI VFQ-25 was significantly worse in the uveitis group compared to the non-uveitis group (respectively, 83.4 [range 15.2-94.7] and 94.9 [range 46.3-100]; P < 0.001). Nearly all subscale scores were lower in patients with uveitis than in patients without uveitis (P < 0.001 for all). After adjusting for duration of arthritis, JIA subtype, arthritis onset before or after 1990, and the use of systemic immunomodulatory medication, the QoL was still worse in patients with uveitis (NEI VFQ-25 OCS regression coefficient = -11.7; P = 0.002). No significant differences were found between the groups for the SF-36 and the EQ-5D. In the total JIA group, the use of systemic medication appeared to negatively influence some general QoL scores. CONCLUSION: Having a history of uveitis has a substantial negative effect on the vision-related QoL in JIA in adulthood, despite good visual acuity. General QoL scores did not differ between uveitis and non-uveitis patients, but the use of systemic immunomodulatory treatment, independent of uveitis, did negatively influence general QoL scores in adult JIA patients.

Impact of Juvenile Idiopathic Arthritis Associated Uveitis in Early Adulthood.

BACKGROUND: Typically juvenile idiopathic arthritis (JIA)-associated uveitis (further referred as 'JIA-uveitis') has its onset in childhood, but some patients suffer its, sometimes visual threatening, complications or ongoing disease activity in adulthood. The objective of this study was to analyze uveitis activity, complications and visual prognosis in adulthood. METHODS: In this multicenter study, 67 adult patients (129 affected eyes) with JIA-uveitis were retrospectively studied for best corrected visual acuity, visual fields, uveitis activity, topical/systemic treatments, ocular complications, and ocular surgeries during their 18th, 22nd and 30th year of life. Because treatment strategies changed after the year 1990, outcomes were stratified for onset of uveitis before and after 1990. RESULTS: Sixty-two of all 67 included patients (93%) had bilateral uveitis. During their 18th life year, 4/52 patients (8%) had complete remission, 28/52 (54%) had uveitis activity and 37/51 patients (73%) were on systemic immunomodulatory treatment. Bilateral visual impairment or legal blindness occurred in 2/51 patients (4%); unilateral visual impairment or legal blindness occurred in 17/51 patients (33%) aged 18 years. The visual prognosis appeared to be slightly better for patients with uveitis onset after the year 1990 (for uveitis onset before 1990 (n = 7) four patients (58%) and for uveitis onset after 1990 (n = 44) 13 patients (30%) were either visual impaired or blind). At least one ocular surgery was performed in 10/24 patients (42%) between their 18th and 22nd year of life. CONCLUSIONS: Bilateral visual outcome in early adulthood in patients with JIA-uveitis appears to be fairly good, although one third of the patients developed one visually impaired or blind eye. However, a fair amount of the patients suffered from ongoing uveitis activity and needed ongoing treatment as well as surgical interventions. Awareness of these findings is important for ophthalmologists and rheumatologists treating patients with JIA-uveitis, as well as for the patients themselves.

Ocular Fluid Analysis in Children Reveals Interleukin-29/Interferon-λ1 as a Biomarker for Juvenile Idiopathic Arthritis-Associated Uveitis.

OBJECTIVE: Childhood uveitis is a vision-threatening inflammatory eye disease commonly attributed to juvenile idiopathic arthritis (JIA). The pathogenesis is poorly understood, which makes clinical management challenging. We analyzed soluble mediators in ocular fluid (aqueous humor [AqH]) and serum from children with JIA-associated uveitis and common childhood uveitis to identify potential biomarkers and investigate the ocular microenvironment of this sight-threatening eye disease. METHODS: AqH (n = 73) and paired serum (n = 66) samples were analyzed for 51 soluble mediators of inflammation by multiplex immunoassay. Twenty-one children with JIA-associated uveitis were compared to 15 children with chronic anterior uveitis without arthritis, 29 children with noninfectious idiopathic uveitis, and 8 children with noninflammatory conditions (controls). For visualization of the joint effect of multiple mediators, we used the radial coordinate visualization (Radviz) method. Optimal biomarker level cutoffs were also determined. RESULTS: The levels of interleukin-29 (IL-29)/interferon-λ1 (IFNλ1) were decreased (P < 0.001) and the levels of latency-associated peptide and osteoprotegerin were increased (P = 0.002 and P = 0.001, respectively) in samples of AqH, but not serum, from patients with JIA-associated uveitis. Multivariate analysis correcting for disease activity and treatment revealed that intraocular levels of IL-29/IFNλ1 were specifically decreased in patients with JIA-associated uveitis as compared to those with idiopathic uveitis. Indeed, JIA-associated uveitis patients and idiopathic uveitis patients showed distinct profiles of intraocular soluble mediators. IL-29/IFNλ1 showed a high area under the curve value (0.954), with 23.5 pg/ml as the optimal cutoff value. CONCLUSION: We identified IL-29/IFNλ1 as an intraocular biomarker for JIA-associated uveitis, which suggests that aberrant IFNλ signaling might be important in JIA-associated uveitis and distinct from other forms of childhood uveitis.