Researchers have identified a potential association between Epstein–Barr virus and pediatric autoimmune uveitis, particularly among patients carrying the HLA-DRB1*15:01 genetic risk allele.
Using high-density peptide microarrays, researchers from the University Medical Center Utrecht profiled intraocular and serum antibody responses to 196 pathogens in children with noninfectious uveitis and matched controls. Their study revealed that elevated antibodies targeting a specific epitope of Epstein-Barr virus nuclear antigen 1 (EBNA-1) were significantly enriched in the aqueous humor of affected children.
The research involved 18 pediatric patients who were diagnosed with autoimmune uveitis (noninfectious, based on SUN criteria) and 6 age-matched pediatric controls without ocular inflammation. All patients underwent extensive diagnostic workups, including PCR and serological testing for herpesviruses, rubella, and toxoplasmosis.
Using the PEPperCHIP Infectious Disease Epitope Microarray, which includes 3760 linear B-cell epitopes from 196 human pathogens, the team analyzed immunoglobulin G (IgG) antibodies in paired aqueous humor (AqH) and serum samples. In total, 3697 peptides passed quality filtering for analysis.
IgG antibodies against enteroviruses (eg, polio, coxsackievirus) were common in both patients and controls, likely due to routine vaccinations. Strong intraocular IgG binding was detected against multiple Epstein-Barr virus (EBV)-derived peptides. A specific peptide motif within EBNA-1, designated RRPFFHPV (amino acids 402-409), was significantly elevated in the aqueous humor of uveitis patients compared with controls (Padj = .048). The difference was not significant in serum however (Padj = 1), which suggested “a persistent IgG response against a specific EBNA1 epitope after EBV infection is implicated in the pathogenesis of noninfectious uveitis,” wrote lead author Jytte Hendrikse, with colleagues.
Among 12 genotyped uveitis patients, 6 carried the HLA-DRB1*15:01 allele. These HLA-DRB1*15:01–positive patients showed significantly higher intraocular and serum IgG responses to the EBNA-1 RRPFFHPV motif (Padj = .00007 in AqH and Padj = .00015 in serum), as well as intermediate or panuveitis and optic nerve involvement (eg, papillitis or papilledema).
The EBNA-1 RRPFFHPV motif overlaps with epitopes that were previously implicated in multiple sclerosis (MS)—another HLA-DRB1*15:01–associated autoimmune disorder. Inflammatory involvement of the optic nerve in the form of optic neuritis is also a notable MS symptom, the authors described. Further, the RRPFFHPV motif shares similarity with the autoantigen alpha-crystallin B (CRYAB), which is expressed in the retina, lens, and retinal pigment epithelium, and has been associated with both MS and uveitis in previous literature.
The authors added, “Given the clinical and genetic relationship between (specifically intermediate) uveitis and MS, the intraocular elevation of antibodies against this epitope is significant and may provide an explanation for the longstanding association between MS and uveitis.”
Supplementation has been shown in other studies to reduce anti-EBNA-1 antibody levels, particularly in young HLA-DRB1*15:01–positive patients. For example, observational studies have linked low vitamin D with increased uveitis activity. Although no licensed vaccine exists yet, 2 EBV vaccine candidates (Moderna and NIH) are currently in early-phase clinical trials. Prophylactic vaccination targeting EBNA-1 could potentially mitigate risk of autoimmune responses in genetically susceptible patients.
The study was limited by modest sample size due to the rarity of pediatric uveitis and limited access to aqueous humor samples. Microarray also focused only on linear B-cell epitopes, so cross-reactivity to autoantigens such as CRYAB was inferred but not directly tested. The authors suggested that follow-up studies should use phage display and recombinant peptide assays to further explore molecular mimicry and immune cross-reactivity.
The study provides evidence that a specific antibody response to the EBNA-1 RRPFFHPV motif is elevated in the eyes of children with autoimmune uveitis and is strongly associated with HLA-DRB1*15:01. These findings align with mechanisms that have been proposed in other autoimmune diseases such as MS and suggest a potential viral trigger that contributes to pediatric uveitis pathogenesis.
The authors declared no conflicts of interest.
Source: The Lancet