Background/Purpose: Autoimmune uveitis is a chronic inflammatory disorder of the eye that often requires lifelong immunosuppression as uveitis relapse occurs in 85% of patients who discontinue medications. However, the pathogenesis of chronic, relapsing eye inflammation is poorly understood. To determine the local mediators of chronic uveitis, we assessed the intraocular cytokine and immune cell profiles within the aqueous humor (AQH) of patient with autoimmune uveitis.

Methods: We obtained AQH samples from adult and pediatric patients with uveitis or non-inflammatory conditions undergoing eye surgery at Boston Children’s Hospital, Massachusetts Eye Research & Surgery Institution and Cincinnati Children’s Hospital Medical Center. We also collected clinical information such as slit-lamp examinations and medications at the time of surgery. Cytokine content of the AQH was assessed through the Olink proximity extension multiplex immunoassay and samples were assigned an Inflammatory Score based on the sum of normalized cytokine values. AQH samples were pooled for 10x single-cell RNA sequencing then de-multiplexed using SNP profiles determined by low-pass whole genome sequencing.

Results: We evaluated AQH samples from controls (n=16) and patients with autoimmune uveitis (n=29). At the time of sample collection, all patients had near-quiet disease activity on slit-lamp examination with anterior chamber cell grades between 0 and 0.5+ by SUN criteria. Non-inflammatory control patients displayed low cytokine levels in their AQH, while 41% of patients with uveitis had elevated inflammatory cytokines (positive Inflammatory Score). Strikingly, >85% of children displayed
a positive Inflammatory Score compared to 28% of adults. Single-cell RNA sequencing of 37 control and uveitis samples revealed distinct immune cell populations associated with patient age and clinical disease activity. Namely, monocyte populations were detected in adult samples while none were detected in pediatric samples. This was supported by proteomic data which showed an association with adult uveitis and myeloid-related inflammatory cytokines. There was no correlation between monocytes and Inflammatory Score. In contrast, the Inflammatory Score correlated with increased CD8⁺ T cell populations, specifically resident memory T cells (TRM), and decreased CD4⁺ T cell populations. Proteomic analysis confirmed a direct correlation between IL-15, which supports CD8+ T cells and TRM survival, and the Inflammatory Score.

Conclusion: Subclinical immune activity is common within the AQH of uveitis patients with clinically inactive disease, an observation that is particularly striking in children. Subclinical activity correlated with an increased TRM cells, known mediators of relapsing autoimmune inflammation, providing a possible pathogenic mechanism to chronic, relapsing ocular inflammation. Further, the intraocular immune profile differed between children and adults, highlighting distinctions between pediatric and adult uveitis that may warrant different considerations in therapeutic approaches.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/age-and-activity-dependent-differences-in-intraocular-immune-profile-of-chronic-autoimmune-uveitis/