Peripheral immune profiles separate disease activity stages in Birdshot Uveitis

Purpose

To characterize peripheral immune alterations in treated birdshot uveitis (BU) patients using high-dimensional mass cytometry and multiplex serology.

Design

Cohort study.

Subjects

36 BU patients on immunomodulatory treatment (IMT) and 31 healthy controls (HCs).

Methods

Detailed ophthalmologic examinations were performed, and peripheral blood and serum samples were collected for immune profiling using mass cytometry and multiplex cytokine analysis.

Main Outcome Measures

Imaging-based indicators of ocular inflammation; peripheral immune cell frequencies; serum cytokine levels.

Results

Compared to HCs, BU patients showed increased frequencies of Th17, CD146 ⁺ T cells, intermediate effector/central memory T cells co-expressing CXCR3 and CCR4, CD56 ^dim NK cells and elevated IL-18 levels. Patients were clinically stratified by an expert ophthalmologist into three disease activity groups: Inactive, Active (comprising combinations of surface retina, deep retina and choroid activity) and Burned-out. Inactive patients harbored more quiescent effector T cells, e.g. Tim-3 ⁺ Tc17-Tc22 intermediates and more CD8 ⁺ T _SCM , potentially representing a resting pool of autoimmune T cells. Active patients exhibited increased in vivo activation of relevant T cells, with stronger HLA-DR, CD38 or PD-1 expression, and highest levels of CD56 ^dim NK cells.

Immune profiles were also linked to treatment subgroups: csDMARDs (conventional synthetic disease-modifying antirheumatic drugs) were associated with higher CD56 ^bright NK frequencies, and absence of therapy showed elevated PD-1⁺/SLAMF7⁺ Tc17+1 and PD- 1⁺CD57⁺ CD8⁺ T _EMRA cells. IL-6R blockade (tocilizumab) resulted in loss of IL-6R⁺ T-cells accompanied by increased SLAMF7⁺ T cells, due to epitope masking.

Conclusions

Peripheral CyTOF profiling anchored to thorough clinical stratification revealed disease activity-associated immune signatures and therapy-associated imprints in BU.