Adalimumab-Induced Changes in NK Cells Phenotype, Receptors, and Functions After Clinical Remission of Behçet's Uveitis.

Abstract

To elucidate adalimumab's mechanism of action in two class-I MHC-associated diseases by characterizing NK cell phenotype and function in Behçet's uveitis (BU) and axial ankylosing spondylitis (AS). Prospective clinical cohort with repeated measures (baseline and month 3). BU (n = 14, active), AS (n = 13, disease control), and healthy controls (HC; n = 23). BU activity was assessed by slit-lamp/fundus exam, best-corrected visual acuity (BCVA), OCT, and fluorescein angiography (FFA) leakage score; AS activity by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Peripheral NK cells were profiled by flow cytometry for six CD56/CD16 subsets, checkpoint receptors (NKG2A, NKG2D, NKp46), degranulation/cytotoxic molecules (CD107a, granzyme A, perforin), and intracellular cytokines (IFN-γ, TNF-α, IL-17, IL-4, IL-10, TGF-β). Plasma cytokines/soluble cytotoxic mediators were quantified by multiplex bead-based assays. Sampling occurred during active disease and after adalimumab-induced clinical remission (month 3). Frequencies of six NK-cell subsets (CD56/CD16), surface NKG2A/NKG2D/NKp46 expression, NK degranulation/cytotoxicity (CD107a, granzyme A, perforin; ±K562 stimulation), intracellular NK cytokines (IFN-γ, TNF-α, IL-17, IL-4, IL-10, TGF-β), and plasma cytokines/soluble mediators RESULTS: Adalimumab improved BU activity (FFA leakage, BCVA, CMT) and BASDAI in AS. During activity, BU and AS showed higher NKG2D and lower NKG2A expression than controls; adalimumab increased NKG2A expression on NK cells. In BU, adalimumab shifted NK phenotype toward CD56^dimCD16⁻ (exhausted-like) and reduced CD56⁻CD16^bright cells. BU NK cells exhibited elevated IL-10/IL-17 signatures, while AS favored TNF-α/IFN-γ. Cytotoxic activity (CD107a, granzyme A) remained inducible in BU after remission. BU and AS share similar NK activation pathways. In BU, adalimumab rebalances NK activating/inhibitory receptors (increased NKG2A with persistent NKG2D), contracts cytotoxic effector cells, and shifts toward an exhausted-like phenotype in parallel with clinical improvement, supporting NK-receptor balance as a pharmacodynamic biomarker candidate.