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

OBJECTIVE

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).

DESIGN

Prospective clinical cohort with repeated measures (baseline and month 3).

SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: BU (n = 14, active), AS (n = 13, disease control), and healthy controls (HC; n = 23).

METHODS, INTERVENTION, OR TESTING: 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).

MAIN OUTCOME MEASURES: 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 CD56dimCD16⁻ (exhausted-like) and reduced CD56⁻CD16bright 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.

CONCLUSIONS

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.