Abstract
IntroductionBehçet's disease (BD) is a multisystem inflammatory disorder, in which a T-helper 1 (Th1)-polarized immune response plays a major role in the pathogenic process. We evaluated the regulatory role of natural killer (NK) cells in Th1-biased immune responses in patients with BD.MethodsWe studied 47 patients with BD, including 10 with active disease (aBD) and 37 with inactive disease (iBD), and 29 healthy controls. The activation status and cytotoxic activity of NK cells were examined by flow cytometry. The levels of mRNAs for immune modulatory and cytotoxic molecules in NK cells were determined by quantitative PCR. The IL-12 signal strength in NK cells was determined by assessing the phosphorylation state of its downstream component, signal transducer and activator of transduction 4, by immunoblotting. Finally, NK cells' ability to modulate the Th1 response was evaluated by co-culturing NK cells and T cells without cell contact.ResultsCD69+-activated NK cells were significantly increased in aBD compared with iBD or control samples, although their cytotoxic activities were similar. The iBD NK cells showed downregulated IL-12 receptor β2 mRNA levels compared with aBD or control NK cells. The increased IL-13 expression was detected in a subset of BD patients: most of them had iBD. The IL-13 expression level in iBD patients was significantly higher than the level in controls, but was not statistically different compared with the level in aBD patients. The gene expression profile in iBD patients was consistent with the NK type 2 phenotype, and the shift to NK type 2 was associated with disease remission. NK cells from iBD patients showed impaired IL-12-induced signal transducer and activator of transduction 4 phosphorylation. Finally, iBD, but not control, NK cells suppressed IFNγ expression by aBD-derived CD4+ T cells in vitro.ConclusionsNK cells may control disease flare/remission in BD patients via NK type 2-mediated modulation of the Th1 response.
Highlights
Behçet's disease (BD) is a multisystem inflammatory disorder, in which a T-helper 1 (Th1)-polarized immune response plays a major role in the pathogenic process
We found that the level of IFNγ expressed by Th1 cells was reduced after their co-culture with the natural killer (NK) cells derived from inactive Behçet's disease (iBD) patients
The relative IFNγ expression level was significantly lower in the Th1 cells co-cultured with iBD patients' NK cells compared with the level in those cocultured with healthy controls' NK cells (P = 0.02). These findings suggest that the NK type 2 (NK2) cells from iBD patients can suppress the Th1 response in active Behçet's disease (aBD) patients without cognate cell-cell contact
Summary
Behçet's disease (BD) is a multisystem inflammatory disorder, in which a T-helper 1 (Th1)-polarized immune response plays a major role in the pathogenic process. We evaluated the regulatory role of natural killer (NK) cells in Th1-biased immune responses in patients with BD. Behçet's disease (BD) is a multisystem inflammatory disorder characterized by recurrent attacks of uveitis, genital ulcers, oral aphtoid lesions, and skin lesions such as erythema nodosum [1]. The etiology of BD remains unclear, but previous studies on the circulating CD4+ T cells and affected lesions of BD patients with active disease showed elevated levels of T-helper 1 (Th1) cytokines, such as IFNγ and IL-12, indicating that a Th1polarized immune response plays a major role in the pathogenic process [2,3,4].
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