Natural killer cells protect white matter integrity in bipolar disorder.

BACKGROUND

Bipolar Disorder (BD) associates with disrupted white matter (WM) microstructure and functional connectivity, and with a perturbation of the immune system. Higher cytokines, and reduced T cells, correlated with WM disruption and fMRI responses. A core component of the innate immune system, natural killer (NK) cells were detected in brain parenchyma, but never studied in BD.

METHODS

We studied Diffusion Tensor Imaging (DTI) measures of water diffusion, fMRI corticolimbic functional response and connectivity, and multi-parameter cytofluorometry analysis of NK (CD56) subpopulations, in 30 inpatients with active Bipolar Disorder type I. NK cells were also obtained in 36 healthy controls.

RESULTS

Patients had significantly higher circulating counts of CD56GMCSF, CD56INFγ, and CD56IL17. NK cell levels positively associated to fractional anisotropy (FA) measures. CD56TNFα, CD56INFγ, and CD56GMCSF directly correlated with FA, and inversely with radial (RD) and mean (MD) diffusivity. Duration of lithium treatment associated with higher CD56TNFα, CD56IL2, and CD56IL4, and positively associated with FA in tracts were NKs had significant effects. A mediation model suggested a partial mediation of CD56TNFα cells, higher in patients on lithium, on the effects of lithium on FA. Frequencies of the same cytokine-producing NK cells also influenced fMRI cortico-limbic functional connectivity during processing of both, emotional and non-emotional stimuli.

DISCUSSION

Higher circulating cytokine-producing NK cells associated with lithium treatment, and with DTI measures of WM integrity, partially mediating the effect of lithium on WM. The same cells associated with fMRI responses and connectivity, thus suggesting an effect on structural and functional connectomics in BD.