Natural killer (NK) cells in bipolar disorders

Abstract

Neuroinflammation and peripheral immune dysregulations, affecting both innate and adaptive immune responses, have repeatedly been demonstrated in bipolar disorder (BD). Given the increased susceptibility to infections, the chronic inflammation and autoimmune processes, abnormalities affecting the natural killer (NK) cells compartment are likely to play an important role in the pathophysiology of BD. We here address this question by describing current knowledge regarding phenotypic and functional characteristics of NK cells in BD in the context of well-established environmental risk factors as well as crosstalk between NK cells and other immune cells. Patients with BD show a permanent activation of NK cells along with a specific expansion of a cell subset, called "adaptive NK cells", usually associated with several viral infections. We thus discuss the putative role of non-resolved infectious events in BD, possibly arising from suboptimal, genetically determined, anti-infectious responses or from yet to be identified other pathophysiological processes. The observed deregulation of NK cells in patients with BD may contribute to impaired immune functions, heightened inflammation, neuro-immune damage as well as cognitive decline and resistance to treatment, thus stressing the need of a deeper analysis of these immune cells in BD.

Keywords: Bipolar disorder; Infections; Inflammation; Natural killer cells.

Fig. 1

Characteristics of peripheral blood NK cells. Panel A: NK cells express several cell surface receptors that can be grouped into activating (blue), and inhibitory (red) receptors. The list of cell surface molecules involved in the regulation of NK cell function is not exhaustive. Panel B: The dynamic regulation of NK cell effector function. NK cells sense the density of activating and inhibitory receptors and their respective ligands. The integration of these distinct signals dictates the quality and the intensity of the NK cell responses. NK cells spare healthy cells that express self-MHC class I molecules and low amounts of stress-induced self-molecules, whereas they selectively kill target cells “in distress” that down-regulate MHC class I molecules and/or up-regulate stress-induced molecules. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Characteristics of peripheral blood NK cells in BD and their potential role in the CNS (central nervous system) parenchyma. Panel A: In BD, peripheral blood NK cells overexpress markers of cell-activation (CD69 and HLA-DR), and inhibitory receptors (red). In contrast, most of the activating receptors (blue) are down-modulated, excepted NKG2C that recognized HLA-E. Consequently, NK cells are cytotoxic (perforin/granzyme capacities) but exhibited a lack of efficient IFN-γ production. Panel B: Although NK cells could be recruited in the CNS in response to several neurological disorders, there is no data about the phenotype/function of CNS NK cells in BD. Some first evidence suggest that NK cells could interact with astrocytes and microglia to control neuro-inflammation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)