NK cells and psoriasis

Abstract

Psoriasis is a chronic condition of the skin characterised by distinctive scaly plaques. The immune system is now thought to play a major role in the development and pathogenesis of psoriasis with immune cells and cytokines influencing keratinocyte function. Keratinocytes in turn, can activate and recruit immune cells leading to a positive feedback loop in disease. Natural Killer (NK) cells are lymphocytes that are best known for killing virally infected and cancer cells. However, evidence is emerging to support a role for NK cells in psoriasis. NK cells are found in the inflammatory infiltrate in psoriatic skin lesions. They can produce a range of inflammatory cytokines, many of which are important in the pathogenesis of psoriasis. Recent genetic studies have identified a range of potential molecules relating to NK cell biology that are known to be important in psoriasis. This paper will discuss the evidence, both cellular and genetic, for NK cell involvement in psoriasis.

Figure 1

NK cells can interact with keratinocytes through a range of cell surface receptors. NK cells express cell surface receptors that regulate their interactions with other cell types including keratinocytes. Among these receptors is the NKG2A/CD94 inhibitory receptor that recognises and binds to HLA-E on target cells. NK cells also express a number of activating receptors including NKG2D which recognises MICA/B stress antigen and the Fas receptor which can activate cytokine secretion by NK cells. The activating KIR receptor 2DS1 (and its inhibitory counterpart, 2DL1) binds the HLA-Cw6 molecule and HLA-Cw6 is the strongest genetic association known in psoriasis. There is evidence in the literature to suggest that these receptors play a role in psoriasis. Activated NK cells are triggered to release their cytotoxic granule contents which contain perforin and granzymes.

Figure 2

Subsets of NK cells secrete distinct cytokine profiles. Conventional NK cells, consisting of CD56^bright and CD56^dim subsets, are found in the general blood circulation. They are responsive to cytokines, with IL-2, IL-12, IL-15, and IL-18 being viewed as most important. These cytokines, some of which may act alone while others are only effective in as part of a milieu, activate effector functions such as secretion of cytokines including IFN-γ and TNF-α and degranulation of cytotoxic granules. In contrast, NK22 cells are a recently described subset of NK cells that are primarily resident in mucosal sites within the body. They differentiate towards the NK22 phenotype in response to IL-23 stimulation. NK22 cells secrete IL-22 cytokine (but not IL-17). IL-22 is known to be pathogenic in psoriasis.