Natural killer cells in human autoimmune diseases

Abstract

Natural killer (NK) cells have been implicated in tumour surveillance and in the early control of several microbial infections. In autoimmune disease their involvement in these processes has been evaluated in animal models, with conflicting results. Both a disease-controlling and a disease-promoting role have been suggested. In human autoimmune disease only a few studies, mainly descriptive, have demonstrated qualitative and quantitative modification of NK cells. These changes were observed on blood- or tissue-infiltrating NK cells. Taken together with our expanding knowledge of the genetical variability of NK cell receptors and NK cell physiology, these findings pave the way for the dissection of the role of NK cells in human autoimmune diseases. NK cells may be directly involved in these diseases through their potential autoreactivity or through their interaction with dendritic cells, macrophages or T lymphocytes, thereby inducing excessive inflammation or favouring the adaptive autoimmune response. Thus, NK cells may be implicated in the onset, the maintenance or the progression of autoimmune diseases. Some reports also suggest the involvement of NK cells in the treatment of human autoimmune disease by biotherapies. All these observations suggest that NK cells are involved in the complex processes of autoimmune diseases. Nevertheless, further careful analysis of NK cells at different steps of these diseases, in different tissues and through combined genetical and functional studies will contribute to a better understanding of their role in autoimmune diseases. This knowledge might allow the development of new therapeutic strategies based on NK cells for the treatment of some autoimmune diseases.

Figure 1

Mechanisms by which natural killer (NK) cells can induce tissue/cell injuries in autoimmune diseases. (a) NK cells can lyse target cells by natural cytotoxicity. Natural cytotoxicity is regulated by the balance of inhibitory [recognition of human leucocyte antigen (HLA) class I molecules] and activating signals. Both changes in major histocompatibility complex (MHC) class I recognition and the expression of activation ligands by the target cell can modulate NK cell cytotoxicity. For example, the expression of MHC class I polypeptide-related sequence (MIC) molecules that are ligands for the activating NKG2D receptor is induced in stressed cells in inflammatory conditions. (b) NK cells are responsible for antibody dependent cellular cytotoxicity. They can bind autoantibodies through the FcγRIIIa. (c) NK cells produce several cytokines. They can induce an inflammatory response and promote the recruitment and activation of immune cells in tissues. GM-CSF, granulocyte–macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; MIP, macrophage inflammatory protein; TNF, tumour necrosis factor.

Figure 2

Hypothesis for the protective role of natural killer (NK) cells in autoimmune diseases. NK cells may participate in the control of an autoimmune disease at different stages. First, NK cells could control the release of autoantigens, for example by modulating the control of environmental factors such as viral infections. NK cells may also control the adaptive immune response through its interaction with dendritic cells (DCs) by killing immature DCs that present autoantigens. By producing interleukin (IL)-10, NK cells can also modulate the adaptive immune response. Finally, NK cells can control the activation of macrophages that are responsible for tissue injury through chronic inflammation.

Figure 3

Hypothesis for the detrimental role of natural killer (NK) cells in autoimmune diseases. NK cells may participate in the induction, the maintenance of the autoimmune reaction and the direct cell or tissue injuries in autoimmune diseases. First, NK cell cytotoxicity can lead to abnormal exposure of autoantigens. Secondly, during the adaptive immune response they can induce the maturation of autoantigen-presenting dendritic cells (DCs) and induce the differentiation of monocytes into antigen-presenting cells in inflamed tissues such as the joints of patients with rheumatoid arthritis (RA). Finally, NK cells can directly promote cell or tissue injuries during chronic inflammation in autoimmune diseases by exerting natural cytotoxic effects against cells expressing activating ligands for natural cytotoxicity receptors (NCRs), by ADCC and indirectly through activation of macrophages. ADCC, antibody dependent cellular cytotoxicity.