It has been demonstrated that NK cells can mediate damage to neurons, oligodendrocytes and microglia (12) yet the biological relevance of these findings has to be definedin vivo

It has been demonstrated that NK cells can mediate damage to neurons, oligodendrocytes and microglia (12) yet the biological relevance of these findings has to be definedin vivo. Contrasting the potentially detrimental effects of NK cells around the CNS, emerging evidence in MS and its animal model, experimental autoimmune encephalomyelitis (EAE), has supported the possibility of regulatory functions of NK cells during CNS inflammation (11). EAE is induced in C57BL/6 mice with myelin oligodendrocyte glycoprotein (MOG) peptide, which activates T cells and other lymphocytes in the periphery. may require collaboration between the innate and adaptive immune systems == Autoimmune diseases derive from the failure of self/non-self discrimination for the immune system. Virtually most, if not all tissues, can become targeted for autoimmune destruction. The etiology of autoimmune disease remains elusive. In addition to susceptibility genes, several immune mechanisms have been proposed to explain the emergence and progression of autoimmunity. The elements that trigger immune responses toward self components and the mechanisms that control autoimmune disease progression are a matter of debate. Investigations conducted thus far on these aspects have focused on several aspects. First, foreign invaders (including bacteria, computer virus and parasites) elicit protective immunity in the secondary lymphoid tissues where the recruitment of NK cells, monocytes, dendritic cells, together with T and B cells, can induce local inflammation. However, unabated inflammation can sometimes cause bystander damage to host tissue. Additionally, molecular mimicry (shared genetic identity between foreign and self tissues that has been demonstrated in several experimental models) can lead to the spreading of immune responses to self antigens. Second, endogenous dead cells and tissues can expose self antigens and induce autoimmunity. Third, infected cells lose self identity because of the expression of new antigens and can become targets of innate immune cells, and autoimmune disease exacerbation may associate with infectious episodes or defective immune regulation. == Effector functions of NK cells and their relevance to the adaptive inflammatory and autoimmune responses == Natural killer (NK) cells are large granular cells that constitute 510% of circulating lymphocytes in humans and 13% Bosentan in mice, thus being third in lineage among lymphocytes, after T and B cells. NK cells are dispersed throughout lymphoid and non-lymphoid tissues, and can rapidly home to target organs under pathological situations (1). An important arm of the innate immune system, the NK cells lack T and B cell receptors and undergo activation without antigen presentation from antigen presenting cells (APCs). Certain viruses, mutant cells, common -chain cytokines and interferons produced during inflammatory responses can modulate the activity of NK cells through several activating and inhibitory receptors (Fig. 1). Upon activation, NK cells exhibit two types of functions: cytotoxicity and cytokine production. NK cell-mediated natural cytotoxicity against certain microbes and several cell types seems to be controlled by levels self MHC class I expression (Fig. 1). NK cells can produce large numbers of cytokines, sometimes at high concentrations, including interferon (IFN)-, tumor necrosis factor (TNF)-, immunoregulatory cytokines such as IL-5, IL-10, IL-13, IL-22, the growth factor GM-CSF, and the chemokines MIP-1, MIP-1, IL-8, and RANTES (24). == Fig. 1. Phenotype of human NK cells. == Human NK cells can be classified functionally as cytotoxic- and cytokine producing-NK cells. Cytotoxic NK cells are CD16highCD56dim. These cells express higher levels of KIR and lower levels of NKG2A, they carry receptors for IL-2/IL-15R and c, do not have chains. In contrast, cytokine producing-NK cells are CD16dim/negCD56birght, they express lower levels of KIR and higher levels of NKG2A. In addition to IL-2/IL-15R and c, these NK cells also express IL-2 R (Fig 1). Both cytotoxic- and cytokine-producing NK cells can amplify innate immune responses by releasing inflammatory mediators and by lysing antigen presenting cells Bosentan and infected or transformed cells. Subsequently, NK cells may promote or inhibit adaptive immune responses (see details inFig. 3). NK cells play an active role in the pathogenesis of autoimmune diseases because of their cytolytic activity, cytokine production, interaction with APCs and T and B cells. == NK cells Rabbit Polyclonal to ABHD12 actively participate in sequential events that lead to autoimmune disease == The natural cytotoxicity and the swift and bursting release of cytokines equips the NK cells with the ability to affect significantly the adaptive immune response to foreign invaders and self-antigens. Moreover, NK cells are active players in the mechanisms that influence the initiation and progression of autoimmunity (Fig. 2). First, NK cells orchestra the magnitude of inflammatory responses that can induce bystander self tissue damage, as demonstrated in a viral model of type 1 diabetes (T1D) (5). Second, NK cells profoundly affect immune responses by interacting with APCs such as dendritic cells and macrophage, or by directly interacting with autoreactive T and B cells (Fig 2, and Ref6). Third, direct activation of NK cells due to reduced MHC class I molecules can associate, at least in groups of autoimmune patients, with mutations Bosentan in the genes encoding for transport association with antigen processing (TAP) (7,8). Those mutations can lead to reduced cell-surface expression of HLA class I molecules, that coupled with chronic contamination and aberrant (increased) IFN production.