Abstract
Autoimmune diseases recognize a multifactorial pathogenesis, although the exact mechanism responsible for their onset remains to be fully elucidated. Over the past few years, the role of natural killer (NK) cells in shaping immune responses has been highlighted even though their involvement is profoundly linked to the subpopulation involved and to the site where such interaction takes place. The aberrant number and functionality of NK cells have been reported in several different autoimmune disorders. In the present review, we report the most recent findings regarding the involvement of NK cells in both systemic and organ-specific autoimmune diseases, including type 1 diabetes (T1D), primary biliary cholangitis (PBC), systemic sclerosis, systemic lupus erythematosus (SLE), primary Sjögren syndrome, rheumatoid arthritis, and multiple sclerosis. In T1D, innate inflammation induces NK cell activation, disrupting the Treg function. In addition, certain genetic variants identified as risk factors for T1D influenced the activation of NK cells promoting their cytotoxic activity. The role of NK cells has also been demonstrated in the pathogenesis of PBC mediating direct or indirect biliary epithelial cell destruction. NK cell frequency and number were enhanced in both the peripheral blood and the liver of patients and associated with increased NK cell cytotoxic activity and perforin expression levels. NK cells were also involved in the perpetuation of disease through autoreactive CD4 T cell activation in the presence of antigen-presenting cells. In systemic sclerosis (SSc), in addition to phenotypic abnormalities, patients presented a reduction in CD56hi NK-cells. Moreover, NK cells presented a deficient killing activity. The influence of the activating and inhibitory killer cell immunoglobulin-like receptors (KIRs) has been investigated in SSc and SLE susceptibility. Furthermore, autoantibodies to KIRs have been identified in different systemic autoimmune conditions. Because of its role in modulating the immune-mediated pathology, NK subpopulation could represent a potential marker for disease activity and target for therapeutic intervention.
Highlights
Natural killer (NK) cells are a heterogeneous population of innate lymphoid cells (ILCs)
Even though the pathogenesis of autoimmune disorders is mainly due to T and B lymphocytes, natural killer (NK) cells have been recognized to be involved in the promotion and/or maintenance of altered adaptive immune responses or in peripheral tolerance mechanisms and, for such reasons, could be therapeutically exploitable in the context of T cell-mediated autoimmune diseases [1]
It is evident that our ability to modulate NK cells for therapeutic purposes might depend on a deeper knowledge of the biology of these cells and their link with autoimmunity
Summary
Natural killer (NK) cells are a heterogeneous population of innate lymphoid cells (ILCs). The initially recognized function of NK cells was their ability to kill cancer cells of hematopoietic origin [1] They exert elevated cytotoxicity toward tumoral cells and virus-infected cells through a critical balance of signals transmitted by a wide repertoire of activating and inhibitory receptors defined as killer cell immunoglobulin(Ig)-like receptors (KIRs) (Table 1). Activating NK cell receptors, including NK group protein 2 family member D (NKG2D); natural cytotoxicity receptors (NKp30, NKp46, and NKp44); DNAX accessory molecule-1 (DNAM-1); and the co-receptors NTB-A, 2B4, NKp80, and CD59 [5], are critically involved in NK cell activities They recognize stress-induced ligands expressed on cancer cells and allow NK cells to kill them by releasing cytotoxic granules containing perforin and granzyme B or engaging death receptors tumor necrosis factor (TNF)–related apoptosisinducing ligand or Fas ligand, or through antibody-dependent cellular cytotoxicity [6]. Inhibitory signals halting the activation of NK cells and preventing cytotoxicity in case of ligand encounter are usually due to the constitutive binding of KIRs and HLA class
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