The Role of NKG2D and Its Ligands in Autoimmune Diseases: New Targets for Immunotherapy

Abstract

Natural killer (NK) cells and CD8+ T cells can clear infected and transformed cells and generate tolerance to themselves, which also prevents autoimmune diseases. Natural killer group 2 member D (NKG2D) is an important activating immune receptor that is expressed on NK cells, CD8+ T cells, γδ T cells, and a very small percentage of CD4+ T cells. In contrast, the NKG2D ligand (NKG2D-L) is generally not expressed on normal cells but is overexpressed under stress. Thus, the inappropriate expression of NKG2D-L leads to the activation of self-reactive effector cells, which can trigger or exacerbate autoimmunity. In this review, we discuss the role of NKG2D and NKG2D-L in systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), type I diabetes (T1DM), inflammatory bowel disease (IBD), and celiac disease (CeD). The data suggest that NKG2D and NKG2D-L play a pathogenic role in some autoimmune diseases. Therefore, the development of strategies to block the interaction of NKG2D and NKG2D-L may have therapeutic effects in some autoimmune diseases.

Functional MICA Variants Are Differentially Associated with Immune-Mediated Inflammatory Diseases

“…This finding implies MICA plays an essential part in the onset of autoimmune inflammatory illnesses. Additionally, a growing list of evidence indicates that NKG2D-positive CD4+ T cells and NK cells contribute to the pathogenesis of SLE and RA through interactions with MICA and sMICA/B [ 14 ]. Accordingly, NKG2D and NKG2D-L are important therapeutic targets in the treatment of autoimmune disorders by blocking the interaction between NKG2D of immune cells and MICA on non-immune cells.…”

Immunotherapy in the context of sepsis-induced immunological dysregulation

“…Although immunotherapy was initially and most extensively applied in the field of oncology, as research has revealed that virtually all diseases have some form of direct or indirect relation with the immune system, the scope of immunotherapy has extended beyond cancer treatment. It now encompasses therapies aimed at inducing, enhancing, or suppressing the patient’s own immune response to treat a wide array of diseases related to immune molecules, immune cells, and the immune system itself, including infectious diseases (such as sepsis) ( 26 ), autoimmune diseases (such as systemic lupus erythematosus) ( 27 , 28 ), and diseases related to immunosenescence and inflammaging (such as atherosclerosis, Alzheimer’s disease, and diabetes) ( 29 – 32 ). It is commonly accepted that the core pathophysiological mechanism of sepsis involves a dysregulated immune response characterized by acute-phase hyperinflammation followed by late-phase immune suppression, triggered by pathogens.…”