Pogoda-Wesołowska Aleksandra, Sługocka Nina, Synowiec Agnieszka, Brodaczewska Klaudia, Mejer-Zahorowski Marcin, Ziękiewicz Maciej, Szypowski Wojciech, Szymański Piotr, Stępień Adam
Neurology Clinic, Military Institute of Medicine- National Research Institute, Warsaw, Poland.
Faculty of Medicine, University of Warsaw, Warsaw, Poland.
Front Mol Neurosci. 2025 Jan 10;17:1493308. doi: 10.3389/fnmol.2024.1493308. eCollection 2024.
Multiple sclerosis (MS) is a chronic central nervous system (CNS) disease with demyelinating inflammatory characteristics. It is the most common nontraumatic and disabling disease affecting young adults. The incidence and prevalence of MS have been increasing. However, its exact cause remains unclear. The main tests used to support the diagnosis are magnetic resonance imaging (MRI) examination and cerebrospinal fluid (CSF) analysis. Nonetheless, to date, no sensitive or specific marker has been identified for the detection of the disease at its initial stage. In recent years, researchers have focused on the fact that the number of natural killer cell group 2 member D (NKG2D) family of C-type lectin-like receptor + (NKG2D+) T cells in the peripheral blood, CSF, and brain tissue has been shown to be higher in patients with MS than in controls. The activating receptor belonging to the NKG2D is stimulated by specific ligands: in humans these are major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) and MHC class I polypeptide-related sequence B (MICB) proteins and UL16 binding 1-6 proteins (ULBP1-6). Under physiological conditions, the aforementioned ligands are expressed at low or undetectable levels but can be induced in response to stress factors. NKG2D ligands (NKG2DLs) are involved in epigenetic regulation of their expression. To date, studies in cell cultures, animal models, and brain tissues have revealed elevated expression of MICA/B, ULPB4, and its mouse homolog murine UL16 binding protein-like transcript (MULT1), in oligodendrocytes and astrocytes from patients with MS. Furthermore, soluble forms of NKG2DLs were elevated in the plasma and CSF of patients with MS compared to controls. In this review, we aim to describe the role of NKG2D and NKG2DLs, and their interactions in the pathogenesis of MS, as well as in other autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and celiac disease (CeD). We also assess the potential of these proteins as diagnostic markers and consider future perspectives for targeting NKG2D ligands and their pathways as therapeutic targets in MS.
多发性硬化症（MS）是一种具有脱髓鞘炎症特征的慢性中枢神经系统（CNS）疾病。它是影响年轻人的最常见的非创伤性致残疾病。MS的发病率和患病率一直在上升。然而，其确切病因仍不清楚。用于支持诊断的主要检查是磁共振成像（MRI）检查和脑脊液（CSF）分析。尽管如此，迄今为止，尚未发现用于在疾病初期检测该疾病的敏感或特异性标志物。近年来，研究人员关注到一个事实，即多发性硬化症患者外周血、脑脊液和脑组织中C型凝集素样受体+（NKG2D+）T细胞的自然杀伤细胞组2成员D（NKG2D）家族数量高于对照组。属于NKG2D的激活受体由特定配体刺激：在人类中，这些配体是主要组织相容性复合体（MHC）I类多肽相关序列A（MICA）和MHC I类多肽相关序列B（MICB）蛋白以及UL16结合蛋白1 - 6（ULBP1 - 6）。在生理条件下，上述配体以低水平或不可检测的水平表达，但可在应激因素作用下被诱导表达。NKG2D配体（NKG2DLs）参与其表达的表观遗传调控。迄今为止，细胞培养、动物模型和脑组织研究表明，MS患者的少突胶质细胞和星形胶质细胞中MICA/B、ULPB4及其小鼠同源物小鼠UL16结合蛋白样转录本（MULT1）的表达升高。此外，与对照组相比，MS患者血浆和脑脊液中NKG2DLs的可溶性形式升高。在本综述中，我们旨在描述NKG2D和NKG2DLs的作用及其在MS发病机制中的相互作用，以及在类风湿性关节炎（RA）、炎症性肠病（IBD）、系统性红斑狼疮（SLE）和乳糜泻（CeD）等其他自身免疫性疾病中的作用。我们还评估了这些蛋白质作为诊断标志物的潜力，并考虑将NKG2D配体及其途径作为MS治疗靶点的未来前景。
