scholarly journals Role of Natural Killer Cells in Multiple Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
A. A. Maghazachi
Keyword(s):  
Multiple Sclerosis ◽  
Nk Cells ◽  
Myelin Proteins ◽  
Target Cells ◽  
Autoimmune Encephalomyelitis ◽  
Cytokines And Chemokines ◽  
Activating Receptors ◽  
Great Discovery ◽  
Adaptive Immune Systems

Although the etiology of multiple sclerosis (MS) is not known, the consensus is that Th1 cells sensitized to myelin proteins in the periphery are recruited into the CNS and damage the myelin sheath. Natural killers (NK) are cells that spontaneously lyse tumor target cells and have immunoregulatory activity secreting multiple cytokines and chemokines, as well as interacting with cells of innate and adaptive immune systems. A great discovery in the field is the cloning of several inhibitory and activating receptors. Another important contribution is the discovery that these cells express many seven-transmembrane-spanning domain receptors which aid them in extravasations into injured tissues. Despite all this progress, the role of NK cells in autoimmune diseases including MS is still not quite clear. In this paper, I will summarize recent findings related to the effects of these cells in both MS and the animal model of experimental autoimmune encephalomyelitis (EAE). Hence, I will discuss the effects of drugs used to treat MS/EAE and then explain their effects on NK cells. These include anti-CD25 or daclizumab, interferon-β (IFN-β), natalizumab, glatiramer acetate (GA), and fingolimod (FTY720). Finally, I will explain the contribution of the recently discovered NK17/NK1 cells in MS disease.

scholarly journals GSK-3α Inhibition in Drug-Resistant CML Cells Promotes Susceptibility to NK Cell-Mediated Lysis in an NKG2D- and NKp30-Dependent Manner

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1802
Author(s):  
Nayoung Kim ◽  
Mi Yeon Kim ◽  
Woo Seon Choi ◽  
Eunbi Yi ◽  
Hyo Jung Lee ◽  
...  
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Negative Regulator ◽  
Target Cells ◽  
Dependent Manner ◽  
Cell Functions ◽  
Cell Based Therapy ◽  
Activating Receptors ◽  
Gsk 3Β

Natural killer (NK) cells are innate cytotoxic lymphocytes that provide early protection against cancer. NK cell cytotoxicity against cancer cells is triggered by multiple activating receptors that recognize specific ligands expressed on target cells. We previously demonstrated that glycogen synthase kinase (GSK)-3β, but not GSK-3α, is a negative regulator of NK cell functions via diverse activating receptors, including NKG2D and NKp30. However, the role of GSK-3 isoforms in the regulation of specific ligands on target cells is poorly understood, which remains a challenge limiting GSK-3 targeting for NK cell-based therapy. Here, we demonstrate that GSK-3α rather than GSK-3β is the primary isoform restraining the expression of NKG2D ligands, particularly ULBP2/5/6, on tumor cells, thereby regulating their susceptibility to NK cells. GSK-3α also regulated the expression of the NKp30 ligand B7-H6, but not the DNAM-1 ligands PVR or nectin-2. This regulation occurred independently of BCR-ABL1 mutation that confers tyrosine kinase inhibitor (TKI) resistance. Mechanistically, an increase in PI3K/Akt signaling in concert with c-Myc was required for ligand upregulation in response to GSK-3α inhibition. Importantly, GSK-3α inhibition improved cancer surveillance by human NK cells in vivo. Collectively, our results highlight the distinct role of GSK-3 isoforms in the regulation of NK cell reactivity against target cells and suggest that GSK-3α modulation could be used to enhance tumor cell susceptibility to NK cells in an NKG2D- and NKp30-dependent manner.

scholarly journals Emerging Role of Extracellular Vesicles in the Pathophysiology of Multiple Sclerosis

2020 ◽  
Vol 21 (19) ◽  
pp. 7336
Author(s):  
Ettore Dolcetti ◽  
Antonio Bruno ◽  
Livia Guadalupi ◽  
Francesca Romana Rizzo ◽  
Alessandra Musella ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Extracellular Vesicles ◽  
Target Cells ◽  
Autoimmune Encephalomyelitis ◽  
Alternative Mode ◽  
Intensive Investigation ◽  
Neuronal Functions ◽  
Ms Pathogenesis ◽  
Experimental Autoimmune

Extracellular vesicles (EVs) represent a new reality for many physiological and pathological functions as an alternative mode of intercellular communication. This is due to their capacity to interact with distant recipient cells, usually involving delivery of the EVs contents into the target cells. Intensive investigation has targeted the role of EVs in different pathological conditions, including multiple sclerosis (MS). MS is a chronic inflammatory and neurodegenerative disease of the nervous system, one of the main causes of neurological disability in young adults. The fine interplay between the immune and nervous systems is profoundly altered in this disease, and EVs seems to have a relevant impact on MS pathogenesis. Here, we provide an overview of both clinical and preclinical studies showing that EVs released from blood–brain barrier (BBB) endothelial cells, platelets, leukocytes, myeloid cells, astrocytes, and oligodendrocytes are involved in the pathogenesis of MS and of its rodent model experimental autoimmune encephalomyelitis (EAE). Most of the information points to an impact of EVs on BBB damage, on spreading pro-inflammatory signals, and altering neuronal functions, but EVs reparative function of brain damage deserves attention. Finally, we will describe recent advances about EVs as potential therapeutic targets and tools for therapeutic intervention in MS.

scholarly journals A requirement for CD45 distinguishes Ly49D-mediated cytokine and chemokine production from killing in primary natural killer cells

2005 ◽  
Vol 201 (9) ◽  
pp. 1421-1433 ◽  
Author(s):  
Nicholas D. Huntington ◽  
Yuekang Xu ◽  
Stephen L. Nutt ◽  
David M. Tarlinton
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Intracellular Signaling ◽  
Nk Cell ◽  
Chemokine Production ◽  
Cytokines And Chemokines ◽  
Activating Receptors ◽  
Phosphoinositide 3 Kinase ◽  
Activation Motif

Engagement of receptors on the surface of natural killer (NK) cells initiates a biochemical cascade ultimately triggering cytokine production and cytotoxicity, although the interrelationship between these two outcomes is currently unclear. In this study we investigate the role of the cell surface phosphatase CD45 in NK cell development and intracellular signaling from activating receptors. Stimulation via the major histocompatibility complex I–binding receptor, Ly49D on CD45−/− primary NK cells resulted in the activation of phosphoinositide-3-kinase and normal cytotoxicity but failed to elicit a range of cytokines and chemokines. This blockage is associated with impaired phosphorylation of Syk, Vav1, JNK, and p38, which mimics data obtained using inhibitors of the src-family kinases (SFK). These data, supported by analogous findings after CD16 and NKG2D stimulation of CD45−/− primary NK cells, place CD45 upstream of SFK in NK cells after stimulation via immunoreceptor tyrosine-based activation motif-containing receptors. Thus we identify CD45 as a pivotal enzyme in eliciting a precise subset of NK cell responses.

scholarly journals Influenza A Virus Hemagglutinin and Other Pathogen Glycoprotein Interactions with NK Cell Natural Cytotoxicity Receptors NKp46, NKp44, and NKp30

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 156
Author(s):  
Jasmina M. Luczo ◽  
Sydney L. Ronzulli ◽  
Stephen M. Tompkins
Keyword(s):  
Influenza Virus ◽  
Nk Cells ◽  
Influenza A Virus ◽  
Influenza A ◽  
Nk Cell ◽  
Influenza Virus Infection ◽  
Target Cells ◽  
Natural Cytotoxicity ◽  
Activating Receptors ◽  
Natural Cytotoxicity Receptors

Natural killer (NK) cells are part of the innate immunity repertoire, and function in the recognition and destruction of tumorigenic and pathogen-infected cells. Engagement of NK cell activating receptors can lead to functional activation of NK cells, resulting in lysis of target cells. NK cell activating receptors specific for non-major histocompatibility complex ligands are NKp46, NKp44, NKp30, NKG2D, and CD16 (also known as FcγRIII). The natural cytotoxicity receptors (NCRs), NKp46, NKp44, and NKp30, have been implicated in functional activation of NK cells following influenza virus infection via binding with influenza virus hemagglutinin (HA). In this review we describe NK cell and influenza A virus biology, and the interactions of influenza A virus HA and other pathogen lectins with NK cell natural cytotoxicity receptors (NCRs). We review concepts which intersect viral immunology, traditional virology and glycobiology to provide insights into the interactions between influenza virus HA and the NCRs. Furthermore, we provide expert opinion on future directions that would provide insights into currently unanswered questions.

scholarly journals The Immune-Modulatory Role of Apolipoprotein E with Emphasis on Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

2010 ◽  
Vol 2010 ◽  
pp. 1-10 ◽  
Author(s):  
Hong-Liang Zhang ◽  
Jiang Wu ◽  
Jie Zhu
Keyword(s):  
Multiple Sclerosis ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Apolipoprotein E ◽  
T Cell Proliferation ◽  
Special Focus ◽  
Autoimmune Encephalomyelitis ◽  
Multiple Functions ◽  
Lipid Antigen ◽  
Experimental Autoimmune

Apolipoprotein E (apoE) is a 34.2 kDa glycoprotein characterized by its wide tissue distribution and multiple functions. The nonlipid-related properties of apoE include modulating inflammation and oxidation, suppressing T cell proliferation, regulating macrophage functions, and facilitating lipid antigen presentation by CD1 molecules to natural killer T (NKT) cells, and so forth. Increasing studies have revealed that APOEεallele might be associated with multiple sclerosis (MS), although evidence is still not sufficient enough. In this review, we summarized the current progress of the immunomodulatory functions of apoE, with special focus on the association of APOEεallele with the clinical features of MS and of its animal model experimental autoimmune encephalomyelitis (EAE).

N-linked oligosaccharides can protect target cells from the lysis mediated by NK cells but not by cytotoxic T lymphocytes: role of NKG2-A

1999 ◽  
Vol 54 (2) ◽  
pp. 113-121 ◽  
Author(s):  
M.-A. Sol ◽  
N. Vacaresse ◽  
J. Lule ◽  
C. Davrinche ◽  
B. Gabriel ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Nk Cells ◽  
Cytotoxic T Lymphocytes ◽  
Target Cells

scholarly journals Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Barakat Alrashdi ◽  
Bassel Dawod ◽  
Andrea Schampel ◽  
Sabine Tacke ◽  
Stefanie Kuerten ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Retinal Ganglion Cells ◽  
Axonal Degeneration ◽  
Ganglion Cells ◽  
Neuronal Degeneration ◽  
Retinal Ganglion ◽  
Autoimmune Encephalomyelitis ◽  
Aav Vector ◽  
Α Subunit

Abstract Background In multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na+/Ca2+ exchanger (NCX) at the nodes of Ranvier, associates with β-APP, a marker of neural injury. The persistent influx of sodium through Nav1.6 is believed to reverse the function of NCX, resulting in an increased influx of damaging Ca2+ ions. However, direct evidence for the role of Nav1.6 in axonal degeneration is lacking. Methods In mice floxed for Scn8a, the gene that encodes the α subunit of Nav1.6, subjected to EAE we examined the effect of eliminating Nav1.6 from retinal ganglion cells (RGC) in one eye using an AAV vector harboring Cre and GFP, while using the contralateral either injected with AAV vector harboring GFP alone or non-targeted eye as control. Results In retinas, the expression of Rbpms, a marker for retinal ganglion cells, was found to be inversely correlated to the expression of Scn8a. Furthermore, the gene expression of the pro-inflammatory cytokines Il6 (IL-6) and Ifng (IFN-γ), and of the reactive gliosis marker Gfap (GFAP) were found to be reduced in targeted retinas. Optic nerves from targeted eyes were shown to have reduced macrophage infiltration and improved axonal health. Conclusion Taken together, our results are consistent with Nav1.6 promoting inflammation and contributing to axonal degeneration following demyelination.

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