Editing Natural killer cell

[[File:Natural killer cell.png|thumb|Natural killer cells are a type of white blood cell.]]
'''Natural killer (NK) cells''' are a type of [[Leucocyte|white blood cell]] that forms part of the [[innate immune system]]. Their function involves the recognition and destruction of tumor and virally infected cells.<ref name="MaleD2007" /> Numerous studies have found evidence of reduced natural killer cell function in patients with [[ME/CFS|myalgic encephalomyelitis/chronic fatigue syndrome]] (ME/CFS).<ref name="Barker1994" /><ref name="WhitesideTL1998" /><ref name="BrenuEW2014" /><ref name="FletcherMA2002" /><ref name="BrenuEW2012" /> 

==Function==
[[File:Nk cell.jpg|thumb|Natural Killer cells]]
The majority of [[lymphocyte]]s, a [[leucocyte]] subgroup, are [[B cell|B]] or [[T cell]]s but approximately 15% of the lymphocyte population lack B or T cell receptors; these are NK cells.<ref name="MaleD2007" /> The latter develop in the [[bone marrow]] and have a half-life of approximately 7 days.<ref name="SompayracL2008" /> Most NK cells are found in the [[blood]], [[spleen]] or [[liver]] and enter tissues at sites of [[inflammation]] following [[infection]]. There are two NK cell subgroups dependent on the expression of either [[CD16]] (FcγRIII) or [[CD56]] [[cell surface receptors]].<ref name="Robson2014" />

NK cells play a major role in eliminating virally infected cells. Following infection, [[Virus|viruses]] block cell synthesis of [[major histocompatibility complex]] class I (MHCI) molecules.<ref name="MaleD2007" /> Presentation of MHC class I molecules at an infected cell’s surface is used by [[Cytotoxicity|cytotoxic]] T cells (Tc cells) to target and destroy the cell. By preventing MHC class I presentation, viruses ensure the cell is unrecognised and escapes elimination by Tc cells: this is where NK cells prove vitally important in the body’s immune response.<ref name="MaleD2007" /> NK cells express specialized receptors – [[killer inhibitory receptors]] (KIRs) – which can identify MHC class I molecules. Following recognition of the MHC class I molecule, the KIR inhibits NK cell cytotoxic activity and destruction of the target.<ref name="MaleD2007" /> Virally infected cells, lacking the surface expression of MHC class I molecules, can be targeted and eliminated by NK cells.

NK cells can also target virally infected cells via expression of the [[IgG]] receptor CD16. This receptor binds antibodies attached to viral molecules on infected cell surfaces in a process called [[antibody-dependent cell mediated cytotoxicity]] (ADCC).<ref name="MaleD2007" />

'''NK Cell Cytotoxic Mechanisms'''    

NK cells can terminate an infected cell via several mechanisms including: 

*Direct cell-to-cell contact

*Cytokine synthesis and release<ref name="MaleD2007" />

As [[Large Granular Lymphocytes]] (LGLs), NK cells utilize their granular structure to kill infected cells. On fusing with virally infected cells’ [[plasma membranes]], granules release their contents into the cell<ref name="MaleD2007" />. These contents include the [[protein]] [[perforin]], which perforates the infected cell's membrane, enabling entry of specialized ‘suicide’ [[Enzyme|enzymes]], including [[granzyme B]], into the virally infected cell; these initiate apoptosis (programmed cell death).<ref name="MaleD2007" /><ref name="SompayracL2008" /> Granzymes can also damage the infected cell directly and play a vital role in virally infected cell destruction. Apoptosis can also be triggered via the attachment of [[Fas ligands]] (FasL) on the NK cell surface to Fas proteins on the target cell, activating apoptosis-inducing signalling.<ref name="SompayracL2008" />

NK cells express two receptor types:

*Activating

*Inhibitory

[[Activating receptors]] induce NK cells to eliminate infected cells, while [[inhibitory receptors]] block killing mechanisms<ref name="SompayracL2008" />. Resting NK cells synthesize [[Cytokine|cytokines]] and are capable of destroying virally infected cells but activated NK cells produce higher numbers of cytokines and are more efficient at eliminating infected cells<ref name="SompayracL2008" />. 

'''Factors Leading to NK cell Activation'''

Several elements can produce NK cell activation, including:

*The detection of [[Lipopolysaccharides|lipopolysaccharide]] (LPS, a bacterial cell wall constituent)

*The release of various cytokines, e.g. [[Interferon alpha|IFN-α]] and [[Interferon beta|IFN-β]], when cells are infected with viruses

LPS is bound by NK cell surface receptors, inducing responses including IFN-γ synthesis, which can prepare [[Macrophage|macrophages]] for activation. Following activation, macrophages synthesize TNF ([[Tumor necrosis factor|tumour necrosis factor]]), which binds a macrophage’s own surface receptors<ref name="SompayracL2008" />. This initiates [[interleukin 12|IL-12]] (interleukin-12) activation. The combination of TNF and IL-12 expression induces increased NK cell synthesis of [[Interferon gamma|IFN-γ]] leading to more macrophage priming, an example of an enhanced immune response via a positive feedback loop<ref name="SompayracL2008" />. TNF synthesis by macrophages also upregulates [[interleukin 2|IL-2]] expression on NK cell surfaces, NK cells respond to their own IL-2 synthesis and undergo rapid division<ref name="SompayracL2008" />.

==In human disease==

===ME/CFS ===
Numerous studies of [[myalgic encephalomyelitis]] and [[chronic fatigue syndrome]] have found evidence of reduced natural killer cell function.<ref name="Barker1994" /><ref name="WhitesideTL1998" /><ref name="BrenuEW2014" /><ref name="FletcherMA2002" /><ref name="BrenuEW2012" /> Some studies have showed natural killer cell function correlates with illness severity.<ref name="OjoAmaize1994" /> One study found increased differentiation in NK cells.<ref name="HuthTK2016" /> Inconsistency in laboratory preparation and analysis have made it difficult to compare results between laboratories or use NK function as a consistent [[Diagnostic biomarker|biomarker]].{{citation needed}}

In 2015, [[David Strayer]], et al., published "Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity," in the ''Journal of Clinical & Cellular Immunology.'' The study reviewed previous studies that concluded that the more decreased the natural killer cell [[cytotoxicity]] was in patients, the greater the severity of the disease. The study also reported that ''in vitro'' exposure of peripheral blood mononuclear cells from CFS patients (who fulfilled both the [[Centers for Disease Control and Prevention|CDC]] 1988 and 1994 case definitions) to [[Ampligen]] increased natural killer cell cytotoxicity 100-178%. The conclusion of the study was that low NK cell cytotoxicity is commonly seen in CFS and was associated with increased symptom severity.<ref name="strayer2015" />

==== Causes ====
The following mechanisms have some degree of evidence that they cause NK dysfunction in ME:

* '''Altered MAPK signaling'''.<ref name="Chacko, 2016" /><ref name=":0" />
* '''Calcium channel dysfunction'''.<ref>{{Cite journal|title=Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of myalgic encephalomyelitis/chronic fatigue syndrome patients|date=2022-02-16|url=https://doi.org/10.1186/s12967-022-03297-8|journal=Journal of Translational Medicine|volume=20|issue=1|pages=94|last=Eaton-Fitch|first=Natalie|last2=Du Preez|first2=Stanley|last3=Cabanas|first3=Hélène|last4=Muraki|first4=Katsuhiko|last5=Staines|first5=Donald|last6=Marshall-Gradisnik|first6=Sonya|doi=10.1186/s12967-022-03297-8|pmc=PMC8848670|pmid=35172836|issn=1479-5876}}</ref>
* '''MicroRNAs'''. Transfecting primary NK cells with microRNAs that were upregulated in ME, resulted in gene expression changes consistent with NK cell activation but diminished cytotoxicity.<ref name="PettyD2016" />

==== Relevance ====
It's currently unknown what the consequences are of NK dysfunction in ME, and how significant they are. One potential consequences is impaired clearance of pathogens.

===Multiple sclerosis===
In 2009 a team led by Dr Hugh Brady from the Department of Life Sciences at Imperial College London, identified a master gene [[E4bp4]] which causes blood [[stem cells]] to turn into disease-fighting 'Natural Killer' [[autoimmune cells]]. Using a mouse model scientists successfully 'knocked out' the gene known as E4bp4, creating the world's first animal model entirely lacking 'Natural Killer' cells, leaving all other blood cells and immune cells intact. This breakthrough model should help solve the mystery of the role that Natural Killer cells play in autoimmune diseases, such as [[diabetes]] and [[multiple sclerosis]]. This could now lead to new ways of treating these conditions with a drugs which will react with the protein expressed by their E4bp4 gene.<ref name="E4bp4Press">{{Cite web | title = Master gene that switches on disease-fighting cells identified by scientists - Press release | date = September 15, 2009 | website = Imperial College London | url =https://www.imperial.ac.uk/news/73201/master-gene-that-switches-disease-fighting-cells/|access-date=Sep 14, 2022}}</ref><ref name="GascoyneD2009" />

== Brain and spinal cord injury ==
Low NK function is associated with pathologies and experimental models of [[neural strain]].{{Citation needed|reason= | date = 7 July 2020}}, including [[spinal cord injury]].{{Citation needed|reason= | date = 7 July 2020}}
== Modulating NK function ==

=== Probiotics ===

Some [[probiotics]] have been shown to increase NK function, including ''[[Lactobacillus rhamnosus]]'' HN001,<ref name="GillHS2001" /> ''[[Bifidobacterium lactis]]'' HN019<ref name="GillHS2001" /><ref name="ChiangBL2000" /> and ''[[Lactobacillus casei]]'' Shirota<ref name="TakagiA2001" /><ref name="TakedaK2006" /><ref name="MorimotoK2005" />

=== AHCC ===

In animal models, [[Active Hexose Correlated Compound]] (AHCC) has been show to increase NK activity.<ref name="RitzBW2006" /> A randomized, controlled trial of healthy volunteers found no significant effect of AHCC on NK function.<ref name="TerakawaN2008" />

=== Stress ===

There is evidence in humans and animal models that psychological stress<ref name="GlaserR1986" /><ref name="SieberW1992" /> and physical stress, for example surgery,<ref name="PollockRE1991" /><ref name="Pollock1984" /> decreases NK function and promotes tumor development and metastasis.<ref name="Pollock1984" /> Mindfulness based meditation or stress reduction may increase natural killer cell function.<ref name="linda2008" />

=== Smoking ===
Smoking decreases natural killer cell function.<ref name="MorimotoK2005" />

===Ampligen===
In 2015, David Strayer, et al., published a study that ''in vitro'' exposure of peripheral blood mononuclear cells from CFS patients (fulfilling both the CDC 1988 and 1994 case definitions) to [[Ampligen]] increased Natural Killer cell cytotoxicity 100-178%.<ref name="strayer2015" />

===Nutritional deficiencies===
[[Vitamin B12]] deficiency may be associated with decreased natural killer cell activity.<ref name="tamura1999" />

==Notable studies==

*1987, Phenotypic and functional deficiency of natural killer cells in patients with [[chronic fatigue syndrome]] [https://www.ncbi.nlm.nih.gov/pubmed/2824604 (Abstract)]
*2003, Predictive immunophenotypes: Disease-related profile in chronic fatigue syndrome [http://onlinelibrary.wiley.com/doi/10.1002/cyto.b.10034/full (Full Text)]
*2015, Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity [https://www.omicsonline.org/open-access/low-nk-cell-activity-in-chronic-fatigue-syndrome-cfs-and-relationship-to-symptom-severity-2155-9899-1000348.php?aid=59415 (Full Text)]
*May 2015 - [http://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-015-0101-4 Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)], ''BMC Immunology'', 2015 16:35
*May 2015 - [https://journals.sagepub.com/doi/full/10.4137/III.S25147 Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients]<ref>{{Cite journal | last = Marshall-Gradisnik | first = Sonya M. | authorlink = Sonya Marshall-Gradisnik | last2 = Smith | first2 = Peter | authorlink2 = Peter Smith | last3 = Brenu | first3 = Ekua W. | authorlink3 = Ekua Brenu | last4 = Nilius | first4=Bernd | authorlink4 = Bernd Nilius | last5 = Ramos | first5 = Sandra B. | authorlink5 = Sandra Ramos | last6 = Staines | first6 = Donald R. | date = 2015-01-01 | title = Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients|url=https://doi.org/10.4137/III.S25147|journal=[[Immunology and Immunogenetics Insights]]|language=en|volume=7|issue=|pages=III.S25147|doi=10.4137/III.S25147|issn=1178-6345|quote=|via=}}</ref> (small study - 115 people with ME/CFS)
*May 2015 - [http://www.la-press.com/examination-of-single-nucleotide-polymorphisms-snps-in-transient-recep-article-a4824 Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients], ''Immunology and Immunogenetics Insights'', 2015:7 1-6. (small study - 115 people with ME/CFS)

*Dec 2015, [http://onlinelibrary.wiley.com/doi/10.1111/sji.12388/abstract Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis]<ref name="NKcells-2015">{{Cite journal | last = Huth | first = T.K. | authorlink = Teilah Huth | last2 = Brenu | first2 = E.W.  | authorlink2 = Ekua Brenu | last3 = Ramos | first3 = S. | authorlink3 = Sandra Ramos | last4 = Nguyen | first4=T. | authorlink4 = Thao Nguyen | last5 = Broadley | first5 = S. | authorlink5 = Simon Broadley | last6 = Staines | first6 = D.  | authorlink6 = Donald Staines | last7 = Marshall‐Gradisnik | first7 = S. | authorlink7 = Sonya Marshall-Gradisnik | date = 2016 | title=Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/sji.12388|journal=[[Scandinavian Journal of Immunology]]|language=en|volume=83|issue=1 | pages = 44–51|doi=10.1111/sji.12388|issn=1365-3083|quote=|via=}}</ref> (Abstract)

*Jan 2016, [https://journals.sagepub.com/doi/full/10.4137/III.S37042 Genotype Frequencies of Transient Receptor Potential Melastatin M3 Ion Channels and Acetylcholine Muscarinic M3 Receptor Gene Polymorphisms in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients Genotype Frequencies of Transient Receptor Potential Melastatin M3 Ion Channels and Acetylcholine Muscarinic M3 Receptor Gene Polymorphisms in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients]<ref name="Genotype-2016">{{Cite journal | last = Marshall-Gradisnik | first = S.M. | authorlink = Sonya Marshall-Gradisnik | last2 = Chacko | first2 = A. | authorlink2 = A Chacko | last3 = Johnston | first3 = S. | authorlink3 = Samantha Johnston | last4 = Smith | first4 = P. | authorlink4 = Peter Smith | last5 = Nilius | first5 = B. | authorlink5 = B Nilius | last6 = Staines | first6 = D.R. | authorlink6 = Donald Staines | date = 2016-01-01 | title = Genotype Frequencies of Transient Receptor Potential Melastatin M3 Ion Channels and Acetylcholine Muscarinic M3 Receptor Gene Polymorphisms in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients|url=https://doi.org/10.4137/III.S37042|journal=Immunology and Immunogenetics Insights|language=en|volume=8|issue=|pages=III.S37042|doi=10.4137/III.S37042|issn=1178-6345|quote=|via=}}</ref> [https://journals.sagepub.com/doi/full/10.4137/III.S37042 (Full text)]

*Apr 2016, [http://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-0859-z ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56dimCD16+ and CD56brightCD16dim/− natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients]<ref name=":0">{{Cite journal | last = Huth | first = Teilah Kathryn | authorlink = Teilah Huth | last2 = Staines | first2 = Donald | authorlink2 = Donald Staines | last3 = Marshall-Gradisnik | first3 = Sonya | authorlink3 = Sonya Marshall-Gradisnik  | authorlink4 =  | authorlink5 =  | date = 2016-04-21 | title = ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56dimCD16+ and CD56brightCD16dim/− natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients|url=https://doi.org/10.1186/s12967-016-0859-z|journal=[[Journal of Translational Medicine]]|volume=14|issue=1 | pages = 97|doi=10.1186/s12967-016-0859-z|issn=1479-5876|pmc=4839077|pmid=27098723|quote=|via=}}</ref> (Full text)

*May 2016, [https://biolres.biomedcentral.com/articles/10.1186/s40659-016-0087-2 Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients]<ref name="TRPM3-2016">{{Cite journal | last = Nguyen | first = T. | authorlink = Thao Nguyen | last2 = Staines | first2 =  D.  | authorlink2 = Donald Staines | last3 = Nilius | first3 = B. | authorlink3 = B Nilius | last4 = Smith | first4 = P. | authorlink4 = Peter Smith | last5 = Marshall-Gradisnik | first5 = S. | authorlink5 = Sonya Marshall-Gradisnik | date = 2016-05-31 | title = Novel identification and characterisation of Transient receptor potential melastatin 3 ion channels on Natural Killer cells and B lymphocytes: effects on cell signalling in Chronic fatigue syndrome/Myalgic encephalomyelitis patients|url=https://doi.org/10.1186/s40659-016-0087-2|journal=[[Biological Research (journal)|Biological Research]]|volume=49|issue=1|pages=27|doi=10.1186/s40659-016-0087-2|issn=0717-6287|pmc=4888729|pmid=27245705|quote=|via=}}</ref> (Full text)

*2016, Dysregulation of Protein Kinase Gene Expression in NK Cells from [[ME/CFS|Chronic Fatigue Syndrome/Myalgic Encephalomyelitis]] Patients<ref name="Chacko, 2016" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003121/ (Full Text)]
*2016, Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome [https://www.dovepress.com/natural-killer-cells-and-single-nucleotide-polymorphisms-of-specific-i-peer-reviewed-fulltext-article-TACG (Full Text)]
*2016, Killer Cell Immunoglobulin-like Receptor [[Genotype]] and [[Haplotype]] Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients [http://journals.sagepub.com/doi/full/10.4137/GRSB.S39861 (Full Text)]
*2016, [[MicroRNA|MicroRNAs]] [[hsa-miR-99b]], [[hsa-miR-330]], [[hsa-miR-126]] and [[hsa-miR-30c]]: Potential Diagnostic Biomarkers in Natural Killer (NK) Cells of Patients with Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME)<ref name="PettyD2016" />
*2018, Association of [[T cell|T]] and NK cell phenotype with the diagnosis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)<ref name="Rivas, 2018" /> [https://www.frontiersin.org/articles/10.3389/fimmu.2018.01028/abstract (Abstract)]
*2018, [[Rituximab]] impedes natural killer cell function in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients: A pilot in vitro investigation<ref name="Eaton, 2018" /> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870391/ (Full Text)]

*Aug 2018, Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients<ref>{{Cite journal | last = Cabanas | first = Hélène | authorlink = Hélène | last2 = Muraki | first2 = Katsuhiko | authorlink2 = Katsuhiko Muraki | last3 = Eaton | first3 = Natalie | authorlink3 = Natalie Eaton-Fitch | last4 = Balinas | first4=Cassandra | authorlink4 = Cassandra Balinas | last5 = Staines | first5 = Donald | authorlink5 = Donald Staines | last6 = Marshall-Gradisnik | first6 = Sonya | authorlink6 = Sonya Marshall-Gradisnik | date = 2018-08-14 | title = Loss of Transient Receptor Potential Melastatin 3 ion channel function in natural killer cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092868/|journal=Molecular Medicine|volume=24|issue=|pages=|doi=10.1186/s10020-018-0046-1|issn=1076-1551|pmc=6092868|pmid=30134818|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092868/#__ffn_sectitle (Full text)]

*May 2019, Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients<ref>{{Cite journal | last = Cabanas | first = H. | authorlink = Hélène Cabanas | last2 = Muraki | first2 = K. | authorlink2 = Katsuhiko Muraki | last3 = Balinas | first3 = C. | authorlink3 = Cassandra Balinas | last4 = Eaton-Fitch | first4 = N. | authorlink4 = Natalie Eaton-Fitch | last5 = Staines | first5 =  D.  | authorlink5 = Donald Staines | last6 = Marshall-Gradisnik | first6 = S. | authorlink6 = Sonya Marshall-Gradisnik | date = 2019-04-23 | title = Validation of impaired Transient Receptor Potential Melastatin 3 ion channel activity in natural killer cells from Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis patients|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480905/|journal=[[Molecular Medicine]]|volume=25|issue=|pages=|doi=10.1186/s10020-019-0083-4|issn=1076-1551|pmc=6480905|pmid=31014226|quote=|via=}}</ref> [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480905/ (Full text)]

==Learn more==

*[https://en.wikipedia.org/wiki/Natural_killer_cell Wikipedia - Natural killer cell]
*[https://www.youtube.com/watch?v=GIJK3dwCWCw&feature=youtu.be Crash Course - The Immune System Part 1]
*2016, [https://www.actionforme.org.uk/resources/questions-and-answers/what-was-the-research-into-immune-responses-in-cfs/m.e.-you-funded-about/ What was the research into immune responses in CFS/M.E. you funded about?]
*2016, [http://www.wehi.edu.au/news/immune-cell-switch-discovery-raises-hopes-cancer-fight Immune cell 'switch' discovery raises hopes in cancer fight]<ref name="WEHIMR20160226" />

==See also==

*[[GcMAF]]
*[[Immune system]]
*[[TRPM3]]
*[[Diagnostic biomarker]]

==References==
<references>
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[[Category:Body systems]]
[[Category:Immunology]]
[[Category:Immune cells]]
[[Category:Blood components]]