Natural killer cell: Difference between revisions

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'''Natural killer (NK) cells''' are a type of white blood cell that forms part of the [[innate immune system]]. Their function involves the recognition and destruction of tumour and virally infected cells.<ref name="MaleD2007"/>
==Function==
==Function==


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 '''natural killer (NK) cells'''.<ref name="MaleD2007"/> NK cells are large granular lymphocytes (LGLs) and form part of the innate [[immune system|immune response]], functioning through the recognition and destruction of tumour and virally infected cells<ref name="MaleD2007"/>. NK cells 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 their expression of either CD16 (FcγRIII) or CD56 cell surface receptors<ref name="Robson2014"/>.
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, 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 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 specialised 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 play a major role in eliminating virally infected cells. Following infection, 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 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 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 Cell Cytotoxic Mechanisms'''     
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• Cytokine synthesis and release<ref name="MaleD2007"/>
• Cytokine synthesis and release<ref name="MaleD2007"/>


As LGLs, NK cells utilise 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’ 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"/>.
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’ 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:
NK cells express two receptor types:
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==Evidence==
==Evidence==


Numerous studies of [[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 biomarker.<ref>Reference needed</ref>
Numerous studies of [[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 biomarker.<ref>[[Reference needed]]</ref>


== Modulating NK function ==
== Modulating NK function ==
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=== Stress ===
=== 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>http://onlinelibrary.wiley.com/store/10.1002/(SICI)1097-0215(19990315)80:6%3C880::AID-IJC14%3E3.0.CO;2-Y/asset/14_ftp.pdf?v=1&t=ih3j738n&s=cb52bd209fea486c1221ba37ba0fdbd94521f356</ref><ref name="PollockRE1991"/><ref>http://cancerres.aacrjournals.org/content/44/9/3888.short</ref> decreases NK function and promotes tumor development and metastasis.<ref>http://onlinelibrary.wiley.com/store/10.1002/(SICI)1097-0215(19990315)80:6%3C880::AID-IJC14%3E3.0.CO;2-Y/asset/14_ftp.pdf?v=1&t=ih3j738n&s=cb52bd209fea486c1221ba37ba0fdbd94521f356</ref><ref>http://cancerres.aacrjournals.org/content/44/9/3888.short</ref><ref>http://cancerres.aacrjournals.org/content/44/9/3888.short</ref> Mindfulness based meditation or stress reduction may increase natural killer cell function.<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586059/</ref>
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="unknownlink">http://onlinelibrary.wiley.com/store/10.1002/(SICI)1097-0215(19990315)80:6%3C880::AID-IJC14%3E3.0.CO;2-Y/asset/14_ftp.pdf?v=1&t=ih3j738n&s=cb52bd209fea486c1221ba37ba0fdbd94521f356 [[Broken link]]</ref><ref name="PollockRE1991"/><ref name="Pollock1984" /> decreases NK function and promotes tumor development and metastasis.<ref name="unknownlink" /><ref name="Pollock1984" /> Mindfulness based meditation or stress reduction may increase natural killer cell function.<ref name="linda2008" />


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


==ME/CFS==
==ME/CFS==
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 CFS severity. The study, also, reported that ''in vitro'' exposure of peripheral blood mononuclear cells from CFS patients (who fulfilled both the [[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 is associated with increased symptom severity.<ref name="strayer2015" />
==Multiple sclerosis==
2009 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. ''This is copy and pasted direct from another page – need to find original article'' --[[User:JenB|JenB]] ([[User talk:JenB|talk]]) 23:46, 28 March 2016 (PDT) ''Jen, is this the correct citation ?  if so, move main part to end of page'' --[[User:Suelala|Suelala]] ([[User talk:Suelala|talk]]) 07:46, 29 March 2016 (PDT)
<ref name="GascoyneD2009"/>


==Notable studies==
==Notable studies==
*2016, [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003121/ Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients]<ref name="Chacko, 2016"/>
*2016, [https://www.dovepress.com/articles.php?article_id=26236 Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome]
*2016, [http://www.la-press.com/killer-cell-immunoglobulin-like-receptor-genotype-and-haplotype-invest-article-a5702 Killer Cell Immunoglobulin-like Receptor Genotype and Haplotype Investigation of Natural Killer Cells from an Australian Population of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients]
*2016, [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586059/ 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"/>
*2016, [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2586059/ 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"/>
*2015, [http://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 Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity]
*2003, [http://onlinelibrary.wiley.com/doi/10.1002/cyto.b.10034/full Predictive immunophenotypes: Disease-related profile in chronic fatigue syndrome]
*1987, [https://www.ncbi.nlm.nih.gov/pubmed/2824604 Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome]


==Learn more==
==Learn more==
*[https://en.wikipedia.org/wiki/Natural_killer_cell Wikipedia - Natural killer cell]
*[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"/>
*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"/>
*2016, [https://selfhacked.com/2016/04/15/intro-natural-killer-cells-increase-decrease/ All About Natural Killer Cells and How to Increase and Decrease Them]


==See also==
==See also==
*[[GcMAF]]
*[[GcMAF]]
*[[Immune system]]


==References==
==References==
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[[Category:Body systems]]
[[Category:Body systems]]

Revision as of 17:49, March 12, 2017

Natural killer (NK) cells are a type of white blood cell that forms part of the innate immune system. Their function involves the recognition and destruction of tumour and virally infected cells.[1]

Function[edit | edit source]

The majority of lymphocytes, a leucocyte subgroup, are B or T cells but approximately 15% of the lymphocyte population lack B or T cell receptors; these are NK cells.[1] The latter develop in the bone marrow and have a half-life of approximately 7 days.[2] 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.[3]

NK cells play a major role in eliminating virally infected cells. Following infection, viruses block cell synthesis of major histocompatibility complex class I (MHCI) molecules.[1] Presentation of MHC class I molecules at an infected cell’s surface is used by 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.[1] 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.[1] 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).[1]

NK Cell Cytotoxic Mechanisms

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

• Direct cell-to-cell contact

Cytokine synthesis and release[1]

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[1]. These contents include the protein perforin, which perforates the infected cell's membrane, enabling entry of specialized ‘suicide’ enzymes, including granzyme B, into the virally infected cell; these initiate apoptosis (programmed cell death).[1][2] 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.[2]

NK cells express two receptor types:

• Activating

• Inhibitory

Activating receptors induce NK cells to eliminate infected cells, while inhibitory receptors block killing mechanisms[2]. Resting NK cells synthesize 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[2].

Factors Leading to NK cell Activation

Several elements can produce NK cell activation, including:

• The detection of lipopolysaccharide (LPS, a bacterial cell wall constituent)

• The release of various cytokines, e.g. IFN and 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 macrophages for activation. Following activation, macrophages synthesize TNF (tumour necrosis factor), which binds a macrophage’s own surface receptors[2]. This initiates IL-12 (interleukin-12) activation. The combination of TNF and IL-12 expression induces increased NK cell synthesis of IFN-γ leading to more macrophage priming, an example of an enhanced immune response via a positive feedback loop[2]. TNF synthesis by macrophages also upregulates IL-2 expression on NK cell surfaces, NK cells respond to their own IL-2 synthesis and undergo rapid division[2].

Evidence[edit | edit source]

Numerous studies of Chronic Fatigue Syndrome have found evidence of reduced natural killer cell function.[4][5][6][7][8] Some studies have showed natural killer cell function correlates with illness severity.[9] One study found increased differentiation in NK cells.[10] Inconsistency in laboratory preparation and analysis have made it difficult to compare results between laboratories or use NK function as a consistent biomarker.[11]

Modulating NK function[edit | edit source]

Probiotics[edit | edit source]

Some probiotics have been shown to increase NK function, including Lactobacillus rhamnosus HN001,[12] Bifidobacterium lactis HN019[12][13] and Lactobacillus casei Shirota[14][15][16]

AHCC[edit | edit source]

In animal models, Active Hexose Correlated Compound (AHCC) has been show to increase NK activity.[17] Other studies have found no significant increase in NK function.[18]

Stress[edit | edit source]

There is evidence in humans and animal models that psychological stress[19][20] and physical stress, for example surgery,[21][22][23] decreases NK function and promotes tumor development and metastasis.[21][23] Mindfulness based meditation or stress reduction may increase natural killer cell function.[24]

Smoking[edit | edit source]

Smoking decreases natural killer cell function.[16]

Ampligen[edit | edit source]

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%.[25]

Nutritional deficiencies[edit | edit source]

Vitamin B12 deficiency may be associated with decreased natural killer cell activity.[26]

ME/CFS[edit | edit source]

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 CFS severity. The study, also, reported that in vitro exposure of peripheral blood mononuclear cells from CFS patients (who fulfilled both the 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 is associated with increased symptom severity.[25]

Multiple sclerosis[edit | edit source]

2009 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. This is copy and pasted direct from another page – need to find original article --JenB (talk) 23:46, 28 March 2016 (PDT) Jen, is this the correct citation ? if so, move main part to end of page --Suelala (talk) 07:46, 29 March 2016 (PDT) [27]

Notable studies[edit | edit source]

Learn more[edit | edit source]

See also[edit | edit source]

References[edit | edit source]

  1. 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Male, D (2007), Immunology, Milton Keynes, The Open University/Milton Keynes, The Open University
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Sompayrac, L (2008), How the Immune System Works, Oxford, Blackwell Publishing
  3. Robson, NC; Hidalgo, L; McAlpine, T; Wei, H; Martínez, VG; Entrena, A; Melen, GJ; MacDonald, AS; Phythian-Adams, A; Sacedón, R; Maraskovsky, E; Cebon, J; Ramírez, M; Vicente, A; Varas, A (2014), "Optimal Effector Functions in Human Natural Killer Cells rely upon Autocrine Bone Morphogenetic Protein Signaling", Cancer Res., 74 (18): 5019-5031, doi:10.1158/0008-5472.CAN-13-2845
  4. Barker, Edward; Fujimura, Sue F.; Fadem, Mitchell B; Landay, Alan L.; Levy, Jay A. (1994), "Immunologic Abnormalities Associated with Chronic Fatigue Syndrome", Clin Infect Dis., 18 (Supplement 1): S136-S141, doi:10.1093/clinids/18.Supplement_1.S136
  5. Whiteside, TL; Friberg, D (1998), "Natural killer cells and natural killer cell activity in chronic fatigue syndrome.", Am J Med, 105 (3A): 27S–34S, PMID 9790479
  6. Brenu, EW; Huth, TK; Hardcastle, SL; Fuller, K; Kaur, M; Johnston, S; Ramos, Sandra; Staines, Donald; Marshall-Gradisnik, Sonya (2014), "Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis", Int Immunol, 26 (4): 233-42, doi:10.1093/intimm/dxt068, PMID 24343819
  7. Fletcher, Mary Ann; Maher, Kevin J; Klimas, Nancy (April 2002), "Natural killer cell function in chronic fatigue syndrome", Clinical and Applied Immunology Reviews, 2 (2): 129–139, doi:10.1016/S1529-1049(01)00047-2
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