Natural killer cell
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. The latter develop in the bone marrow and have a half-life of approximately 7 days. 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.
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. 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. 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. 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).
NK Cell Cytotoxic Mechanisms
NK cells can terminate an infected cell via several mechanisms including:
• Direct cell-to-cell contact
• Cytokine synthesis and release
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. 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). 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.
NK cells express two receptor types:
Activating receptors induce NK cells to eliminate infected cells, while inhibitory receptors block killing mechanisms. 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.
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-α 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. 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. 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.
Numerous studies of Chronic Fatigue Syndrome have found evidence of reduced natural killer cell function. Some studies have showed natural killer cell function correlates with illness severity. One study found increased differentiation in NK cells. Inconsistency in laboratory preparation and analysis have made it difficult to compare results between laboratories or use NK function as a consistent biomarker.
Modulating NK function
There is evidence in humans and animal models that psychological stress and physical stress, for example surgery, decreases NK function and promotes tumor development and metastasis. Mindfulness based meditation or stress reduction may increase natural killer cell function.
Smoking decreases natural killer cell function.
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%.
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.
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) 
- 2016, Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients
- 2016, Natural killer cells and single nucleotide polymorphisms of specific ion channels and receptor genes in myalgic encephalomyelitis/chronic fatigue syndrome
- 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
- 2016, 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)
- 2015, Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity
- 2003, Predictive immunophenotypes: Disease-related profile in chronic fatigue syndrome
- 1987, Phenotypic and functional deficiency of natural killer cells in patients with chronic fatigue syndrome
- Wikipedia - Natural killer cell
- Crash Course - The Immune System Part 1
- 2016, What was the research into immune responses in CFS/M.E. you funded about?
- 2016, Immune cell 'switch' discovery raises hopes in cancer fight
- Male, D (2007), Immunology, Milton Keynes, The Open University/Milton Keynes, The Open University
- Sompayrac, L (2008), How the Immune System Works, Oxford, Blackwell Publishing
- 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
- 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
- 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
- Brenu, EW; Huth, TK; Hardcastle, SL; Fuller, K; Kaur, M; Johnston, S; Ramos, S; Staines, D; Marshall-Gradisnik, S (2014), "The Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis", International Immunology, 26 (4): 233-42, doi:10.1093/intimm/dxt068, PMID 24343819
- 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
- Brenu, Ekua W; van Driel, Mieke L; Staines, Donald R; Ashton, Kevin J; Hardcastle, Sharni L; Keane, James; Tajouri, Lotti; Peterson, Daniel; Ramos, Sandra B; Marshall-Gradisnik, Sonya M (2012), "Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis", Journal of Translational Medicine, 10: 88, doi:10.1186/1479-5876-10-88
- Ojo-Amaize, Emmanuel A.; Conley, Edward J.; Peter, James B. (1994), "Decreased Natural Killer Cell Activity Is Associated with Severity of Chronic Fatigue Immune Dysfunction Syndrome", Clin Infect Dis., 18 (Supplement 1): S157-S159., doi:10.1093/clinids/18.Supplement_1.S157
- Huth, TK; Brenu, EW; Ramos, S; Nguyen, T; Broadley, S; Staines, D; Marshall-Gradisnik, S (Jan 2016), "Pilot Study of Natural Killer Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis", Scand J Immunol, 83(1): 44-51, doi:10.1111/sji.12388, PMID 26381393
- Reference needed
- Gill, HS; Rutherfurd, KJ; Cross, ML (Jul 2001), "Dietary probiotic supplementation enhances natural killer cell activity in the elderly: an investigation of age-related immunological changes", J Clin Immunol, 21(4): 264-71, PMID 11506196
- Chiang, BL; Sheih, YH; Wang, LH; Liao, CK; Gill, HS (2000), "Enhancing immunity by dietary consumption of a probiotic lactic acid bacterium (Bifidobacterium lactis HN019): optimization and definition of cellular immune responses]", European Journal of Clinical Nutrition, 54(11): 849-855, doi:10.1038/sj.ejcn.1601093
- Takagi, Akimitsu; Matsuzaki, Takeshi; Sato, Mikiko; Nomoto, Koji; Morotomi, Masami; Yokokura, Teruo (2001), "Enhancement of natural killer cytotoxicity delayed murine carcinogenesis by a probiotic microorganism", Carcinogenesis, 22 (4): 599-605, doi:10.1093/carcin/22.4.599
- Takeda, K; Suzuki, T; Shimada, SI; Shida, K; Nanno, M; Okumura, K (Oct 2006), "Interleukin‐12 is involved in the enhancement of human natural killer cell activity by Lactobacillus casei Shirota", Clin Exp Immunol, 146(1): 109-15, PMID 16968405
- Morimoto, Kanehisa; Takeshita, Tatsuya; Nanno, Masanobu; Tokudome, Shinkan; Nakayama, Kunio (May 2005), "Modulation of natural killer cell activity by supplementation of fermented milk containing Lactobacillus casei in habitual smokers", Preventive Medicine, 40 (5): 589–594, doi:10.1016/j.ypmed.2004.07.019
- Ritz, Barry W.; Nogusa, Shoko; Ackerman, Elizabeth A.; Gardner, Elizabeth M. (Nov 2006), "Supplementation with Active Hexose Correlated Compound Increases the Innate Immune Response of Young Mice to Primary Influenza Infection", J. Nutr., 136 (11): 2868-2873, PMID 17056815
- Terakawa, Naoyoshi; Matsui, Yoichi; Satoi, Sohei; Yanagimoto, Hiroaki; Takahashi, Kanji; Yamamoto, Tomohisa; Yamao, Jun; Takai, Soichiro; Kwon, A-Hon; Kamiyama, Yasuo (2008), "Immunological Effect of Active Hexose Correlated Compound (AHCC) in Healthy Volunteers: A Double-Blind, Placebo-Controlled Trial", Nutrition and Cancer, 60 (5), doi:10.1080/01635580801993280
- Glaser, Ronald; Rice, John; Speicher, Carl E.; Stout, Julie C.; Kiecolt-Glaser, Janice K. (Oct 1986), "Stress depresses interferon production by leukocytes concomitant with a decrease in natural killer cell activity.", Behavioral Neuroscience, 100(5): 675-678, doi:10.1037/0735-7044.100.5.675
- Sieber, William J.; Rodin, Judith; Larson, Lynn; Ortega, Susan; Cummings, Nancy; Levy, Sandra; Whiteside, Theresa; Herberman, Ronald (June 1992), "Modulation of human natural killer cell activity by exposure to uncontrollable stress", Brain, Behavior, and Immunity, 6 (2): 141–156, doi:10.1016/0889-1591(92)90014-F
- Pollock, Raphael E.; Lotzová, Eva; Stanford, Susan D. (1991), "Mechanism of Surgical Stress Impairment of Human Perioperative Natural Killer Cell Cytotoxicity", Arch Surg, 126 (3): 338-342, doi:10.1001/archsurg.1991.01410270082013
- Pollock, Raphael E.; Babcock, George F.; Romsdahl, Marvin M.; Nishioka, Kenji (1984-09-01), "Surgical Stress-mediated Suppression of Murine Natural Killer Cell Cytotoxicity", Cancer Research, 44 (9): 3888–3891, ISSN 0008-5472, PMID 6744305, retrieved 2016-12-19
- Witek-Janusek, Linda; Albuquerque, Kevin; Chroniak, Karen Rambo; Chroniak, Christopher; Durazo, Ramon; Mathews, Herbert L. (August 2008), "Effect of Mindfulness Based Stress Reduction on Immune Function, Quality of Life and Coping In Women Newly Diagnosed with Early Stage Breast Cancer", Brain, behavior, and immunity, 22 (6): 969–981, doi:10.1016/j.bbi.2008.01.012, ISSN 0889-1591, PMID 18359186, retrieved 2016-12-19
- Strayer, David; Scott, Victoria; Carter, William (2015-07-29), "Low NK Cell Activity in Chronic Fatigue Syndrome (CFS) and Relationship to Symptom Severity", Journal of Clinical & Cellular Immunology: 1–9, doi:10.4172/2155-9899.1000348, ISSN 2155-9899, retrieved 2016-12-19
- Tamura, J.; Kubota, K.; Murakami, H.; Sawamura, M.; Matsushima, T.; Tamura, T.; Saitoh, T.; Kurabayshi, H.; Naruse, T. (1999-04-01), "Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatment", Clinical & Experimental Immunology, 116 (1): 28–32, doi:10.1046/j.1365-2249.1999.00870.x, ISSN 1365-2249, retrieved 2016-12-19
- Gascoyne, Duncan M; Long, Elaine; Veiga-Fernandes, Henrique; de Boer, Jasper; Williams, Owen; Seddon, Benedict; Coles, Mark; Kioussis, Dimitris; Brady, Hugh JM (13 Sep 2009), "The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development", Nature Immunol, 10: 1118-1124, doi:10.1038/ni.1787, PMID 19749763
- Chacko, Anu; Staines, Donald R.; Johnston, Samantha C.; Marshall-Gradisnik, Sonya M. (2016), "Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients", Gene Regulation and System Biology (10): 85–93, doi:10.4137/GRSB.S40036, PMID 27594784
- Petty, Robert D.; McCarthy, Neil E.; Le Dieu, Rifca; Kerr, Jonathan R. (2016), "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)", PLOS One, doi:10.1371/journal.pone.0150904, PMID 26967895
- Walter & Eliza Hall Institute of Medical Research (26 Feb 2016), Immune cell 'switch' discovery raises hopes in cancer fight