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Immunology

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Definition

NK cells are a subset of T lymphocytes (white blood cells) which function as a first line of defense against cancer cells and viral infection. Their primary function is 'cytotoxicity', which basically can be thought of as the ability to cause spontaneous cell destruction of either a cancer or viral-infected cell.(1)

This cytotoxicity or overall activity level of NK cells (usually expressed as Lytic Units or LU) is far more important than the total quantity or overall number of cells.

However, NK cells do not kill indiscriminately. NK cells have several very specialized lectin-like receptors that recognize Major Histocompatibility Complex (MHC) class I molecules expressed on normal cells. The lack of expression of one or more HLA class I alleles leads to NK-mediated target cell lysis (2)

These receptors express several type II glycoproteins of the calcium-dependent lectin superfamily.

Discussion

In essence, specialized chains of carbohydrates are crucial to the functions of NK cells (just as they are for the expression of your blood type and the recognition of other-blood type substances found in nature).

Almost certainly, the number of diverse observations implies roles for carbohydrates in multiple areas of NK function, probably including target recognition, tissue distribution and post-binding events in the lytic cascade (3)

NK activity as a functional marker of health

Decreased NK activity is linked to a variety of diseases and according to the Center for Disease Control, low NK activity is present in most chronic illnesses. NK cell activity appears to be a reliable functional marker of health and for susceptibility to disease.

NK activity and malignancy

Changes in NK activity have been reported to be reliably associated with both the likelihood of metastasis and tumor response to therapy, matching in its reliability the tumor markers reflective of prostate cancer (PSA and TPS). (4)

Natural Killer cell activity in breast cancer

In breast cancer, a negative correlation is seen between NK cell activity levels and the maximum tumor diameter, meaning that the larger the tumor the more the patient had low NK cell activity. (5)

NK cell activity was also predictive of advanced disease (or spread of disease) in women with breast cancer. Destruction of cancer cells by NK cells is much lower in women with advanced disease (stages II, III, and IV) than in women with limited disease (stage I).(6)

Many of the new adjuvant approaches to cancer treatment that are currently being researched include the use of biological response modifiers (substances with the potential to modulate immune function). And, that at present, the most promising approach to immune modulation appears to be the utilization of biotherapeutic agents with the capability to positively impact natural killer (NK) cell cytotoxicity. (7)

NK activity and viral disease

Studies in humans consistently point towards a vital role of NK cells in the defence against chronic fatigue immunodeficiency syndrome (CFIDS), human immunodeficiency virus (HIV), herpesviruses, hepatitis B and C and other viral disorders. (8)

Chronic Fatigue Syndrome (CFIDS)

It is generally well-accepted that a viral component probably plays a role in the development of the symptomology. So, it is no surprise to find that CFIDS has been associated with low NK cell activity. In people with CFIDS, NK cell activity is also associated with the severity of CFIDS. (9)

Researchers have discovered that in an extended family with many members with CFIDS (5 of 6 siblings with CFIDS and 3 other immediate family members with CFIDS), NK cell activity was not only significantly lower in affected family members, but even non-CFIDS family members had NK cell activity levels lower than normal (falling between the very low level of the CFIDS individuals and normal values). (10)

In CFIDS, restoration of NK cell activity is associated with clinical recovery. (11)

Low NK cell activity has also been shown in HIV, chronic herpes simplex virus infection, and chronic viral hepatitis. (12,13,14)

Depletion of NK cells can drastically reduce survival time of animals infected with herpes simplex virus type 2 (HSV-2). (15)

An acute response against hepatitis B is actually associated with increased NK cell activity in the early phase of illness. However, in the recovery phase of illness NK cell activity moves back towards normal. Suggesting that NK cytotoxicity may be one mechanism that controls the HBV infection before other cytotoxic mechanisms become fully operative. (16)

In viral myocarditis, 80 % of cases had less than 14% of normal NK cell activity. However, after treatment for 3 months with Chinese herbs, average NK cell activity increased from 12.26 to 31.99 and at the same time clinical manifistations and EKG improved or returned to normal. (17)

References


1. Hauer J, Anderer FA. Mechanism of stimulation of human natural killer cytotoxicity by arabinogalactan from Larix occidentalis. Cancer Immunol Immunother 1993;36:237-44

2. Moretta L, Mingari MC, Pende D, et al. The molecular basis of natural killer (NK) cell recognition and function. J Clin Immunol 1996 Sep;16(5):243-53

3. McCoy JP Jr, Chambers WH. Carbohydrates in the functions of natural killer cells. Glycobiology 1991 Sep;1(4):321-8

4. Kastelan M, Kovacic K, Tarle R, et al. Analysis of NK cell activity, lymphocyte reactivity to mitogens and serotest PSA and TPS values in patients with primary and disseminated prostate cancer, PIN and BPH. Anticancer Res 1997;17:1671-5.

5. Fulton A, Heppner G, Roi L, et al. Relationship of natural killer cytotoxicity to clinical and biochemical parameters of primary human breast cancer. Breast Cancer Res Treat 1984;4(2):109-16

6. Garner WL, Minton JP, James AG, Hoffmann C. Human breast cancer and impaired NK cell function. J Surg Oncol 1983 Sep;24(1):64-6

7. Lauer J, Anderer FA. Mechanism of stimulation of human natural killer cytotoxicity by arabinogalactan from Larix occidentalis. Cancer Immunol Immunother 1993;36:237-44.

8. DM, Khemka P, Sahl L, et al. The role of natural killer cells in viral infections. Scand J Immunol 1997 Sep;46(3):217-24

9. Ojo-Amaize EA, Conley EJ, Peter JB. Decreased natural killer cell activity is associated with severity of chronic fatigue immune dysfunction syndrome. Clin Infect Dis 1994;18:S1559.

10. Levine PH, Whiteside TL, Friberg D, et al. Dysfunction of natural killer activity in a family with chronic fatigue syndrome. Clin Immunol Immunopathol 1998;88:96-104

11. Uchida A. Therapy of chronic fatigue syndrome. Nippon Rinsho 1992;50:2679-2683 [article in Japanese]

12. Droge W, Holm E. Role of cysteine and glutathione in HIV infection and other diseases associated with muscle wasting and immunological dysfunction. FASEB 1997;11:1077-89.

13. Corado J, Toro F, Rivera H, et al. Impairment of natural killer (NK) cytotoxic activity in hepatitis C virus (HCV) infection. Clin Exp Immunol 1997;109:451-7.

14. Leszczyszyn-Pynka M. Natural cytotoxicity of peripheral blood mononuclear cells in Herpes simplex and Varicella-zoster virus infections. Acta Haematol Pol 1995;26(4):393-402 [Article in Polish]

15. Hellstrand K, Asea A, Hermodsson S. Role of histamine in natural killer cell-dependent protection against herpes simplex virus type 2 infection in mice. Clin Diagn Lab Immunol 1995 May;2(3):277-80

16. Echevarria S, Casafont F, Miera M, et al. Interleukin-2 and natural killer activity in acute type B hepatitis. Hepatogastroenterology 1991 Aug;38(4):307-10

17. Chen S, Chang P, Wang C. Therapeutic effect of yupingfeng san and shengmai yin on Coxsackie B viral myocarditis. Chung Hsi I Chieh Ho Tsa Chih 1990;10:20-21

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