What are Natural Killer (NK) Cells?

Natural Killer (NK) cells are specialized immune cells of the innate, nonspecific immune system. Comprising about 10% of white blood cells they are densest in the liver, spleen, blood, lung, bone marrow, and lymph nodes.

In response to an immune threat, NK cells release a class of chemical messengers (cytokines, IFN-y) that recruit T lymphocytes and other immune cells to attack. They also function to communicate to other immune cells to curtail their offenses, thus inhibiting an overactive response.

Why Are They Important?

NK cells provide surveillance for the immune system. They circulate looking for viruses and cancer cells, in particular. Once in range, they release chemical grenades—perforins and granzymes—which poke holes the enemy cells resulting in cell death, or apoptosis. It is now believed that NK cells have the potential to “remember” previous immune insults, leading to better coordinated immune cell responses with repeat exposure.

What Does ME/CFS Research Say About NK Cells?

Natural Killer cell deficiency is a consistent finding in ME/CFS patients. In fact, some argue that NK cell measurement may be diagnostic (1). There are two types of NK cell deficiency: classical and functional. A classical NK cell deficiency is defined as an absence of NK cells in peripheral blood. This is thought to be a rare genetic condition involving three key genes (MCM4, FCGR3A, & GATA2).

While no concrete study has examined this specifically in ME/CFS, a 2010 study from Nancy Klimas’ group detected a functional deficiency in CFS patients when compared to controls. In their study, NK cell numbers were not significantly different between groups, but markers of activation were far lower in the CFS group (1).

Not mentioned in this study, but worth noting, is that many ME/CFS patients also have perforin deficiency—the grenade-like ammunition of NK cells. This finding, which has been duplicated by others, suggests that NK cell function is most affected in ME/CFS.

Does Poor Natural Killer Cell Functioning Really Matter?

Few would argue that NK cell counts in the high normal range are beneficial for long term health. Studies have found that those with genetic polymorphisms (classical type) that result in deficient NK cells have increased incidence of some cancers and greater susceptibility to Herpes family viral infections (EBV, CMV, HPV, HSV). Furthermore, some preliminary cancer therapies exploit NK cells to decrease tumor size and improve survival (2).But what effect might this bring for ME/CFS?

In Klimas’ 2010 study, the researchers stated that NK cell activity was a strong indicator of illness severity—those with the lowest scores had more severe symptoms (1). Also, the recent trials using Rituximab for ME/CFS highlight the importance of NK cell activity for recovery and symptom relief. These drugs are thought to work at least in part due to their ability to enhance NK cell activity. Clinical trails are still underway using Rituximab for ME/CFS, so it is too soon to tell the exact effects. The side effects and potential dangers of this type of therapy should not be overlooked, however.

In lieu of clinical trials, many ME/CFS doctors opt for natural ingredients to boost NK cell activity. Here are three supplements with well documented evidence of raising NK cell number AND function.

Colostrum

Bovine-derived colostrum has been used to enhance immune health for over a hundred years. In fact before antibiotics were developed colostrum, which refers to a densely immune factor and nutrient rich milk produced late in pregnancy, was used frequently to provide immunoglobulins to fight infections.

Among others colostrum contains immunoglobins that target Escherichia coli, Cryptosporidium parvum, Shigella flexneri, Salmonella, Staphylococcus and rotavirus. With antibiotic resistance on the rise, more people are turning to colostrum as a natural alternative to antibiotics.

Colostrum contains a large percentage of Proline-rich Polypeptides (PRP’s), also known as Transfer Factors, which act as intercellular signaling molecules that modulate the immune system. Human studies have shown that PRPs from colostrum induce IFN-y –a robust promoter of NK cell activity.

A small placebo-controlled, double-blinded, randomized crossover trial concluded that consumption of colostrum resulted in increased NK cell release from bone marrow as well as homing of NK cells into tissues (4). Other studies relating to Alzheimer’s research have also highlighted the immunomodulating effects of colostrum (5).

While research studies looking at colostrum’s use in ME/CFS are limited (3), its effects on exercise are intriguing. Runners have been able to reduce their recovery time from peak exercise efforts using colostrum (6) and colostrum reduced gut permeability that occurred as a result of exercise (7).

Melatonin

Although traditionally thought of as a sleep-inducing hormone, the melatonin receptors dotting immune organs and cells indicate that melatonin plays substantial immunomodulatory role in humans as well. Numerous animal and human studies have shown melatonin increases NK cell number and function and production of IFN-y. Melatonin’s immune enhancing effects have led to many interventional studies in cancers (8).

Melatonin also reduces the TLR4 innate immune inflammatory pathway that has been implicated in many inflammatory disorders and may be upregulated in ME/CFS (9). The inflammatory and neuropathic pain models in animals also suggest melatonin may have significant anti-pain properties (10). Studies indicate melatonin secretion in Fibromyalgia is reduced (11) and melatonin can improve fatigue and concentration in ME/CFS (12).

General sleep supportive doses are recommended at 1-3 mg, but larger doses of 10-20 mg may be required to achieve immune support effects.

Medicinal Mushrooms

Medicinal Mushrooms used for millennia in Traditional Chinese Medicine, Western researchers are beginning to catch up and elucidate many of the health promoting effects of medicinal mushrooms. Certain varietals are better studied than others. Maitake, shitake, reishi, and cordyceps species have been studied predominantly and highlight various potent immune stimulating effects including effects on NK cells.

The key components of these mushrooms are fruit body polysaccharide-proteins and mycelia that are administered in broths, distilled tinctures, or concentrated extracts. Several of these mushrooms have undergone phases I, II, and III clinical trials and are used extensively and successfully in Asia to treat various cancers and other diseases (7).

References

1 Fletcher MA, et al. (2010) Biomarkers in chronic fatigue syndrome: evaluation of natural killer cell function and dipeptidyl peptidase IV/CD26. PLoS One. 5(5):e10817.

2 Campbell KS, Hasegawa J. (2013) Natural killer cell biology: an update and future directions. J Allergy Clin Immunol. 132(3):536-44. Epub 2013 Jul 30.

3. De Vinci C, Levine PH, Pizza G, Fudenberg HH, Orens P, Pearson G, Viza D. (1996) Lessons from a pilot study of transfer factor in Chronic Fatigue Syndrome. Biotherapy. 9(1-3): 87-90.

4 Jensen GS, Patel D, Benson KF. (2012) A novel extract from bovine colostrum whey supports innate immune functions. II. Rapid changes in cellular immune function in humans. Prev Med. 54 Suppl:S124-9. Epub 2012 Jan 17.

5 Janusz M, Zabłocka A. (2010) Colostral proline-rich polypeptides–immunoregulatory properties and prospects of therapeutic use in Alzheimer’s disease. Curr Alzheimer Res. 7(4):323-33.

6. Buckley, JD.; Abbott, MJ.; Brinkworth, GD.; Whyte, PB. (Jun 2002). “Bovine colostrum supplementation during endurance running training improves recovery, but not performance”. J Sci Med Sport 5 (2): 65–79. doi:10.1016/S1440-2440(02)80028-7 . PMID 12188088.

7. Ray Playford et al. (2011). The nutriceutical, bovine colostrum, truncates the increase in gut permeability caused by heavy exercise in athletes. American Journal of Physiology-Gastrointestinal and Liver Physiology, (March 2011).

8. Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway.Lucas K, Maes M. Mol Neurobiol. 2013 Aug;48(1):190-204. doi: 10.1007/s12035-013-8425-7 . Epub 2013 Feb 26. Review.

9. Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. (2008) Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther. 7(3):189-203. http://www.ncbi.nlm.nih.gov/pubmed/21682138

10. Curr Neuropharmacol. 2012 Jun;10(2):167-78. doi: 10.2174/157015912800604489 . Melatonin in antinociception: its therapeutic applications. Srinivasan V1, Lauterbach EC, Ho KY, Acuña-Castroviejo D, Zakaria R, Brzezinski A.

11. Indian J Biochem Biophys. 2011 Apr;48(2):82-7.Abnormality of circadian rhythm of serum melatonin and other biochemical parameters in fibromyalgia syndrome.Mahdi AA1, Fatima G, Das SK, Verma NS.

12. Influence of melatonin on fatigue severity in patients with chronic fatigue syndrome and late melatonin secretion.van Heukelom RO1, Prins JB, Smits MG, Bleijenberg G.

13. Wasser SP. (2011) Current findings, future trends, and unsolved problems in studies of medicinal mushrooms. Appl Microbiol Biotechnol. 89(5):1323-32. Epub 2010 Dec 29.