Natural Killer Cells and Pregnancy: Research Review

Natural killer (NK) cells are immune cells that have a bad reputation as “killers.” However, in addition to killing cells (through cytotoxic activity), NK cells can do many other things like encouraging healthy placental development in the uterus. A natural killer cell cytotoxicity test measures how much the patient’s NK cells are primed towards killing. High circulating NK cytotoxic activity has been associated with recurrent pregnancy loss.

Physiology

Natural killer (NK) cells are a population of cytotoxic innate lymphocytes^1. Natural killer cell activity has been found elevated in patients with autoimmune diseases such as Graves’ disease, Hashimoto’s thyroiditis as compared to a heathy control population².

NK cells may be directly involved in these diseases through their potential autoreactivity or through their interaction with dendritic cells, macrophages or T lymphocytes, thereby inducing excessive inflammation or favoring the adaptive autoimmune response³. 

NK cells constitute the dominant population of lymphocytes in decidua during early pregnancy⁴.
Although endometrial NK cells are phenotypically different from circulating NK cells (with a weak cytotoxicity and immunoregulatory activities)⁵, it is speculated that peripheral blood NK cells are strongly related to NK cell populations found in the decidua⁶.

Published clinical data

NK cell activity has been associated with the pathogenesis of reccurent pregnancy loss^7-8, even when the embryo was chromosomally normal⁹.

A clinical study has shown that women with high NK cell activity pre-conception have a higher risk for pregnancy loss (3.5- fold higher risk) than women with normal levels⁷. More recent studies showed a strong correlation between high NK cell activity and recurrent spontaneous abortion^10-12 and suggested that NK cell activity can be used as a predictive biomarker.

IVIG can induce a down-regulation of NK cell activity among women with reccurent pregnancy losses¹³ which may help improve a patient’s pregnancy outcome. Nevertheless, the significance of pre-conceptional NK activity as a predictive value remains debated as a study showed no correlation between NK activity and risk for a subsequent loss¹⁴. This study could be bias as it is considering clinical losses only as miscarriages (excluding all chemical losses).

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References

1. Moffett, A., & Shreeve, N. (2015). First do no harm: Uterine natural killer (NK) cells in assisted reproduction. Human Reproduction, 30(7),1519–1525.
2. Hidaka Y, Amino N, Iwatani Y, Kaneda T, Nasu M, Mitsuda N, Tanizawa O, Miyai K. Increase in peripheral natural killer cell activity in patients with autoimmune thyroid disease. Autoimmunity. 1992;11(4):239-46.
3. Fogel LA, Yokoyama WM, French AR. Natural killer cells in human autoimmunedisorders. Arthritis Res Ther. 2013 Jul 11;15(4):216. doi: 10.1186/ar4232. Review.
4. Ntrivalas, E. I., Kwak‐Kim, J. Y. H., Gilman‐Sachs, A., Chung‐Bang, H., Ng, S. C., Beaman, K. D., … Beer, A. E. (2001). Status of peripheral blood natural killer cells in women with recurrent spontaneous abortions and infertility of unknown aetiology. Human Reproduction, 16(5), 855–861.
5. Koopman, L. A., Kopcow, H. D., Rybalov, B., Boyson, J. E., Orange, J. S., Schatz, F, Strominger, J. L. (2003). Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. Journal of Experimental Medicine, 198(8), 1201–1212.
6. Male, V., Hughes, T., McClory, S., Colucci, F., Caligiuri, M. A., & Moffett, A. (2010). Immature NK cells, capable of producing IL‐22, are present in human uterine mucosa. The Journal of Immunology, 185(7), 3913–3918.
7. Aoki K, Kajiura S, Matsumoto Y, et al. Preconceptional natural-killer cell activity as a predictor of miscarriage. Lancet (London, England). 1995; 345:1340–1342.
8. Higuchi, K., Aoki, K., Kimbara, T., Hosoi, N., Yamamoto, T., & Okada, H. (1995). Suppression of natural killer cell activity by monocytes following immunotherapy for recurrent spontaneous aborters. American Journal of Reproductive Immunology, 33(3), 221–227.
9. Kwak‐Kim, J., & Gilman‐Sachs, A. (2008). Clinical implication of natural killer cells and reproduction. American Journal of Reproductive Immunology, 59(5), 388–400.
10. Perricone C, De Carolis C, Giacomelli R, et al. High levels of NK cells in the peripheral blood of patients affected with anti-phospholipid syndrome and recurrent spontaneous abortion: a potential new hypothesis. Rheumatology (Oxford, England). 2007; 46:1574–1578.
11. Seshadri S, Sunkara SK. Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum Reprod Update. 2014; 20:429–438.
12. Miyaji M, Deguchi M, Tanimura K, Sasagawa Y, Morizane M, Ebina Y, Yamada H. Clinical factors associated with pregnancy outcome in women with recurrent pregnancy loss. Gynecol Endocrinol. 2019 Apr 23:1-6.
13. Ahmadi M, Ghaebi M, Abdolmohammadi-Vahid S, Abbaspour-Aghdam S, Hamdi K, Abdollahi-Fard S, Danaii S, Mosapour P, Koushaeian L, Dolati S, Rikhtegar R, Oskouei FD, Aghebati-Maleki L, Nouri M, Yousefi M. NK cell frequency and cytotoxicity in correlation to pregnancy outcome and response to IVIG therapy among women with recurrent pregnancy loss. J Cell Physiol. 2019 Jun;234(6):9428-9437.
14. Katano K, Suzuki S, Ozaki Y, Suzumori N, Kitaori T, Sugiura-Ogasawara M. Peripheral natural killer cell activity as a predictor of recurrent pregnancy loss: a large cohort study. Fertil Steril. 2013 Dec;100(6):1629-34.