The Major Role of Natural Killer cells in unexplained Infertility, RSAs, and Failed IVFs
Dr. Ioannis Toliopoulos, PhD, Molecular Biologist, Physiologist, Post doc in Reproductive Medicine
Dr. Spyridon Papageorgiou, Gynecologist, Obstetrician, Specialized in infertility
NK cells are the most important cells of the immune system, which are responsible for cleaning up abnormal cells in our bodies, such as early cancer cells, viruses, and bacteria. However, the role of the NK cells in reproductive medicine is quite different and unique. The number of the NK cells and as well as the activity of these cells are associated with the unexplained infertility, rapid spontaneous abortions (RSAs), and failed IVFs.
High NK cell activity has been associated with miscarriage and embryo implantation failure, because these cells attack the embryo in its eary development in the uterus and recognize as a foreign body. Further randomised trials are clearly needed to prove that treatment leads to better pregnancy outcomes. However, the results of the research to date are promising, and there are exciting possibilities for the future.
We agree that the NK cell population found in the uterine endometrium and in the decidua (typically CD16 negative, CD56 bright) are both
phenotypically and functionally different from those NK cells in the peripheral circulation (typically CD16+, CD56 dim). However, Fukui et al
(1999) have shown a significant increase in the percentage of endometrial CD16+ CD56dim peripheral blood type NK cells in women who failed IVF and embryo transfer compared to those who were successful. Additionally, Polgar and Hill (2002) have shown peripheral blood NK cells to produce embyrotoxic levels of Th1 type cytokines when stimulated with a trophoblast antigen extract. Thus, some of the NK cells that accumulate at the site of implantation are potentially of peripheral blood origin and are capable of damaging trophoblastic cells.
However, our provisional work does suggest that therapy aimed at reducing NK cell activation leads to an improved outcome
of IVF treatment and prevent miscarriages. Indeed glucocorticoids may be helpful in RM or recurrent idiopathic failed IVF precisely because they can inhibit the production of Th1 type cytokines and encourage Th2 type cytokines by antigen presenting cells and T helper cells (Elenkov, 2004).
The couples should ask and test the fertility or IVF centers about their diagnostic and therapeutic approach of the NK cells, the endometrial NK cells, and the activity of the NK cells. If they don’t check professionally these 3 biomarkers for NK cells, they lack of knowledge and the can lead to false diagnosis the therefore their treatment would be inadequate and will still lead the couples to remain infertile.
Chaouat G, Ledee-Bataille N, Dubanchet S, Zourbas S, Sandra O, Martal J. TH1/TH2 paradigm in pregnancy: paradigm lost? Cytokines in
pregnancy/early abortion: reexamining the TH1/TH2 paradigm. Int Arch Allergy Immunol. 2004; 134(2): 93-119.
Coulam CB, Roussev RG. Correlation of NK cell activation and inhibition markers with NK cytoxicity among women experiencing immunologic implantation failure after in vitro fertilization and embryo transfer. J Assist Reprod Genet. 2003; 20: 58-62.
Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004; 1024: 138-46.
Fukui A, Fujii S, Yamaguchi E, Kimura H, Sato S, Saito Y. Natural killer cell subpopulations and cytotoxicity for infertile patients
undergoing in vitro fertilization. Am J Reprod Immunol. 1999; 41: 413-22.
Strengell M, Sareneva T, Foster D, Julkunen I, Matikainen S. IL-21 up-regulates the expression of genes associated with innate immunity and Th1 response. J Immunol. 2002; 169: 3600-5.