Abortion caused by Natural Killer cell attack on the embryo

By (gynecologist) and (embryologist).
Last Update: 05/06/2022

Immunological infertility refers to alterations and disorders of the cells of the immune system that prevent pregnancy from occurring or developing normally.

Natural Killer (NK) cells are a type of cells of this immune system that, if they do not perform their function correctly, can cause repeated miscarriages by attacking the embryo.

Today, advanced diagnostic tests and specific treatments are available to enable these women to have a full-term pregnancy with the birth of a healthy baby.

What are Natural Killer?

Natural Killer cells are a type of lymphocyte that are part of the individual's innate immune system.

Its function is to identify and destroy foreign bodies, such as tumor cells or cells infected by pathogens, in order to protect the organism.

In addition to their defense function, NK cells are also involved in the regulation of the immune response through the secretion of substances known as cytokines.

To prevent these killer cells from destroying any healthy cells in the body itself, there are very strict control mechanisms in place. Natural Killer cells express inhibitory receptors that recognize class I molecules of the major histocompatibility complex (MHC class I) present on all of the body's own cells and therefore will not attack them.

These inhibitory receptors of Natural Killer cells are also known as KIR (Killer Immunoglobulin-like Receptor) kIR receptors killer Immunoglobulin-like Receptor (KIR).

In summary, the interaction of KIR with the MHC class I of healthy cells functions as a control system that prevents the destruction of the human body's own cells and tissues.

Adaptation of the immune system to pregnancy

Pregnancy is a special situation in a woman's body, because in principle the embryo is a "foreign body" that the immune system could attack and destroy.

Fortunately, the mother's body develops a tolerance mechanism in her immune system so as not to attack the baby growing inside her uterus.

The embryo has cells different from those of the mother, since half of its chromosomes have a paternal origin, so the Natural Killer lymphocytes could recognize it as foreign and cause rejection.

It is imperative that Natural Killer cells are well regulated throughout gestation. Otherwise, there will be a high risk of gestational loss and miscarriage.

Failure of the immune tolerance mechanism

Despite all of the above, the immune system and its regulatory mechanisms can fail and give rise to unexpected responses.

NK cells may exhibit an exaggerated and uncontrolled response that leads them to attack the embryo by recognizing it as foreign.

This type of infertility is known as alloimmune infertility alloimmune infertilitythis type of infertility is known as alloimmune infertility, since it is the consequence of a rejection of the embryo by the mother's own body.

Although these alterations can occur in apparently healthy women without any clinical manifestations, alloimmune infertility has a higher risk of occurring in women suffering from other immune system disorders, such as, for example:

  • Systemic lupus erythematosus (SLE).
  • Rheumatoid arthritis.
  • Vasculitis

In all cases, the main consequence of this disorder in women is recurrent miscarriages.

Diagnosis and Treatment

In the case of repeated early miscarriages without any apparent cause, such as genetic alterations or uterine malformation for example, it is recommended that the woman undergo specific tests such as a coagulation study and NK cell concentration in the blood.

Numerous investigations have revealed that there is a high probability of recurrent early miscarriage in women with an abnormally high number of Natural Killer cells.

To date, there is no 100% effective treatment to cure this immune disorder. However, there are some therapies or drugs aimed at reducing this abnormal response of the immune system without affecting the woman's health or fetal development:

  • Corticosteroids
  • Immunoglobulins
  • Heparin-based immune system modulators

Thanks to these drugs, many women with miscarriages or repeated failures in in vitro fertilization (IVF) treatments have achieved a successful pregnancy and the birth of a healthy child.

Numerous studies on the immune system continue today with important findings contributing to the solution of infertility caused by excessive Natural Killer lymphocyte response.

FAQs from users

Do natural killer cells provoke implantation failures?

By Zaira Salvador B.Sc., M.Sc. (embryologist).

Yes, recent studies have shown that women with repeated implantation failure have a higher number of NK cells and this increase is more significant in the endometrium than in the woman's blood.

What are the reference values for Natural Killer cells?

By Zaira Salvador B.Sc., M.Sc. (embryologist).

A percentage of NK cells higher than 24% in peripheral blood indicates a high risk of implantation failure or miscarriage. In addition, if the woman is older than 35 years, this reference value decreases to 18%.

Suggested for you

If you want to learn more about the types of both female and male immunological infertility, don't miss the following article: Immunological infertility: types, causes and treatments.

In addition to the attack by NK cells, the causes of repeated early miscarriages can be very varied, such as aneuploidy, uterine alterations or other disorders of the immune system. You can read more about it here: What is recurrent miscarriage?

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References

Alecsandru D, García-Velasco JA. Why natural killer cells are not enough: a further understanding of killer immunoglobulin-like receptor and human leukocyte antigen. Fertil Steril. 2017 Jun;107(6):1273-1278.

Chen X, Mariee N, Jiang L, Liu Y, Wang CC, Li TC, Laird S. Measurement of uterine natural killer cell percentage in the periimplantation endometrium from fertile women and women with recurrent reproductive failure: establishment of a reference range. Am J Obstet Gynecol. 2017 Dec;217(6):680.e1-680.e6.

Hanssens S, Salzet M, Vinatier D. Aspectos inmunológicos de la gestación. EMC - Ginecología-Obstetricia, 2013; 49(2):1-21

Koo HS, Kwak-Kim J, Yi HJ, Ahn HK, Park CW, Cha SH, Kang IS, Yang KM. Resistance of uterine radial artery blood flow was correlated with peripheral blood NK cell fraction and improved with low molecular weight heparin therapy in women with unexplained recurrent pregnancy loss. Am J Reprod Immunol. 2015 Feb;73(2):175-84.

Kuon RJ, Weber M, Heger J, Santillán I, Vomstein K, Bär C, Strowitzki T, Markert UR, Toth B. Uterine natural killer cells in patients with idiopathic recurrent miscarriage. Am J Reprod Immunol. 2017 Oct;78(4).

Seshadri S, Sunkara SK. Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis. Hum Reprod Update. 2014 May-Jun;20(3):429-38.

FAQs from users: 'Do natural killer cells provoke implantation failures?' and 'What are the reference values for Natural Killer cells?'.

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Authors and contributors

 Miguel Dolz Arroyo
Miguel Dolz Arroyo
M.D., Ph.D.
Gynecologist
Bachelor's Degree in Medicine and Surgery from the Medicine Faculty of the University of Valencia (UV) and Doctor in Medicine, finished in 1988 and 1995, respectively. Physician specialized in Obstetrics & Gynecology. Expert in Reproductive Medicine, with more than 20 years' experience in the field. He is the Medical Director and founder of FIV Valencia. More information about Miguel Dolz Arroyo
License: 464614458
 Zaira Salvador
Zaira Salvador
B.Sc., M.Sc.
Embryologist
Bachelor's Degree in Biotechnology from the Technical University of Valencia (UPV). Biotechnology Degree from the National University of Ireland en Galway (NUIG) and embryologist specializing in Assisted Reproduction, with a Master's Degree in Biotechnology of Human Reproduction from the University of Valencia (UV) and the Valencian Infertility Institute (IVI) More information about Zaira Salvador
License: 3185-CV

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