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NK cells

Natural Killer cells

Natural Killer cells (NK cells) make up about 5-10% of the white blood cells (lymphocytes) and are an essential part of the immune system. They keep the body healthy by removing unhealthy, old or foreign cells and play a crucial role in stopping infections and removing tumours.  NK cell actions are essential for restructuring and enabling growth. NK cells also have immune functions beyond this direct role, as their numbers and activity influence how other parts of the immune system behave. i

The immune system is very complex, and different types of cells have slightly different roles. NK cells are part of the innate immunity that spontaneously identifies and kill abnormal cells they encounter (hence “natural killer”) with chemicals that destroy them. They function slightly differently from specialist T and B cells that are part of our acquired immunity (Immune infertility).

Natural killer cells have two types of receptors on their surface which literally ‘switch’ them ‘ON’ or ‘OFF’. There are hundreds of types of NK cells, which have been coded (in CDs) according to the receptors on their surface. A “classic” white blood cell is the CD56+ which attacks non-self and altered-self cells like bacteria and cancer cells.

The NK cells are usually in the ‘OFF’ mode, but contact with abnormal cells turn them ‘ON’. In some circumstances, they can become hyper-activated ‘killing machines’ that release high levels of cytokines in a heightened immune response. It’s generally true to say that:

  • Low NK cell activity is associated with susceptibility to infections and tumours. Cancer patient blood is often analysed for NK-cell activity and numbers to assess their ability to fight off illnesses.
  • A high level of active NK cells is associated with autoimmune illnesses and some fertility problems.

Different NK cell types

The various specialist NK cells have different properties and can be specific to parts of the body (including the uterus). NK cells circulating in the blood can also be in the uterus, and they’re usually more aggressive than Uterine NK cells (uNK). CD56+/CD16– are a type of uNK cell; they’re numerous in the womb lining during the “window of implantation” and for the first 20 weeks of pregnancy. These particular uNK cells have an essential role by:

  1. Protecting the placenta from other white blood cells.
  2. Encouraging implantation by helping the placenta establish a good blood supply, yet preventing it from “burrowing” into the womb’s muscle.

The number and types of NK cells vary depending on the part of the body, time of the cycle and emotional and physical triggers. This includes a fall in the NK cell numbers in the blood on days when implantation is possible. Uterine natural killer cell numbers are known to be affected by:

  • The day of the cycle.
  • Whether the woman’s had intercourse recently.
  • The woman’s mood (being depressed or not).

Elevated natural killer cell numbers

Implantation usually happens 7 to 10 days after ovulation. It should coincide with lower levels of general circulating NK cells, reducing the chances of NK cells actively accumulating at the implantation site. If this does happen, they can attach to placental tissue and release toxins (such as cytokines) that disrupt and kill cells and affect pregnancy by:

  • Stopping cell division. ii
  • Preventing implantation. iii
  • Delaying the development of the embryo. iv
  • Causing bleeding and blood-cyst formation behind the placenta. v

High levels of these cytokines also alert the rest of the immune system to a problem, which encourages more NK cells to join and release other cytokines, creating a massive hurdle for pregnancy to overcome.

Natural killer cells and female fertility

Some women who have high levels of NK cells and cytokines in their blood will notice the flu-like symptoms of an immune response (such as fever, aching limbs, cramps and fatigue) around the time of a failed implantation or miscarriage. Blood testing for NK cell levels can indicate the status of the immune response:

‘When the level of NK cells in a normal blood sample is over 18%, the likelihood of a successful pregnancy is greatly reduced’ vi

The natural killer cells directly associated with infertility are CD56+, CD57+, CD69+ and CD19+5. Women with the highest level of NK cell activity have usually had the experience of:

  • Three or more implantation failures with IVF.
  • One successful pregnancy, but then experienced secondary infertility.
  • Three or more miscarriages.
  • Antibodies to the thyroid gland.
  • Abnormal APA test results and pelvic disease such as pelvic inflammatory disease (PID).
  • A known autoimmune disease (such as Crohn’s disease).
  • Endometriosis.
  • A history of human papillomavirus (HPV), abnormal cervical cells, cervicitis (inflammation of the cervix) or genital warts.

Natural killer cells have a complex role in fertility that’s not fully explained yet:

  • Some natural killer cells create antibodies to hormones that are essential to the menstrual cycle; for instance, insufficient progesterone in the luteal phase (luteal phase deficiency) may be due to raised NK cell numbers and activity.
  • High levels of active NK cells are associated with raised cytokine levels, and the newly discovered tumour necrosis factor type of cytokine (TNF-α-MMP9-SRC-1 isoform) promotes the progression of endometriosis, vii which raises further questions about the wider role of the immune system in fertility.
  • Elevated and overactive levels of NK cells are also associated with other immune disorders:

IVF and natural killer cell activity

The stimulation that’s part of most IVF cycles requires abnormally high oestrogen levels. High oestrogen also stimulates the bone marrow to produce more NK cells, which is associated with infertility problems for women who have:

  • Poor egg quality. vii
  • Abnormal cell division of the developing embryo. ix
  • Irregularly shaped gestational sacs. x
  • Blighted ova. xi

Testing and Treatment

Blood samples will show raised and overactive NK cells in the blood. However, the fertility-related NK cells (CD57+) requires an endometrial biopsy.

Currently, the treatment for raised NK cells is to suppress the immune system with interventions using IVIg, intralipids, adalimumab (Humira) and steroids (dexamethasone or prednisolone) + calcium.

Herbal medicine has effective treatment options for raised NK cells. One regime resulted in 96% (of 277 patients) xii re-testing to within normal levels after three months of herbs, while in another option, 92% of patients re-tested as normal in eight weeks. To access science-based fertility support, choose one of the morefertile packages.