NK cells

Natural Killer cells (NK cells) make up about 5-10% of our white blood cells (lymphocytes) and are an essential part of the immune system, keeping us healthy by removing unwanted, damaged or foreign cells. They play a crucial role in stopping infections and removing tumours and are essential for restructuring and enabling growth. NK cell numbers and activity also influence how other parts of the immune system behave, which extends their immune function beyond a direct “killer” role. ⁱ

NK cells are part of the innate immunity that identify and kill any abnormal and “non-self” cells they encounter (hence “natural killer”) with chemicals. They function differently from specialist T and B cells that are part of our acquired immunity, but the immune system is complex, and different cell types have slightly different roles. 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 are coded (in CDs) according to the receptors on their surface
• A “classic” white blood cell is 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 turns them “ON”, and in some circumstances, they can become hyper-activated “killing machines” that release high levels of cytokines in a heightened immune response called a “cytokine storm”. It’s generally true to say that:

• Low NK cell activity is associated with susceptibility to infections and tumours, and cancer patients’ blood is often analysed for NK-cell activity and numbers to assess the ability to fight off illnesses
• A high level of active NK cells is associated with autoimmune illnesses and some fertility problems

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 generally circulating in the blood can also accumulate in the uterus, and they’re usually more aggressive than Uterine NK cells (uNK). One of the uterine NK cells is CD56+/CD16– and they’re found in higher concentrations in the womb lining during the “window of implantation” and the first 20 weeks of pregnancy. These particular uNK cells play an essential role in pregnancy 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 general NK cell numbers in the blood on days when implantation is possible. We know that uterine NK cell numbers are 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, and this should coincide with lower levels of general circulating NK cells. This reduces the chances of NK cells actively accumulating at the implantation site because if that happens, they can attach to placental tissue and release toxins (including cytokines) that disrupt and kill cells or affect pregnancy by:

• Stopping cell division ⁱⁱ
• Preventing implantation ⁱⁱⁱ
• Delaying the development of the embryo ^iv
• Causing bleeding and blood-cyst to form 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, and women with the highest level of NK cell activity have usually experienced:

• 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)
• An 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 complex roles in fertility that haven’t been fully explained yet:

• Some natural killer cells create antibodies to hormones that are essential to the menstrual cycle. An example of this is that 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 a 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:
  • Antiphospholipid antibodies (APA)
  • Anti-DNA antibodies (ANA)
  • Antisperm antibodies (ASAb)

IVF and natural killer cell activity

The stimulation that’s part of most IVF cycles results in abnormally high estrogen levels from the many large follicles. Estrogen is inflammatory and it stimulates the bone marrow to produce more NK cells, which creates further 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, which works for most of the NK cells except for CD57+, which requires an endometrial biopsy.

1. The current standard treatment for raised NK cells is to suppress the immune system with IVIg, intralipids, adalimumab (Humira) and steroids (dexamethasone or prednisolone) + calcium.
2. An alternative approach with herbal medicine offers 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
  • Another option resulted in 92% of patients re-testing as normal in eight weeks.

Access to this science-based fertility support is part of the morefertile PFP packages.