The NK (Natural Killer) Cell Assay

Natural Killer (NK) Cells
NK (Natural Killer) cells are a type of immune cell involved in the early detection and elimination of:

  • Virus infected cells
  • Cells of foreign origin
  • Cancer cells

They are called 'Natural Killer' cells because they can identify and eliminate abnormal cells directly, making them an important first line of immune defence.
NK cells can be identified by the presence of a protein called CD56 on their cell surface.

The most common type of NK cell circulating in peripheral blood is CD56+CD16+. This means it has both proteins CD56 and CD16 on it's cell surface. These peripheral NK cells mediate mainly a cytotoxic response which means they can directly attach to abnormal cells and rupture cell walls, causing cell death.

During pregnancy, cells that are genetically different to the mother, invade the lining of the womb. The growing placenta attempts to connect with the mother's blood supply for nourishment. These cells should be recognised by the mother's immune system and targeted for elimination. However during embryo implantation and pregnancy, a special form of immunosuppression exists and there is a shift in the balance of NK cells.

A special type of NK cell exists in the uterus. These NK cells are CD56+CD16- and called uNK (uterine Natural Killer) cells. These cells display less cytotoxic activity but do produce cytokines, including TNF-α (Tumour necrosis factor alpha), IFN-γ (Interferon gamma) and IL-10 . Once an NK cell becomes activated it can attach to the abnormal cell and spray TNF-α on it's cell wall to kill it.

During normal healthy pregnancies uNK cells play an important role. They help the embryo invade the lining of the womb and produce factors that cause the growth of blood vessels (angiogenic growth factors) to support the growth of the placenta.

However uNK cells can become activated and cytotoxic to other cells when there is an infection, an embryo degenerates or a pregnancy fails.
uNK activation can cause:

  • Fertility treatments to fail
  • Blighted ovum
  • A chemical pregnancy where hCG levels rise but quickly returns to original levels
  • Subsequent pregnancies to fail

Increased numbers of uNK cells have been associated with recurrent miscarriage (Quenby, S., et al., 1999), recurrent implantation failure (Tuckerman, E., et al., 2010), uterine fibroids (Kitaya, K., and Yasuo, T., 2010), sporadic miscarriage (Zenclussen, A.C., et al., 2001), fetal growth restriction (Williams, P.J., et al., 2009a) and preeclampsia (Williams, P.J., et al., 2009a).

The NK Assay
NK cell activity or aggression towards other cells can be measured in two ways, either using a peripheral blood test or an endometrial biopsy.
The peripheral blood test looks at the cytotoxic potential of NK cells in the blood. These cells are thought to reflect uNK activity. Normal levels for these cells are 3-12% (Beer A.E. et al., 1996). Levels above 18% are associated with poor reproductive outcomes. However there is controversy over what is considered the normal range (Yamada, H., et al., 2003; Emmer P.M., 2000). Peripheral NK cells can increase significantly with stress and exercise (Timmons, B.W. and Cieslak, T., 2008). There is also debate about the relationship between peripheral NK cells and uNK cells.
Laboratory testing methods involve isolating NK cells and placing them with another cell line, whose rapid cell division and growth mimics that of the placenta or embryo. NK cells attack the other rapidly dividing cells. Once NK cytotoxic activity is measured, scientists add different concentrations of IVIG (intravenous immunoglobulin) or Intralipid in order to determine the level required to suppress NK cytotoxic activity. The correct level of IVIG or Intralipid can then be prescribed to the patient pre-conception. These immunosuppresants help to suppress overactive NK cells in the uterus.
An endometrial biopsy involves taking a tiny piece of the lining of the uterus and testing uNK activity directly.

Treatments to suppress NK cell activity include:

  • High-dose steroids - Corticosteroids e.g. Prednisone
  • Intravenous immunoglobulin (IVIg) - antibodies extracted from donor blood
  • TNF-α blocking agents e.g. Humira

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