Natural Killer Cell Dysfunction

What natural killer cells are

NK cells are part of the innate immune system, the body's first line of defense. They patrol the blood and tissues and destroy cells that look stressed, infected or cancerous, especially cells infected with herpes viruses (such as chickenpox, cold sore and CMV viruses) and human papillomavirus (HPV). They make up roughly 5% to 15% of the lymphocytes in blood.

A different population, uterine NK cells, lives in the lining of the womb. Despite the name, they rarely kill cells. They help remodel blood vessels and support the placenta in early pregnancy. They are normally abundant in the womb lining, which is one reason blood NK tests do not tell us much about what happens in the uterus.

NK cell deficiency (the immune disorder)

What it is

NK cell deficiency is a rare primary immunodeficiency in which NK cells are missing, very low or do not work properly. It is caused by gene changes, such as in GATA2, MCM4, GINS1 or FCGR3A. Two main forms are recognized:

• Classical NK deficiency: NK cells are absent or very low.
• Functional NK deficiency: NK cells are present in normal numbers but do not kill properly.

Symptoms

• severe or widespread chickenpox, or repeated shingles
• severe or recurrent herpes simplex infections
• serious cytomegalovirus or Epstein-Barr virus infections
• extensive warts and HPV-related precancer
• in some genetic forms, low blood counts, lung infections with unusual bacteria, lymphedema and a higher risk of blood cancers

Diagnosis

• Lymphocyte subsets by flow cytometry to count NK cells (CD56 and CD16 markers)
• NK cell function tests, which measure how well NK cells kill target cells in the lab, repeated to confirm
• Genetic testing
• tests to rule out secondary causes of low NK function, such as HIV, chemotherapy, steroids or other immune-suppressing drugs

Treatment

• antiviral medicines to treat and prevent herpes virus infections
• vaccines where safe, including HPV vaccination, and avoiding live vaccines if advised
• close cancer and precancer screening
• stem cell transplant for severe forms, especially GATA2 deficiency

See primary immunodeficiency and immunodeficiency for related conditions.

Other conditions involving NK cell dysfunction

Reduced NK killing also features in familial hemophagocytic lymphohistiocytosis (HLH), a dangerous over-activation of the immune system in infants and children, and has been studied in chronic fatigue syndrome and some autoimmune diseases, although it is not used to diagnose those conditions.

"High NK cells" and fertility

The theory

Some fertility clinics test blood or womb lining NK cells in people with recurrent miscarriage or repeated IVF failure, on the theory that too many or overactive NK cells attack the embryo. People told they have "elevated NK cells" may be offered steroids, intralipid infusions, intravenous immunoglobulin (IVIG) or other immune drugs.

What the evidence shows

• Blood NK cell counts and activity vary with stress, exercise, menstrual cycle phase and the lab method, and they do not reflect uterine NK cells.
• There is no agreed normal range for uterine NK cells, and high levels are found in many women with successful pregnancies.
• Randomized trials have not shown that steroids, intralipids or IVIG improve live birth rates for unexplained recurrent miscarriage or IVF failure.
• These treatments are expensive and carry risks, including infection, blood clots, high blood sugar and allergic reactions.

Major guidelines, including those from ESHRE, the RCOG and ASRM, recommend against routine NK cell testing and immune therapies outside research studies.

What evidence-based care looks like

After two or three pregnancy losses, guidelines support testing for:

• antiphospholipid syndrome, which is treatable with aspirin and heparin
• uterine shape problems, such as a septum, with ultrasound
• thyroid function and thyroid antibodies, and diabetes
• parental chromosome problems in selected couples
• lifestyle factors such as smoking, alcohol and weight

Even without a cause, the chance of a successful future pregnancy is good: most people with unexplained recurrent miscarriage go on to have a live birth, and supportive early pregnancy care helps. For female infertility, standard fertility assessment and treatment remain the priority.

Frequently asked questions

What does it mean to have high natural killer cells?

In a blood test, it means NK cells make up a larger share of lymphocytes than the lab's reference range. This can follow stress, exercise, infection or variation between labs, and it does not reliably mean the immune system is attacking a pregnancy. Most guidelines advise against acting on this result alone.

Do natural killer cells cause miscarriage?

There is no convincing evidence that high blood or uterine NK cells cause miscarriage. Uterine NK cells are normal and helpful in early pregnancy. Treatments aimed at lowering NK activity have not been shown to improve live birth rates, so they are not recommended outside research.

What is NK cell deficiency?

It is a rare inherited immune disorder in which natural killer cells are missing or do not work properly. People get severe or repeated infections with herpes viruses, such as chickenpox, cold sores and CMV, and extensive HPV warts. It is diagnosed with blood tests and genetic testing.

Should I pay for NK cell testing at a fertility clinic?

Current guidelines from ESHRE, ASRM and the RCOG do not recommend it, because results do not predict pregnancy outcomes and the treatments offered have not been shown to work. Ask your clinic what proven tests and treatments are available for your situation first.

How is natural killer cell deficiency treated?

Treatment focuses on preventing and treating viral infections with antiviral medicines, vaccines where safe, and careful screening for HPV-related precancer and blood cancers. In severe genetic forms, such as GATA2 deficiency, a stem cell transplant can cure the immune problem.