Reviews and feature article
Natural killer cell deficiency

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Natural killer (NK) cells are part of the innate immune defense against infection and cancer and are especially useful in combating certain viral pathogens. The utility of NK cells in human health has been underscored by a growing number of persons who are deficient in NK cells and/or their functions. This can be in the context of a broader genetically defined congenital immunodeficiency, of which there are more than 40 presently known to impair NK cells. However, the abnormality of NK cells in certain cases represents the majority immunologic defect. In aggregate, these conditions are termed NK cell deficiency. Recent advances have added clarity to this diagnosis and identified defects in 3 genes that can cause NK cell deficiency, as well as some of the underlying biology. Appropriate consideration of these diagnoses and patients raises the potential for rational therapeutic options and further innovation.

Section snippets

NKD definition

To be considered an NKD, the impact upon NK cells need represent the major immunologic abnormality in the patient. Although many diseases, drugs, infections, and physiologic states can affect NK cell numbers, function, or both, the NKD diagnosis is reserved for abnormalities that are fixed over time and not secondary in nature. Specifically, NKD should be inherent and hardwired. In several cases a genetic mechanism responsible for NKD has been identified. It is also anticipated that the

CNKD

CNKD is characterized by the absence of both NK cells and their functions among peripheral blood lymphocytes. The single most well known case is that published in 1989 in the New England Journal of Medicine of an adolescent girl with multiple severe or disseminated herpesvirus infections, including varicella pneumonia, disseminated cytomegalovirus (CMV), and herpes simplex virus (HSV).22 She was stably deficient in NK cell cytotoxic activity, as measured by using K562 killing assays, and lacked

FNKD

FNKD describes patients with normal numbers of NK cells present in peripheral blood but ones that are functionally disabled in the face of otherwise effective immunity.46, 47, 48, 49, 50, 51 An example of a well-known PID that results in absent NK cell function (cytotoxicity) would be perforin deficiency.52 However, perforin deficiency is not considered an FNKD because it also abrogates the lytic function of CTLs. Thus the FNKD label is reserved for an effect on NK cells in relative isolation.

Known PIDs associated with an NK cell abnormality

Although CNKD and FNKD represent a specific subset of PIDs, there are at least 46 known genetically defined PIDs that include an effect on NK cell numbers, function, or both. They can be divided into diseases that (1) impair NK cell development or survival, (2) impair the mechanics of cytotoxicity, (3) impair signaling for cytotoxicity, and (4) impair some other mechanism. They are listed in Table III,52, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80

Treatment of NKDs

A variety of treatments are reported as having been applied to patients with CNKD and FNKD. That said, there has never been an organized clinical trial of any therapy in these patients. Most therapeutic approaches have focused on the susceptibility to herpesviruses and the application of prophylactic antiviral drugs. Anecdotal cases have described perceived success, with the most common being the use of acyclovir, ganciclovir, and related agents.22, 27, 47, 50 Breakthrough infections might

Conclusion

A growing number of patients have been recognized who have immunodeficiency that affects NK cells as the majority immune defect. A larger number of broader PIDs also include an NK cell abnormality, which has been mechanistically informative and potentially clinically useful. However, detailed clinical and phenotypic evaluation of patients with NKD has allowed paradigms to emerge, which include susceptibility to herpesviruses and HPV, as well as patients who lack NK cells (CNKD) or their

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    Series editors: Donald Y. M. Leung, MD, PhD, and Dennis K. Ledford, MD

    Supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases grant R01067946 and the Jeffrey Modell Foundation.

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