Natural killer cell deficiency

Abstract

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.

Keywords: ADCC; Antibody-dependent cell-mediated cytotoxicity; CMV; CNKD; CTL; Classical natural killer cell deficiency; Cytomegalovirus; Cytotoxic T lymphocyte; DOCK8; Dedicator of cytokinesis 8; FNKD; Functional natural killer cell deficiency; HPV; HSV; Herpes simplex virus; Human papillomavirus; MCM; Minichromosome maintenance; NK; NKD; Natural killer; Natural killer cell deficiency; Natural killer cells; PID; Primary immunodeficiency; VZV; Varicella zoster virus; cytotoxicity; innate immunity; natural killer cell deficiency; primary immunodeficiency.

Figure 1

Flow cytometry depicting peripheral blood NK cell subsets according to CD56. PBMC from a normal donor were evaluated by FACS and gated lymphocytes analyzed for expression of CD3 and CD56 (left). NK cells are CD56⁺/CD3⁻. To illustrate the range of CD56 expression, all CD3⁻ cells (non-T cells) were gated (purple box – left) and displayed as a histogram (right). Here there are 3 clear populations: CD56^neg (blue peak), which are not NK cells, CD56^dim NK cells (green peak), and CD56^bright NK cells (red peak). In this example the CD56^bright NK cells represent 4% of the CD3⁻ cells or 5.8% of the total NK cells (CD56^dim plus CD56^bright). Experimental credit to Dr. Emily Mace, Baylor College of Medicine.

Figure 2

Diagnostic algorithm for NKD. An algorithmic approach to a patient suspected of having NKD is presented. Initial steps include considering alternative diagnoses as they are statistically more likely, as well as quantifying NK cells and their function in peripheral blood. Abnormal results should be repeated with a time interval of approximately one month. Absent NK cells are defined as ≤1% of peripheral blood lymphocytes. Cytotoxicity testing for screening is recommended by ⁵¹Cr-release assay using K562 target cells; normative ranges differ between laboratories and laboratory-specific ranges should be considered. Secondary (2°) causes should be considered as explanations for abnormalities. More advanced functional and phenotypic testing is presently in the domain of research-level interventions.