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Tuesday, September 3, 2013

Primary NK immunodeficiencies

Keeping on the topic of natural killer cells, Jordan Orange, MD, PhD contributes a review on immunodeficiencies associated with NK cell dysfunction [J Allergy Clin Immunol 2013; 132(3):515-525].  The author provides a concise review of NK cell biology, covering their intrinsic activities of cytotoxicity, tumor surveillance, and co-stimulation and signaling.  Orange points out that NK cell deficiency [NKD] is a subset of primary immunodeficiency diseases [PID] that is difficult to diagnose and treat because of the limited clinical information and testing available. 

Like other PID, the author notes that NKD patients are characterized by a susceptibility to chronic and/or severe viral infections, especially herpes viruses.  Accurate diagnosis hinges on determining that the seminal deficiency is associated with NK cells, and that NKD is not secondary to other causes. The author provides an algorithm for identifying primary NKD. 

Orange discusses the current classification of NKD into two types:  classical NKD and functional NKD.  Classical NKD [CNKD] is characterized by severe depletion or absence of NK cells in peripheral blood, while functional NKD [FNKD] is typified by the presence of peripheral NK cells with impaired or abrogated activity.  He points out that there is some overlap in these phenotypes in the reported cases.  Orange further discusses the subtypes of CKND and their associated genetic abnormalities.  In his discussion of FNKD, the author reports on the first identified subtype, FNKD1, which involves a defect in the IgG receptor. 

Orange continues describing the clinical cases that have been reported and the availability and applicability of diagnostics for NKD.  The author also reviews briefly other PID that effect NK cell immunity, but that affect other components of the immune system in the majority.  Addressing the clinical treatment of NKD, he notes that intervention is focused on the herpetic infection susceptibility and employs approved antivirals such as gancyclovir.  Additionally, the author reports that severe presentations of NKD have been treated successfully with stem cell transplantation.  

Natural killer cell interactions in adaptive immunity

This month, Deniz et al. give an overview of current knowledge about natural killer cells [NK cells] and their interface with pathways and mechanisms of adaptive immunity, with attention to allergic disease processes [J Allergy Clin Immunol 2013; 132(3):527-535]. 

The authors cover fundamentals of NK biology, such as their surface marker characterization, IFN-γ secretion, MHC class I interactions, phenotypes, tissue prevalence, cytokine profiles, and cytotoxicity to target cells.  NK cells are characterized by their cytotoxic activity through release of perforin and granzymes that are targeted at tumor cells, virally infected cells, and IgG antibody expressing cells, cytokine and chemokine secretion and signaling of adaptive immune cells, and co-stimulatory interaction with antigen presenting cells [APC] via IL-10 and TGF-β.   Deniz et al. note that NK chemokine secretion is particularly important in the co-localization and mutual maturation of dendritic cells [DC] and NK cells in areas of inflammation. 

The authors discuss the interesting parallels between NK cell subsets and T cells, noting the overlaps in surface markers and cytokine expression.  NK cells subsets consist of NK1 and NK2 cells, analogous to Th1 and Th2 cells, NK regulatory cells, NK-17 cells and NK-22.  They point out that peripheral blood mononuclear cells [PBMC] from patients with asthma showed decreased NK1 and increased NK2 levels, suggesting a NK2 bias that shadows the Th2 bias.  Also discussed was the protective effect that has been associated with NK-17 cells in rheumatoid arthritis and NK-22 cells on epithelial cell response to contact sensitivity. 

The authors discuss the limited evidence that has been reported to date on NK cell interactions in allergic diseases.  They discuss skin NK cells are known orchestration of keratinocyte apoptosis through type I cytokine signaling.  Also covered is the critical role of DCs in the evolution of NK cells.  Deniz et al report that NK cell expression and cytotoxicity is increased in patients with allergic rhinitis.  NK1 cells, but not NK2 cells, are also known to have anti-IgE activity. 

The authors conclude commenting that, while findings are limited, there is growing evidence that NK cells, like many innate immune cells, have important interactions with adaptive immune cells.  The research should now be focused to understand the characteristics of these cells in different endotypes and phenotypes of asthma, atopic dermatitis and other chronic inflammatory diseases.