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    • The role of NK cells in

    2018-11-07

    The role of NK LY2584702 in anti-tumour responses has been extensively studied, for various types of tumour, in animal models and humans (Vivier et al., 2012; Shafer et al., 2013; Velardi et al., 2012). Imai and colleagues reported that low peripheral NK cell cytotoxicity was associated with a higher incidence of cancer (Imai et al., 2000). Surprisingly, in our study comparing CVID patients with different counts of peripheral NK cells, no differences between groups were observed for the incidence of neoplasms, including solid tumours and lymphomas. The median time from the onset of symptoms and evaluation in this study was 18 to 24.3years in the groups studied, and the duration of follow-up would also be unlikely to account for this lack of association. The relatively young age at evaluation (median: from 40.5 to 44.8years, depending on the group considered) in the DEFI study may account for the missing cancers, as many tumours occur after the age of 50years (most of the events in the study by Imai and colleagues) (Imai et al., 2000). The main finding in this study was the high frequency of invasive bacterial infections in CVID patients with severe NK cell lymphopenia (68.7%). This frequency was higher than that in patients with mild (60.2%) or no NK cell lymphopenia (48.8%). This higher incidence of severe bacterial infections was accounted for by a higher incidence of pneumonia and sepsis/bacteremia in particular, with bacteremia being found in 22.2% of patients with severe NK cell lymphopenia (versus only 5.9% and 8.3% of the patients in the other two groups). This higher incidence of severe bacterial infection did not seem to be related to the proportion of splenectomised patients, similar in the 3 studied groups, or to be related to an associated CD4+ T cell deficiency, because it persisted in the NK−T+ group, particularly for sepsis/bacteremia. Several studies have reported protective or deleterious roles of NK cells in various models of bacterial infectious diseases. A protective role for NK cells was demonstrated for infections with Listeriamonocytogenes, Mycobacteriumavium, Mycobacteriumtuberculosis and various strains of Salmonella (Katz et al., 1990; Harshan and Gangadharam, 1991; Bermudez et al., 1990; Wherry et al., 1991; Vankayalapati et al., 2005). Similarly, NK cells have been shown to play a critical protective role in septic arthritis and models of pulmonary infection with Staphylococcus aureus (Nilsson et al., 1999; Small et al., 2008). The mildly protective role of NK cells in these bacterial infections is thought to involve IFN-γ secretion, promoting macrophage phagocytic functions and/or the lysis of infected macrophages through the recognition of as yet unidentified activation ligands (Souza-Fonseca-Guimaraes et al., 2012). By contrast, deleterious effects of NK cell activation were reported after infection with gram-negative bacteria such as with Escherichia coli (Badgwell et al., 2002) or gram-positive bacteria such as with S. pneumoniae (Kerr et al., 2005). In these conditions, NK cells have been shown to contribute to septic shock (Barkhausen et al., 2008; Carson et al., 1999; Emoto et al., 2002; Heremans et al., 1994), but their depletion in S. pneumoniae-infected mice has also been reported to impair bacterial clearance (Elhaik-Goldman et al., 2011). The dual role of NK cells, which may be initially beneficial, helping to control bacterial load, but may then become deleterious in the acute phase of sepsis, mediating tissue damage, requires further investigation. The prevalence of non-infectious disease-related complications, such as granuloma in particular, was also found to be higher in patients with severe NK cell lymphopenia than in patients with mild or no NK cell lymphopenia. In a description of 59 patients with granulomatous disease and CVID from the DEFI study, patients with granulomatous disease had lower NK cell counts (median: 60×106/L) than patients without granulomatous disease (median: 109×106/L) (Boursiquot et al., 2013). NK cell counts were not available in other series of patients with granulomatous disease and CVID (Ardeniz and Cunningham-Rundles, 2009; Bouvry et al., 2013; Mullighan et al., 1997). The etiology and mechanisms involved in granuloma in patients with CVID have yet to be elucidated. Granuloma may be a consequence of a persistent but undetected infection with a virus or another microorganism, leading to weaker cell-mediated, and possibly NK cell immunity. Consistent with this hypothesis, Bodemer and colleagues recently described the long-term persistence of live rubella virus vaccine as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency (Bodemer et al., 2014). Advanced DNA sequencing technologies might be able to detect the presence in granuloma lesions of microbes not detected in conventional in vitro growth assays.