Adaptive Features of Natural Killer Cells in Multiple Sclerosis

Abstract

Human cytomegalovirus (HCMV) has been recently related with a lower susceptibility to multiple sclerosis (MS). HCMV promotes an adaptive development of NK cells bearing the CD94/NKG2C receptor with a characteristic phenotypic and functional profile. NK cells are proposed to play an immunoregulatory role in MS, and expansion of the NKG2C(+) subset was recently associated with reduced disability progression. To further explore this issue, additional adaptive NK cell markers, i.e., downregulation of FcεRIγ chain (FcRγ) and PLZF transcription factor, as well as antibody-dependent NK cell activation were assessed in controls and MS patients considering HCMV serology and clinical features. In line with previous reports, increased proportions of NKG2C(+), FcRγ(–), and PLZF(–) CD56dim NK cells were found in HCMV(+) cases. However, PLZF(–) NK cells were detected uncoupled from other adaptive markers within the CD56bright subset from HCMV(+) cases and among CD56dim NK cells from HCMV(–) MS patients, suggesting an additional effect of HCMV-independent factors in PLZF downregulation. Interferon-β therapy was associated with lower proportions of FcRγ(–) CD56dim NK cells in HCMV(+) and increased PLZF(–) CD56bright NK cells in HCMV(–) patients, pointing out to an influence of the cytokine on the expression of adaptive NK cell-associated markers. In addition, proportions of NKG2C(+) and FcRγ(–) NK cells differed in progressive MS patients as compared to controls and other clinical forms. Remarkably, an adaptive NK cell phenotype did not directly correlate with enhanced antibody-triggered degranulation and TNFα production in MS in contrast to controls. Altogether, our results provide novel insights into the putative influence of HCMV and adaptive NK cells in MS.

Herpesvirus Antibodies, Vitamin D and Short-Chain Fatty Acids: Their Correlation with Cell Subsets in Multiple Sclerosis Patients and Healthy Controls

“…Finally, a statistically significant correlation was also found between VCA IgG titers and the starting age, only among treated MS patients (negative correlation; Supplementary Table S4 ). Although EBV has been repeatedly associated with MS [ 2 , 9 , 65 ], and we have found statistically significant differences in the prevalence of EBNA-1 IgG between MS patients an HC, and in the EBNA-1 and VCA IgG titers between untreated MS patients and HC, we have not found any correlation between them and the other environmental factors, with the clinical variables analyzed or with the immune cells in our study. The only correlation found is the one mentioned above: higher VCA IgG titers were found in those MS patients with a lower age of onset.…”

“…Thus, untreated MS patients showed significantly higher levels of HHV-6A/B IgG ( p = 0.0005), EBNA-1 IgG ( p = 0.0004), VCA IgG ( p = 0.010) and AA ( p = 0.011) in comparison with HC, but significantly lower levels of 25(OH) ( p = 0.007) and a significant decrease of the PA/AA and BA/AA ratios ( p < 0.0001 in both cases). These results would support the possible involvement of these viruses, the vitamin D and the SCFAs in MS etiopathogenesis, as it has been widely published in recent years [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. When we analyzed their possible correlations, we found differences between HC and MS patients.…”

“…Despite the controversial results, the serological status against this virus was found associated with the risk of MS through the induction of differentiated T- and NK-cell subsets [ 8 ]. In another paper of the same group, authors showed that CMV seropositivity was associated with greater proportions of NKG2C(+) NK cells, with no significant differences between MS patients and controls [ 9 ].…”

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

“…The increase of clonally expanded CD8 T cells and of anti-CMV antibodies associate with immunosenescence ( 12 ). In addition, CMV infection occurs more frequently in older individuals in MS and associates with lower production of pro-inflammatory cytokines and ( 36 , 37 ). These data show that M- patients show an early immunosenescence process associated with a down-regulation of the pro-inflammatory adaptive immune response.…”

CD56bright Natural Killer Cells: A Possible Biomarker of Different Treatments in Multiple Sclerosis

“…The antiviral function of CD56 dim NK cells may be important in controlling MS. CD56 dim NK cells are involved in the immune response against infection by cytomegalovirus (CMV), and such an infection is associated with a lower risk of developing MS. A recent study showed that NK cells from patients with progressive MS, and particularly, primary progressive MS, have lower effector function towards target cells; the authors speculate that this might contribute to lower capability of killing viruses such as the Epstein-Barr virus, which may be involved in MS pathogenesis [27]. Others hypothesize that CD56 dim NK cells could be detrimental: increased numbers of CD56 dim NK cells expressing perforin have been found in patients with secondary progressive MS [28].…”