Impaired Natural Killer Cell Activity Research Articles

Gross Total Resection Promotes Subsequent Recovery and Further Enhancement of Impaired Natural Killer Cell Activity in Glioblastoma Patients.

Highlights Natural killer cell activity is dramatically impaired in patients with glioblastoma.Surgical resection of glioblastoma promotes redistribution of NK cell subsets and increases NK cell activity 30 days after surgery.Gross total resection rather than subtotal resection significantly recovers and further increases the impaired NK cell activity in patients with glioblastoma. Glioblastoma is the most common primary malignant brain tumor, and median survival is relatively short despite aggressive standard treatment. Natural killer (NK) cell dysfunction is strongly associated with tumor recurrence and metastasis but is unclear in glioblastoma. NK activity (NKA) represents NK cell-secreted interferon-γ (IFN-γ), which modulates immunity and inhibits cancer progression. This study aimed to analyze NKA in glioblastoma patients to obtain a clearer overview of immunity surveillance. From 2020 to 2021, a total of 20 patients and six healthy controls were recruited. Peripheral blood samples were collected preoperatively and on postoperative days (POD) 3 and 30. Then, NKA was measured using the NK VUE kit. Although NKA decreased on POD3, it recovered and further significantly enhanced on POD30, with a nearly five-fold increase compared to baseline (p = 0.004). Furthermore, the percentage of CD56brightCD16− NK cells decreased significantly on POD3 (p = 0.022) and further recovered on PO30. Subgroup analysis of extent surgical resection further revealed that the recovery of impaired NKA was attributable to gross total resection (GTR) rather than subtotal resection (STR). In conclusion, NKA is significantly impaired in glioblastoma, and GTR has demonstrated superior benefit in improving the suppressed NKA and increased CD56brightCD16− NK subset in glioblastoma patients, which may be associated with subsequent patients’ prognosis. Therefore, the goal of performing GTR for glioblastoma should be achieved when possible since it appears to increase NKA cell immunity.

Mitochondrial Dysfunction Contributes to Impaired Cytokine Production of CD56bright Natural Killer Cells From Human Immunodeficiency Virus-Infected Individuals Under Effective Antiretroviral Therapy.

Human immunodeficiency virus (HIV) infection is associated with impaired natural killer (NK) cell activity, which is only incompletely restored under antiretroviral therapy. Analyzing the bioenergetics profiles of oxygen consumption, we observed that several parameters were significantly reduced in HIV+ NK cells, indicating a mitochondrial defect. Accordingly, we found HIV+ CD56bright NK cells to display a decreased mitochondrial membrane potential and mitochondrial mass. Both parameters were positively correlated with interferon gamma (IFN-γ) production of NK cells. Finally, we demonstrated that stimulation of HIV+ NK cells with MitoTEMPO, a mitochondria-targeting antioxidant, significantly improved IFN-γ production. We identified mitochondrial dysfunction as a mechanism that contributes to impaired NK cell function.

A rare case of secondary hemophagocytic lymphohistiocytosis with severe acute malnutrition in an infant

Hemophagocytic lymphohistiocytosis (HLH) is a rare hematological entity in children that presents with unremitting fever, organomegaly, cytopenias, hemophagocytosis by activated macrophages, and results in a fatal outcome in untreated cases. Other biochemical abnormalities include hyperferritinemia, hypertriglyceridemia, hypofibrinogenemia, increased soluble interleukin-2 receptor levels, histological evidence of benign hemophagocytic macrophage, and impaired natural killer cell activity. It is the result of an aberrant hyper inflammatory response that usually does not respond to conventional treatment. Secondary HLH is mostly associated with infection, malignancy, and autoimmune diseases and usually resolves on the treatment of the primary condition. Severe acute malnutrition (SAM) causing secondary HLH is rare, although hemophagocytosis in bone marrow without other diagnostic features of HLH is seen in many deficiency states including SAM. Here, we present a 1-year-old female child with SAM and secondary HLH focusing on clinical manifestation, diagnosis and treatment.

High-Fat Diet and Feeding Regime Impairs Number, Phenotype, and Cytotoxicity of Natural Killer Cells in C57BL/6 Mice.

Overweight and obesity are major public health challenges worldwide. Obesity is associated with a higher risk for the development of several cancer types, but specific mechanisms underlying the link of obesity and cancer are still unclear. Natural killer (NK) cells are circulating lymphoid cells promoting the elimination of virus-infected and tumor cells. Previous investigations demonstrated conflicting results concerning the influence of obesity on functional NK cell parameters in small animal models. The aim of the present study was to clarify potential obesity-associated alterations of murine NK cells in vivo, implementing different feeding regimes. Therefore, C57BL/6 mice were fed a normal-fat diet (NFD) or high-fat diet (HFD) under restrictive and ad libitum feeding regimes. Results showed diet and feeding-regime dependent differences in body weight, visceral fat mass and plasma cytokine concentrations. Flow cytometry analyses demonstrated significant changes in total cell counts as well as frequencies of immune cell populations in peripheral blood comparing mice fed NFD or HFD in an ad libitum or restrictive manner. Mice fed the HFD showed significantly decreased frequencies of total NK cells and the mature CD11b+CD27+ NK cell subset compared to mice fed the NFD. Feeding HFD resulted in significant changes in the expression of the maturation markers KLRG1 and CD127 in NK cells. Furthermore, real-time PCR analyses of NK-cell related functional parameters in adipose tissue revealed significant diet and feeding-regime dependent differences. Most notable, real-time cytotoxicity assays demonstrated an impaired cytolytic activity of splenic NK cells toward murine colon cancer cells in HFD-fed mice compared to NFD-fed mice. In conclusion, our data demonstrate that feeding a high-fat diet influences the frequency, phenotype and function of NK cells in C57BL/6 mice. Interestingly, restricted feeding of HFD compared to ad libitum feeding resulted in a partial prevention of the obesity-associated alterations on immune cells and especially on NK cells, nicely fitting with the current concept of an advantage for interval fasting for improved health.

Impaired natural killer cell counts and cytolytic activity in patients with severe COVID-19

AbstractThe global pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–driven coronavirus disease 2019 (COVID-19) has caused unprecedented human death and has seriously threatened the global economy. Early data suggest a surge in proinflammatory cytokines in patients with severe COVID-19, which has been associated with poor outcomes. We recently postulated that the inflammatory response in patients with severe COVID-19 disease is not inhibited by natural killer (NK) cells, resulting in a “cytokine storm.” Here, we assessed the NK-cell functional activity and the associated cytokines and soluble mediators in hospitalized COVID-19 patients. Significantly impaired NK-cell counts and cytolytic activity were observed in COVID-19 patients when compared with healthy controls. Also, cytokines like interleukin 12 (IL12), IL15, and IL21 that are important for NK-cell activity were not detected systematically. Serum concentrations of soluble CD25 (sCD25)/soluble IL2 receptor α (sIL2-Rα) were significantly elevated and were inversely correlated with the percentage of NK cells. Impaired NK-cell cytolytic activity together with other laboratory trends including elevated sCD25 were consistent with a hyperinflammatory state in keeping with macrophage-activation syndrome. Our findings suggest that impaired counts and cytolytic activity of NK cells are important characteristics of severe COVID-19 and can potentially facilitate strategies for immunomodulatory therapies.

Нарушение функциональной активности естественных киллеров при экспериментальном инсульте различной степени тяжести

Актуальность. Изучение факторов риска развития инфекционно-воспалительных осложнений и путей их снижения при инсульте является актуальной неврологической проблемой. Цель: оценка функциональной активности клеток естественных киллеров в остром периоде экспериментального инсульта различной степени тяжести. Методы. В проведенном экспериментальном исследовании на животных (крысы линии Вистар, массой 200-220 г, n = 50) изучали функциональная активность естественных киллеров селезенки, при моделировании монополушарного левостороннего экспериментального инсульта (ЭИ) различной степени тяжести. Результаты. Показано, что у животных на 7-й день инсульта отмечается статистически значимое снижение функциональной активности естественных киллеров селезенки: ЭИ легкой степени - 20 (19; 23)%, р = 0,001, ЭИ средней степени - 19 (17; 21)%, р < 0,001, ЭИ тяжелой степени - 18 (16; 22)%, р < 0,001. Нарушения функциональной активности естественных киллеров более выражены на модели ЭИ средней и тяжёлой степени тяжести. Заключение. Показано, что при ЭИ наблюдается снижение функциональной активности естественных киллеров селезёнки, которое нарастает при увеличении степени тяжести инсульта. Background. Studying risk factors for development of infectious and inflammatory complications and ways to reduce them in stroke is a modern challenge to neurology. Aim: Evaluating the functional activity of natural killer (NK) cells in the acute period of experimental stroke (ES) of different severity. Methods. In this experimental study, the functional activity of spleen NK cells was studied in Wistar rats weighing 200-220 g (n = 50) with ES of different severity. Results. On the 7th day of stroke. the functional activity of spleen NK was significantly decreased: in mild ES, 20 (19; 23)%, р = 0.001, in moderate ES, 19 (17; 21)%, р <0.001, and in severe ES, (16; 22)%, р < 0.001. Disorders of the NK functional activity were more pronounced in moderate and severe ES. Conclusion. ES was associated with impaired functional activity of NK cells, which progressed with increasing grade of ES severity.

Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease.

Insulin resistance is a key risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) and may lead to liver fibrosis. Natural killer (NK) cells are thought to exert an antifibrotic effect through their killing of activated hepatic stellate cells (HSCs). Here, we investigated how the interplay between NK cells and HSCs are modified by insulin resistance in NAFLD. Fresh peripheral blood NK cells (clusters of differentiation [CD]56dim, CD16+) were collected from 22 healthy adults and 72 patients with NAFLD not currently taking any medications and without signs of metabolic syndrome. NK cells were assessed for insulin receptor expressions and cytotoxic activity when cultured in medium with HSCs. Fibrosis severities in patients with NAFLD were correlated linearly with elevated serum proinflammatory cytokine expression and insulin resistance severity. At the same time, fibrosis severities inversely correlated with insulin receptor expressions on NK cells as well as with their cytotoxic activities determined by CD107a by flow cytometry. NK cells from donors exhibiting severe fibrosis and insulin resistance exhibited significant mammalian target of rapamycin and extracellular signal‐regulated kinase depletion (through NK cell western blot quantitation), increased apoptosis, and failure to attenuate HSC activation in vitro. While exposure to insulin stimulated the cytotoxic activity of healthy NK cells, rapamycin prevented this effect and reduced NK insulin receptor expressions. Conclusion: Elevated insulin levels in F1 and F2 fibrosis enhances NK cell cytotoxic activity toward HSCs and prevents fibrosis progression by insulin receptors and downstream mammalian target of rapamycin and extracellular signal‐regulated kinase pathways. At more advanced stages of insulin resistance (F3 and F4 fibrosis), impaired NK cell activity rooted in low insulin receptor expression and or low serum insulin levels could further deteriorate fibrosis and may likely lead to cirrhosis development. (Hepatology Communications 2018;2:285‐298)

The significance of peripheral blood natural killer cell surface CD107a, NKG2D and serum sMICA in patients with extranodal NK/T cell lymphoma, nasal type

The expression of CD107a, NKG2D on the surface of natural killer (NK) cells and serum soluble major histocompatibility complex class Ⅰ chain-related A (sMICA) level in patients with extranodal NK/T cell lymphoma, nasal type (ENKL) were detected.We found that CD107a expression was reduced on the surface of NK cells, suggesting impaired NK cell activity in ENKL patients, which may result from decreased NKG2D expression.

Natural Killer Cell Deficits Aggravate Allergic Rhinosinusitis in a Murine Model

Objective: Defective innate immune functions can contribute to chronic rhinosinusitis (RS). Recently, it has been reported that chronic RS patients show impaired function of natural killer (NK) cells. We investigated the role of NK cells in eosinophilic inflammation in an allergic RS mouse model. Methods: Mice sensitized to ovalbumin (OVA) by intraperitoneal injection received nasal challenges with OVA for 5 weeks. NK cell depletion was achieved by intraperitoneal injections of anti-asialo ganglio-N-tetraosylceramide (ASGM1) antibodies 10 days before OVA sensitization and every 5 days thereafter until sacrifice. Sinonasal complex samples were evaluated histologically, and IL-4, IL-5, IL-13, IFN-γ, MIP-2, and eotaxin levels were measured in the nasal lavage fluid. Differential white blood cell counts were also obtained. Results: Allergic RS mice showed significantly more eosinophilic inflammation in the sinonasal mucosa, elevated levels of IL-4, IL-5, IL-13, and eotaxin in the nasal lavage fluid, and peripheral blood eosinophilia compared to control mice. The depletion of NK cells by anti-ASGM1 treatment induced more prominent eosinophilic inflammation and increased secretion of IL-5 and peripheral blood eosinophilia in allergic RS mice. Conclusion: The depletion of NK cells aggravates allergen-induced sinonasal eosinophilic inflammation, suggesting that impaired NK cell activity may be an exacerbating factor in eosinophilic chronic RS.

Decreased CD161 activating and increased CD158a inhibitory receptor expression on NK cells underlies impaired NK cell cytotoxicity in patients with multiple myeloma

AimAs innate immune cells natural killer (NK), NK-like T and CTLγδ are important in antitumour response in multiple myeloma (MM), the aim of this study was to investigate some functional...

A Phase 1b Study of Neoadjuvant Immune Biomarker Modulation With Cetuximab and Motolimod in Head and Neck Cancer (HNC)

Inflamed tumors are known to generate a better response to immunotherapy. HNC has many immunosuppressive features, including impaired natural killer cell (NK) activity. The monoclonal antibody cetuximab (CTX) is effective in a subset of HNC patients, with clinical activity linked to NK-mediated antibody-dependent cellular cytotoxicity (ADCC). Recent data show that CTX increases the frequency of intratumoral CTLA-4+FoxP3+ regulatory T cells (Treg), which suppress ADCC and are associated with poor clinical outcome. In ex vivo experiments, this effect could be attenuated by targeting CTLA-4 on Tregs. It is possible that the clinical efficacy of CTX may be improved by enhancing tumor inflammation, activating the immune system, and/or inhibiting the Treg suppressive effects. Motolimod (VTX-2337), a novel Toll-like receptor 8 (TLR8) agonist. Preclinical data show enhanced CTX and NK-mediated lysis of HNC cells and dendritic cross-priming of EGFR-specific CD8+ T cells. CTX and motolimod in HNC patients was tolerable and active in a phase 1b study, with enhanced NK cell activity. The central hypothesis in this study is that NK and monocyte/mDC activation by CTX is enhanced by concomitant administration of motolimod, thereby amplifying the innate and adaptive immune response in the circulation and in the tumor microenvironment (TM). In this prospective phase 1b clinical trial (NCT02124850) of preoperative treatment with CTX and motolimod, the primary objective is to evaluate how neoadjuvant CTX plus motolimod modulates innate and adaptive immune biomarkers. An exploratory objective of the study is to assess whether this modulation of biomarkers can predict antitumor response. Subjects (n=12) with stage II–IVA HNC received weekly doses of CTX and motolimod followed by definitive surgical resection. Biomarker modulation in tumor and blood are correlated with clinical response by CT or MRI. Tumor apoptosis/proliferation is assessed by biopsy pre- and posttreatment. Phenotypic markers of suppression in Treg were reduced when motolimod was combined with CTX, including lower levels of CTLA-4 (P=.01), CD73 (P=.04), and membrane-bound TGF-β (P=.05). These mediators were induced in nonresponders in our single-agent cetuximab therapy study (P=.005). Myeloid antigen–presenting cells achieved strong maturation and expression of stimulatory markers in the peripheral blood. CTX plus motolimod induces inflammatory changes in the TM and peripheral blood. Treg-suppressive mediators are reduced with CTX/motolimod, overcoming a negative prognostic biomarker (Treg induction) of CTX therapy alone. A pending amendment will assess the impact of adding checkpoint inhibition to the CTX/motolimod combination.

Griscelli Syndrome with hemophagocytosis: a case report

Griscelli syndrome is a rare autosomal recessive disorder characterized by pigmentary dilution of the skin and the hair (silver hair), the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. In one variant, hepatosplenomegaly, lymphohistiocytosis, and a combined T-cell and B-cell immunodeficiency are pronounced. The associated immunodeficiency often involves impaired natural killer cell activity, absent delayed-type hypersensitivity, and a poor cell proliferation response to antigenic challenge. Occasionally, impaired lymphocyte function and an inability to produce normal levels of immunoglobulins have also been described. In another variant, neurologic signs are most prominent. We present a case of 1 year male who presented with fever, jaundice, silver hair, heptoslenomegaly, and pancytopenia.

HIV mono-infection is associated with an impaired anti-hepatitis C virus activity of natural killer cells.

Hepatitis C virus (HCV) infection in HIV(+) patients is associated with faster liver disease progression compared with HCV mono-infection. HIV-associated immune defects are considered to play an important role in this context. Here, we analyzed the effects of HIV infection on natural killer (NK)-cell-mediated anti-HCV activity. NK cell phenotype and interferon gamma (IFN-γ) production, NK cell-mediated inhibition of HCV replication and CD4 T-cell/NK cell interactions were studied in treatment naive HIV (n = 22), and HIV patients under combined antiretroviral therapy (n = 29), compared with healthy controls (n = 20). NK cell-mediated inhibition of HCV replication was analyzed using the HuH7A2HCVreplicon model. IFN-γ production of NK cells as well as interleukin-2 secretion of CD4 T lymphocytes were studied by flow cytometry. Peripheral blood mononuclear cells from HIV(+) patients displayed a significantly impaired anti-HCV activity, irrespective of combined antiretroviral therapy. This could in part be explained by HIV-associated decline in NK cell numbers. In addition, NK cell IFN-γ production was significantly impaired in HIV infection. Accordingly, we found low frequency of IFN-γ(+) NK cells in HIV(+) patients to be associated with ineffective inhibition of HCV replication. Finally, we show that CD4 T-cell-mediated stimulation of NK cell IFN-γ production was dysregulated in HIV infection with an impaired interleukin-2 response of NK cells. HIV infection has a strong suppressive effect on anti-HCV activity of NK cells. This may contribute to low spontaneous clearance rate and accelerated progression of HCV-associated liver disease observed in HIV(+) patients.

WITHDRAWN: Natural Killer Cell Activating Receptor NKG2D Is Involved in the Immunosuppressant Effect of Mycophenolate Mofetil and Infection of Hepatitis B Virus

In this study we investigated whether mycophenolate mofetil (MMF), a new immunosuppressant, and its metabolite mycophenolic acid (MPA) influence the activity of liver resident natural killer (NK) cells, resulting in increased susceptibility to hepatitis B virus (HBV) infection. We isolated the hepatic NK cells of C57BL/6 and C57BL/6JTgN (A1b1HBV) 44Bri) transgenic mice administered MMF in the presence or absence of interleukin (IL)-15, or incubated isolated hepatic NK cells in the presence or absence of MPA and used RT-PCR, immunolabeling to assess the expression of NK receptors Ly49A, NKG2A and NKG2D, and cytokine ELISA and [(3)H]-TdR-release assay to assess the activation and cytotoxic capacity of NK cells. After treatment of MMF in the presence or absence of IL-15, HBsAg titer was also measured in C57BL/6JTgN (A1b1HBV) 44Bri) transgenic mice. After both MPA and MMF treatments, NK cytotoxicity was reduced, NKG2D and Ly49A expression was down-regulated, but NKG2A was up-regulated. Down-regulation of NKG2D could be ameliorated by IL-15, and in HBV-transgenic mice, MMF treatment impaired NK cell activity, but did not influence virus replication, whereas IL-15 treatment depressed HBsAg titer. MPA and MMF mediate down-regulation of NKG2D in vitro and vivo, restricting the cytotoxic capacity of NK cells. Regulation of NKG2D may be important in the effect of immunosuppressant on NK cell activity and involved in HBV infection.

Natural Killer Cell Activating Receptor NKG2D Is Involved in the Immunosuppressive Effects of Mycophenolate Mofetil and Hepatitis B Virus Infection

The purpose of this study is to investigate whether mycophenolate mofetil (MMF), a new immunosuppressant, and its metabolite mycophenolic acid (MPA) affect the activity of liver resident natural killer (NK) cells, resulting in increased susceptibility to hepatitis B virus (HBv) infection. Hepatic NK cells were isolated from C57BL/6 and C57BL/ 6JTgN (A1b1HBV) 44Bri transgenic mice treated with MMF in the presence or absence of IL-15. After incubation of isolated hepatic NK cells in the presence or absence of MPA, reverse transcription polymerase chain reaction and immunolabeling were used to assess the expression of NK receptors Ly49A, NKG2A and NKG2D. In addition, cytokine enzyme-linked immunosorbent assay and [3H]-TdR-release assay were carried out to assess NK cell activation and cytotoxic capacity. After treatment with MMF in the presence or absence of IL-15, HBsAg titers were measured in C57BL/6JTgN (A1b1HBV) 44Bri transgenic mice. Treatment with either MPA or MMF resulted in reduced NK cell cytotoxicity, downregulated NKG2D and Ly49A expression and upregulated NKG2A. Interestingly, NKG2D downregulation was ameliorated by IL-15. In HBV-transgenic mice, MMF treatment impaired NK cell activity but did not affect virus replication, whereas IL-15 treatment reduced HBsAg titers. MPA and MMF mediate NKG2D downregulation both in vitro and in vivo, reducing the cytotoxic capacity of NK cells. These findings indicate that NKG2D regulation may be important in the immunosuppressive effect NK cells and involved in HBV infection.

Natural Killer Cell Deficit Aggravates Eosinophilic Chronic Rhinosinusitis in a Murine Model

RationaleChronic rhinosinusitis (CRS) is a multifactorial inflammatory disease of the nasal and paranasal cavities. Defective immune functions may contribute to the chronic inflammatory state in this disorder. Recently, it has been reported that CRS patients show the impaired function of natural killer (NK) cells, especially in recalcitrant CRS associated with asthma and eosinophilia. We investigated the role of NK cells in mucosal and systemic, particularly eosinophilic, inflammation in an allergic CRS (ACRS) mouse model.MethodsMice sensitized to ovalbumin (OVA) by intraperitoneal injection received nasal challenges with OVA for 5 weeks. NK cell depletion was achieved by intraperitoneal injections of anti-asialo ganglio-N-tetraosylceramide antibodies 10 days before OVA sensitization and every 5 days until sacrifice. Sinonasal complex samples were evaluated histologically, and IL-4, IL-5, IL-13, IFN-γ, IL-8, and eotaxin were measured in nasal lavage fluid. A differential white blood cell count was also performed.ResultsACRS mice showed significantly increased eosinophilic inflammation in sinonasal mucosa, elevated levels of IL-4, IL-5, IL-13, IFN-γ, and eotaxin in nasal lavage fluid, and peripheral blood eosinophilia compared with control mice. The depletion of NK cells induced more prominent eosinophilic inflammation, increased secretion of IL-5, and peripheral blood eosinophilia in ACRS mice.ConclusionsThese results presented that the depletion of NK cells aggravates allergen-induced sinonasal eosinophilic inflammation, suggesting that impaired NK cell activity may be an aggravating factor in eosinophilic CRS. RationaleChronic rhinosinusitis (CRS) is a multifactorial inflammatory disease of the nasal and paranasal cavities. Defective immune functions may contribute to the chronic inflammatory state in this disorder. Recently, it has been reported that CRS patients show the impaired function of natural killer (NK) cells, especially in recalcitrant CRS associated with asthma and eosinophilia. We investigated the role of NK cells in mucosal and systemic, particularly eosinophilic, inflammation in an allergic CRS (ACRS) mouse model. Chronic rhinosinusitis (CRS) is a multifactorial inflammatory disease of the nasal and paranasal cavities. Defective immune functions may contribute to the chronic inflammatory state in this disorder. Recently, it has been reported that CRS patients show the impaired function of natural killer (NK) cells, especially in recalcitrant CRS associated with asthma and eosinophilia. We investigated the role of NK cells in mucosal and systemic, particularly eosinophilic, inflammation in an allergic CRS (ACRS) mouse model. MethodsMice sensitized to ovalbumin (OVA) by intraperitoneal injection received nasal challenges with OVA for 5 weeks. NK cell depletion was achieved by intraperitoneal injections of anti-asialo ganglio-N-tetraosylceramide antibodies 10 days before OVA sensitization and every 5 days until sacrifice. Sinonasal complex samples were evaluated histologically, and IL-4, IL-5, IL-13, IFN-γ, IL-8, and eotaxin were measured in nasal lavage fluid. A differential white blood cell count was also performed. Mice sensitized to ovalbumin (OVA) by intraperitoneal injection received nasal challenges with OVA for 5 weeks. NK cell depletion was achieved by intraperitoneal injections of anti-asialo ganglio-N-tetraosylceramide antibodies 10 days before OVA sensitization and every 5 days until sacrifice. Sinonasal complex samples were evaluated histologically, and IL-4, IL-5, IL-13, IFN-γ, IL-8, and eotaxin were measured in nasal lavage fluid. A differential white blood cell count was also performed. ResultsACRS mice showed significantly increased eosinophilic inflammation in sinonasal mucosa, elevated levels of IL-4, IL-5, IL-13, IFN-γ, and eotaxin in nasal lavage fluid, and peripheral blood eosinophilia compared with control mice. The depletion of NK cells induced more prominent eosinophilic inflammation, increased secretion of IL-5, and peripheral blood eosinophilia in ACRS mice. ACRS mice showed significantly increased eosinophilic inflammation in sinonasal mucosa, elevated levels of IL-4, IL-5, IL-13, IFN-γ, and eotaxin in nasal lavage fluid, and peripheral blood eosinophilia compared with control mice. The depletion of NK cells induced more prominent eosinophilic inflammation, increased secretion of IL-5, and peripheral blood eosinophilia in ACRS mice. ConclusionsThese results presented that the depletion of NK cells aggravates allergen-induced sinonasal eosinophilic inflammation, suggesting that impaired NK cell activity may be an aggravating factor in eosinophilic CRS. These results presented that the depletion of NK cells aggravates allergen-induced sinonasal eosinophilic inflammation, suggesting that impaired NK cell activity may be an aggravating factor in eosinophilic CRS.

VARIATION OF NATURAL KILLER CELLS PHENOTYPE AND ACTIVITY IN VARIOUS STAGES OF HEPATITIS C VIRUS INFECTION IN EGYPTIAN PATIENTS

During the early phases of a hepatitis C virus (HCV) infection, natural killer (NK) cell activation appears to be critical to the innate (non-specific) immune responses that have the potential of clearing the infection. Impaired activity of NK cells has been proposed as a mechanism contributing to viral persistence and chronic infection in HCV infection. We aimed to assess the impact of HCV infections on NK cells regarding frequency, and subset distribution. Peripheral blood (PB) NK cells population of individuals were divided into the following groups: healthy controls (HC) and patients at different stages of HCV: 37 chronic HCV (CHC), 28 cirrhotic HCV and 24 with hepatocellular carcinoma (HCC). The phenotype and frequency of NK cells were characterized by flow cytometry in the different stages in comparison to HC. The potential associations between the frequency of NK cell subsets and the activity of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as indicators of liver function, were analyzed. The correlation between the phenotype of NK subsets and the various stages of HCV infection was assayed. Number of total NK was significantly reduced and a striking shift in NK subsets, with a marked decrease in the CD56dim cell fraction compared to CD56bright cells was identified. Interestingly, we found that the number of NK cells (CD56+) bearing the inhibitory receptor CD158b (KIR) increased in HCV patients at various stages, whereas the percentage of NK cells expressing activating receptors CD314+(NKG2D), CD161+ were significantly reduced, as compared to HC. These results indicated alteration of NK cell subsets in frequency and marker expression in different stages of HCV patients compared to HC as inhibitory NK cells frequency increased, while activated NK cells were reduced, which might be associated with impaired innate immune responses and virus persistence.

An effective interferon-gamma-mediated inhibition of hepatitis C virus replication by natural killer cells is associated with spontaneous clearance of acute hepatitis C in human immunodeficiency virus-positive patients

Hepatitis C virus (HCV) coinfection is an increasing health problem in human immunodeficiency virus-positive (HIV(+) ) individuals. However, a considerable proportion of HIV(+) patients manage to overcome acute hepatitis C (AHC) spontaneously. In the present study, we analyzed the role of natural killer (NK) cells in modulating the course of AHC in HIV(+) patients. Twenty-seven HIV(+) patients with AHC (self-limited course: n = 10; chronic course: n = 17), 12 HIV(+) patients with chronic hepatitis C (CHC), 8 HIV monoinfected individuals, and 12 healthy controls were studied. NK cells were phenotypically analyzed by flow cytometry. Interferon-gamma (IFN-γ) secretion, degranulation (CD107a), and anti-HCV (= inhibition of HCV replication) activity of NK subpopulations were analyzed using the HuH7A2 HCVreplicon cell system. NK cell frequency did not differ significantly between HIV(+) patients with chronic and self-limited course of AHC. However, we found NK cells from patients with self-limiting infection to be significantly more effective in inhibiting HCV replication in vitro than NK cells from patients developing CHC. Of note, antiviral NK cell activity showed no significant correlation with NK cell degranulation, but was positively correlated with IFN-γ secretion, and blocking experiments confirmed an important role for IFN-γ in NK cell-mediated inhibition of HCV replication. Accordingly, NK cells from patients that spontaneously cleared the virus displayed a stronger IFN-γ secretion than those developing chronic infection. Finally, we observed high expression of NKG2D and NKp46, respectively, to be associated with self-limiting course of aHCV. Accordingly, we found that blocking of these NK cell receptors significantly impaired antiviral NK cell activity. Our data suggest a strong IFN-γ-mediated antiviral NK cell response to be associated with a self-limited course of AHC in HIV(+) patients.

Natural killer cell function and dysfunction in hepatitis C virus infection.

Viruses must continually adapt against dynamic innate and adaptive responses of the host immune system to establish chronic infection. Only a small minority (~20%) of those exposed to hepatitis C virus (HCV) spontaneously clear infection, leaving approximately 200 million people worldwide chronically infected with HCV. A number of recent research studies suggest that establishment and maintenance of chronic HCV infection involve natural killer (NK) cell dysfunction. This relationship is illustrated in vitro by disruption of typical NK cell responses including both cell-mediated cytotoxicity and cytokine production. Expression of a number of activating NK cell receptors in vivo is also affected in chronic HCV infection. Thus, direct in vivo and in vitro evidence of compromised NK function in chronic HCV infection in conjunction with significant epidemiological associations between the outcome of HCV infection and certain combinations of NK cell regulatory receptor and class I human histocompatibility linked antigen (HLA) genotypes indicate that NK cells are important in the immune response against HCV infection. In this review, we highlight evidence suggesting that selective impairment of NK cell activity is related to establishment of chronic HCV infection.

Association of Increased Indoleamine 2, 3‐Dioxygenase With Impaired Natural Killer Cell Activity in Hemodialysis Patients

Indoleamine 2, 3-dioxygenase (IDO) suppresses adaptive immune response. However, there was no study to examine whether IDO activity is associated with immune parameters in dialysis patients. In this study, we estimated serum IDO activity by the kynurenine/tryptophan ratio (KTR), and compared KTR with natural killer (NK) cell activity, soluble interleukin-2 receptor (sIL-2R) and serum levels of trace elements such as selenium (Se) and zinc (Zn) that affect T-cell function in 28 hemodialysis (HD) patients (age: 72 ± 13 years old, time on HD: 79 ± 89 months). NK cell activity was decreased in 35.7% of the patients. KTR values were almost 10-times higher in HD patients (380.81 ± 385.46 mM/M) than those in the referred controls (32.9 ± 9.10 mM/M). KTR was lower in patients with impaired NK cell activity than those without (279 ± 111 vs. 565 ± 603 mM/M, P = 0.07). There was no relationship between KTR and sIL-2R and Zn, while KTR was significantly and negatively correlated with serum Se levels that can impair cellular immunity (r = -0.41, P < 0.05). Our findings suggest that increased IDO activity with Se deficiency may be associated with impaired NK cell function in HD patients.