Association between circadian rhythms of endogenous hypothalamic opioid peptides and of natural killer cell activity.

To explore in man the hypothesis that natural killer cell activity and hypothalamic-hypophyseal hormones constitute a mutually coupled multioscillatory system, we analysed and compared, in 11 healthy volunteers, the circadian variations in plasma concentrations of beta-endorphin, met-enkephalin and alpha-MSH, and of natural killer activity of peripheral blood lymphocytes. Natural killer cell activity and plasma beta-endorphin levels showed a similar circadian rhythm with the peak in the morning (acrophases at 06.14 and 08.25, respectively), whereas the circadian rhythm of met-enkephalin was approximately in antiphase to the natural killer rhythm (acrophase close to 17,00 hours). Although daily variation of alpha-MSH showed greater inter-individual variability, a circadian rhythm was statistically validated. Analysis of correlation between rhythmometric parameters (mesor, amplitude, peak and nadir) of natural killer cell activity vs neuro-endocrine hormones revealed that the minimum and medium daily concentrations of beta-endorphin correlated directly with the corresponding parameters of natural killer activity, while the maximum and medium concentrations of met-enkephalin were inversely correlated with the peak and the mesor of natural killer activity. The amplitude of natural killer cell activity oscillations correlated directly with the peak, mesor and nadir concentrations of alpha-MSH. We show here that circadian rhythms of some neuroendocrine hormones of the hypothalamic-hypophyseal axis, i.e. beta-endorphin, met-enkephalin and alpha-MSH, are significantly coupled to daily oscillations of NK cell activity.     

Natural killer cell subsets and natural killer-like T-cell populations in benign and neoplastic B-cell proliferations vary based on clinicopathologic features

Microenvironmental factors play a critical role in B-cell lymphomas. Most studies emphasize the role of lymphoma-infiltrating T-cells and macrophages, with few studies on natural killer cells. Natural killer cells include a less mature (CD56(bright)/CD16-) subset that is more common in lymph nodes and a more mature (CD56(dim)/CD16+) subset that is more numerous in peripheral blood. Therefore, the proportions of natural killer cells, natural killer subsets, and natural killer-like T-cells (CD3+, CD56+, and/or CD16/57+) were determined by flow cytometry in 150 cases of tissue-based B-cell non-Hodgkin lymphoma and 89 nonneoplastic tissue biopsies. Results were correlated with the clinicopathologic findings. A higher percentage of natural killer cells was found in nonneoplastic spleen versus other nonneoplastic tissue (P < .001), in splenic-based B-cell non-Hodgkin lymphoma versus other B-cell non-Hodgkin lymphoma (P < .01), and in stage II to IV diffuse large B-cell lymphoma versus stage I diffuse large B-cell lymphoma (n = 19, P = .02). The more mature natural killer subset was increased in benign spleen (P < .001) and nonsplenic B-cell non-Hodgkin lymphoma (P < .01) versus nonsplenic, nonneoplastic tissue; in diffuse large B-cell lymphoma versus other B-cell non-Hodgkin lymphoma (P < .001); and in follicular lymphoma with an intermediate follicular lymphoma international prognostic index score (n = 17, P = .04). A higher proportion of natural killer-like T-cells was seen in diffuse large B-cell lymphoma versus other B-cell non-Hodgkin lymphoma (P = .001), whereas chronic lymphocytic leukemia/small lymphocytic lymphoma contained fewer natural killer-like T-cells (P < .001). The proportions of natural killer cells, natural killer subsets, and natural killer-like T-cells vary with tissue site, type of B-cell non-Hodgkin lymphoma, and clinical stage in diffuse large B-cell lymphoma and follicular lymphoma. A higher proportion of CD56(dim)/CD16/57+ natural killer cells is found in spleen, in more aggressive B-cell non-Hodgkin lymphoma, and in follicular lymphoma with an intermediate follicular lymphoma international prognostic index score. This may be of importance with increasing therapeutic use of immunomodulatory agents.     

Natural killer T cells and X-linked lymphoproliferative syndrome

PURPOSE OF REVIEW: Recent progress in elucidating the physiopathology of X-linked lymphoproliferative syndrome (XLP) has raised novel and important issues regarding the biology of natural killer T cells. Here I will review this information and discuss the issues involved. RECENT FINDINGS: XLP is a rare inherited immunodeficiency characterized by a high susceptibility to severe infection by the Epstein-Barr virus. Mutations in the gene SH2D1A (or alternatively SAP) underlie 80% of familial XLP (XLP-1) cases. Recently the remaining 20% of familial XLP (XLP-2) cases were shown to harbor mutations in the gene XIAP (X-linked inhibitor of apoptosis protein). Both SAP and XIAP deficiencies are associated with a defect in the development and/or homeostasis of natural killer T cells. SUMMARY: It can be hypothesized that the susceptibility to Epstein-Barr virus in XLP might result from the defect of natural killer T cells. The role of these cells in viral infection is unclear, but several herpes viruses have developed strategies to escape natural killer T cells. The discovery that SAP and XIAP deficiency leads to a defect in natural killer T cells has also shed light on novel signaling pathways required for natural killer T cell development and/or homeostasis.     

Augmentation of natural killer cytotoxicity by alpha or gamma natural and recombinant interferons and interferon inducers. Effect of monocytes

We investigated the effect of human peripheral blood monocytes on the augmentation of natural killer cytotoxicity by alpha or gamma natural and recombinant interferons (IFN) and certain interferon inducers. We observed that: (1) in the majority of the donors examined (75%) human peripheral blood monocytes do not affect natural killer cytotoxicity, determined by a 4-hour chromium-51 release assay, against target cells from hemopoietic human tumor cell lines. (2) Monocytes are not required and do not affect the augmentation of natural killer cytotoxicity by Escherichia coli-derived IFN-gamma, natural human IFN-gamma, E. Coli-derived IFN-alpha 2 or natural human IFN-alpha. E. Coli-derived IFN-gamma and natural human IFN-gamma have been reported to activate monocyte cytotoxicity determined in 72-hour assay. (3) Monocytes are not required for the augmentation of natural killer cytotoxicity against target cells from hemopoietic tumor cell lines by polyinosinic acid-polycytidylic acid or staphylococcal enterotoxin A.     

直接和间接共培养条件下小鼠子宫自然杀伤细胞与树突状细胞相互作用的比较

背景：子宫自然杀伤细胞与树突状细胞可以相互作用,但相互间作用是否必须直接接触还存在不同的观点。 目的：对比直接和间接共培养条件下子宫自然杀伤细胞与树突状细胞之间的相互作用,明确两者相互作用的方式。 方法：将树突状细胞和子宫自然杀伤细胞进行直接接触共培养,设为直接共培养组;在2种细胞Transwell系统中进行共培养,设为间接共培养组。观察培养细胞的生长状况,酶联吸附法检测培养上清白细胞介素10,12、转化生长因子β细胞因子的浓度,流式细胞术检测各组细胞表面标志CD86的表达情况。 结果与结论：与单独培养树突状细胞和子宫自然杀伤细胞相比,直接和间接共培养组培养液上清中白细胞介素10,12、转化生长因子β浓度均增加(P < 0.05),尤以白细胞介素10浓度增加明显(P < 0.05),CD86的表达明显增高 (P < 0.05)。直接共培养组白细胞介素10,12和转化生长因子β浓度更高(P < 0.05),表达CD86的细胞含量更多 (P < 0.05)。证实子宫自然杀伤细胞可以促进树突状细胞成熟,而树突状细胞促进子宫自然杀伤细胞的分泌,两者通过细胞间的直接接触而相互作用。     

Dietary Quercetin, Immune Functions and Colonic Carcinogenesis in Rats

Rats fed 100 mg/kg quercetin (QUE) daily for 7 weeks had significantly enhanced natural killer cell activity compared to their vehicle (VEH)-fed control. In contrast, rats fed 100 mg/kg QUE and treated with the colon carcinogen, azoxymethane had significantly reduced natural killer cell activity compared to their VEH-fed azoxymethane-treated control. There was no significant difference in natural killer cell activity between the two control groups. Antibody production and delayed-type hypersensitivity were not altered by QUE feeding in any treatment group. In vitro exposure of splenic natural killer cells to 1 mM QUE significantly decreased natural killer cell cytotoxicity. Lower QUE concentrations produced a non-significant reduction in natural killer cell activity that was restored to control values at 1×10^-13M QUE. The distribution, multiplicity and total number of colonic preneoplastic lesions, aberrant crypt foci, was not significantly different in the QUE-fed azoxymethane-treated rats when compared to azoxymethane-treated vehicle-fed rats at the conclusion of the 7 week feeding period. We found no correlation between immune function and development of preneoplastic colon lesions in this study.     

Natural Killer and Natural Killer T Cells in Juvenile Systemic Lupus Erythematosus: Relation to Disease Activity and Progression

Archivum Immunologiae et Therapiae Experimentalis - The contribution of innate immune cells, including natural killer (NK) and natural killer T (NKT) cells, in systemic lupus erythematosus (SLE) is...     

Dietary Quercetin,Immune Functions and Colonic Carcinogenesis in Rats

Abstract

Rats fed 100 mg/kg quercetin (QUE) daily for 7 weeks had significantly enhanced natural killer cell activity compared to their vehicle (VEH)-fed control. In contrast, rats fed 100 mg/kg QUE and treated with the colon carcinogen, azoxymethane had significantly reduced natural killer cell activity compared to their VEH-fed azoxymethane-treated control. There was no significant difference in natural killer cell activity between the two control groups. Antibody production and delayed-type hypersensitivity were not altered by QUE feeding in any treatment group. In vitro exposure of splenic natural killer cells to 1 mM QUE significantly decreased natural killer cell cytotoxicity. Lower QUE concentrations produced a non-significant reduction in natural killer cell activity that was restored to control values at 1×10^-13M QUE. The distribution, multiplicity and total number of colonic preneoplastic lesions, aberrant crypt foci, was not significantly different in the QUE-fed azoxymethane-treated rats when compared to azoxymethane-treated vehicle-fed rats at the conclusion of the 7 week feeding period. We found no correlation between immune function and development of preneoplastic colon lesions in this study.     

Natural and antibody-dependent killer cells in the thymus

Thymocytes contain a small population of light (o = 1.067), large cells with high cytolytic potential against natural killer target as well as against IgG- or IgM-coated erythrocytes and nucleated cells, thus displaying natural killer and antibody-dependent cellular cytotoxicity functions, but not exhibiting T killer cell capacity. As far as characterized, the cells show T cell characteristics: they are nonadherent, nonphagocytic, surface immunoglobulin-negative, C3 receptor-negative, partly Fc gamma receptor-positive, carry the receptor for Helix pomatia A agglutinin, and are, at least partly, cortisone-resistant and Thy-1-positive. The implications of this finding with respect to the lineage of natural killer and killer cells and their interdependence will be discussed briefly.     

Natural killer cell activity in chickens: target cell analysis and effect of antithymocyte serum on effector cells.

A battery of lymphoid and nonlymphoid cells was examined for susceptibility to lysis by natural killer cells of chickens. Several susceptible targets were recognized, and most susceptible among these were cells of line LSCC-RP9, derived from a lymphoid tumor induced by Rous-associated virus 2. The natural killer reactivity against LSCC-RP9 target cells did not appear to be directed against an antigen(s) induced by Rous-associated virus 2 because other lymphoid and nonlymphoid cells infected with this were resistant to lysis in vitro by natural killer cells. The effector cells of natural killer reactivity in chickens were refractory to treatment with potent anti-T-cell and anti-B-cell sera. Inoculation of Marek's disease virus in line 15 X 7 chickens resulted in enhanced natural killer cell activity, and the effector cells of this enhanced activity, and the effector cells of this enhanced activity were also resistant to anti-T-cell serum.     

Human natural killer cell deficiencies

PURPOSE OF REVIEW: Human natural killer cell deficiencies are a relevant clinical entity that provides insight into the role of natural killer cells in host defense, as well as the basic biology of natural killer cells. Since previously reviewing these disorders, significant developments warrant their reconsideration. RECENT FINDINGS: Human natural killer cell deficiencies can occur as part of a more pervasive immunodeficiency syndrome or, rarely, in isolation. The most informative examples of the former are in the context of a known genetic defect, because the deficiency of natural killer cell development or activity can be attributed to the specific gene function. Since last reviewed, there are five human gene mutations that are now appreciated to affect natural killer cells, and additional new insights into natural killer cell biology have been obtained through seven others. Six new reports of isolated natural killer cell deficiencies, as well as a suggested classification scheme, are also reviewed. SUMMARY: Appreciation of human genetic syndromes that include natural killer cell deficiencies, as well as new cases of isolated natural killer cell deficiencies, continue to advance the understanding of natural killer cell biology and solidify the role of natural killer cells in defense against human herpesviral infection.     

Inhibition of antibody-dependent cellular cytotoxicity and natural cytotoxicity by retinoic acid

The present study has shown that in vitro antibody-dependent cellular cytotoxicity and natural cytotoxicity of human blood lymphocytes are inhibited by retinoic acid (5 X 10(-4)M). The inhibition of cytotoxicity is due to a specific effect on the effector lymphocytes and not to an effect on the target cells. The reduction of killing is most pronounced with prolonged incubation (20 h) of the killer cells with retinoic acid, recovery of killer and natural killer cell activity occurring with post-treatment incubation (greater than 24 h, 37 degrees C) in medium. Retinoic acid was found to have an antagonistic effect to interferon in modulating in vitro natural killer cell activity. The mechanism of inhibition by retinoic acid was uncertain but modulation of cell membrane receptors appeared to be a likely possibility.     

Inhibition of human natural killer cell activity by cereulide,an emetic toxin from Bacillus cereus

The lipophilic toxin, cereulide, emitted by emetic food poisoning causing strains of Bacillus cereus, is a powerful mitochondria toxin. It is highly lipophilic and rapidly absorbed from the gut into the bloodstream. We tested how this toxin influences natural killer (NK) cells, which are important effectors in defence against infections and malignancy. Cereulide inhibited cytotoxicity and cytokine production of natural killer cells, caused swelling of natural killer cell mitochondria, and eventually induced natural killer cell apoptosis. The suppressive effect on cytotoxicity was fast and toxic concentration low, 20-30 microg/l. As the emesis causing concentration of cereulide is around 10 microg/kg of total body mass, our results suggest that emesis causing or even lower doses of cereulide may also have a systemic natural killer cell suppressive effect.     

Role of natural killer cells in immunotoxicity: an update

As natural killer cells play a significant role in innate immunity against viruses and neoplasia, the measurement of natural killer cell activity has long been recommended for nonclinical immunotoxicity evaluation. A number of agrochemical, industrial and environmental chemicals have been shown to impair natural killer cell activity. However, direct evidence for clinically significant pathologic consequences, such as infections or immunosuppression-related cancer in human beings exposed to these chemicals, is lacking. In addition, extremely few pharmaceuticals, including potent immunosuppressive drugs, have been shown to depress natural killer cell activity reproducibly. Due to this ambiguous situation, the value of measuring natural killer cell activity for the prediction of immunotoxicity is debatable, as reflected by recommendations included in recent guidelines for the nonclinical safety assessment of human pharmaceuticals. Limitations of current analyses of natural killer cell activity may explain this situation. Progress is expected from the utilization of most recent techniques to identify more relevant natural killer cell activation markers or from studying underlying mechanisms.     

Differential loss of natural killer cell activity in patients with acute myocardial infarction and stable angina pectoris

Background: To evaluate the activity of natural killer cells through their inhibitory and activating receptors and quantity in peripheral blood mononuclear cells extracted from patients with acute myocardial infarction, stable angina pectoris and the controls. Methods: 100 patients with myocardial infarction, 100 with stable angina, and 20 healthy volunteers were recruited into the study. 20 randomly chosen people per group were examined for the whole human genome microarray analysis to detect the gene expressions of all 40 inhibitory and activating natural killer cell receptors. Flow cytometry analysis was applied to all 200 patients to measure the quantity of natural killer cells. Results: In myocardial infarction group, the mRNA expressions of six inhibitory receptors KIR2DL2, KIR3DL3, CD94, NKG2A, KLRB1, KLRG1, and eight activating receptors KIR2DS3, KIR2DS5, NKp30, NTB-A, CRACC, CD2, CD7 and CD96 were significantly down-regulated (P<0.05) compared with both angina patients and the controls. There was no statistical difference in receptor expressions between angina patients and control group. The quantity of natural killer cells was significantly decreased in both infarction and angina patients compared with normal range (P<0.001). Conclusions: The significant mRNAs down-regulation of several receptors in myocardial infarction group and reduction in the quantity of natural killer cells in both myocardial infarction and angina patients showed a quantitative loss and dysfunction of natural killer cells in myocardial infarction patients.     

瘤型麻风动物模型的NK细胞活性的体外测定

本文报道了瘤型麻风小鼠模型中脾脏NK细胞活性的体外测定,以及加入外源性IL-2对这一活性的影响。结果表明,随着感染时间的延长,小鼠脾脏中NK细胞活性逐渐降低。感染1月小鼠的NK细胞活性明显低于正常小鼠,感染3月小鼠的NK细胞活性较感染1月小鼠更低(P值均<0.01)。将含有IL-2的上清液加入NK细胞活性检测系统中,发现外源性IL-2可逆转感染小鼠的NK细胞活性,使其恢复达正常水平。结合IL-2与NK细胞活性在免疫调节中的作用,对瘤型麻风动物模型的特殊表现作了讨论。     

T cell- and B cell-independent adaptive immunity mediated by natural killer cells

It is commonly believed that only T lymphocytes and B lymphocytes expressing recombination-dependent antigen-specific receptors mediate contact hypersensitivity responses to haptens. Here we found that mice devoid of T cells and B cells demonstrated substantial contact hypersensitivity responses to 2,4-dinitrofluorobenzene and oxazolone. Those responses were adaptive in nature, as they persisted for at least 4 weeks and were elicited only by haptens to which mice were previously sensitized. No contact hypersensitivity was induced in mice lacking all lymphocytes, including natural killer cells. Contact hypersensitivity responses were acquired by such mice after adoptive transfer of natural killer cells from sensitized donors. Transferable hapten-specific memory resided in a Ly49C-I(+) natural killer subpopulation localized specifically in donor livers. These observations indicate that natural killer cells can mediate long-lived, antigen-specific adaptive recall responses independent of B cells and T cells.     

Natural killer cells in HIV-1 infection: a double-edged sword

In order to propagate and persist within the host, HIV-1 subverts a variety of checkpoints of innate and adaptive viral immunosurveillance. Many of these are related to natural killer cells, which bridge innate and adaptive immunity and play a major role in defeating virus infections. HIV-1 affects cytotoxicity of natural killer cells towards infected cells and natural killer cell-mediated priming of effector cells of the adaptive immune system. Moreover, a subpopulation of natural killer cells was found sensitive to infection by HIV-1. Consequently, an efficient immune response against HIV-1 cannot be mounted in most patients. The current review highlights the molecular interplay between HIV-1 and effector cells of the host immune system with a focus on natural killer cells, and summarizes strategies of HIV-1 to escape from natural killer cell immunosurveillance. A detailed knowledge of these immune escape strategies might lead to the identification of access points for intervention in order to block infection and progression to AIDS.     

Natural killer cells: integrating diversity with function

The key role of natural killer cells in many aspects of the immune response is now being recognized. The last decade has seen an exponential increase in our understanding of the workings of these cells. Receptor diversity is crucial in allowing natural killer cells to respond effectively to a variety of different pathogens. This article reviews aspects of natural killer cell diversity that combine to generate populations of functional natural killer cells that exist within both the individual and throughout the population at large.