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The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

The coordinated activities of innate and adaptive immunity are critical for effective protection against viruses. To counter this, some viruses have evolved sophisticated strategies to circumvent immune cell recognition. In particular, cytomegaloviruses encode large arsenals of molecules that seek to subvert T cell and natural killer cell function via a remarkable array of mechanisms. Consequently, these ‘immunoevasins’ play a fundamental role in shaping the nature of the immune system by driving the evolution of new immune receptors and recognition mechanisms. Here, we review the diverse strategies adopted by cytomegaloviruses to target immune pathways and outline the host’s response.

Background Haemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) is a hyperinflammatory syndrome potentially leading to critical illness. Early treatment reduces mortality but diagnosis requires a high index of suspicion. Highly elevated ferritin levels (HEF) >10,000 μg/L are highly specific for HLH/MAS [1] and should prompt consideration of hyperinflammation. Diagnostic guidelines for HLH, requiring the presence of ≥5/8 criteria [2], and classification criteria for MAS complicating systemic juvenile idiopathic arthritis (sJIA) have been published [3]. Objectives To assess recognition of HLH/MAS in a paediatric population with HEF. Methods This retrospective study was conducted at 11 centres under local service evaluation permissions. Biochemistry databases identified patients ≤16 years with serum ferritin >10,000 μg/L during a 3-year period. Each case was assessed against the 2004 HLH criteria and, for patients with sJIA, the 2016 MAS criteria. Due to limited access to some of the laboratory tests, previously-published modified HLH criteria using a threshold of ≥4/5 (excluding tissue haemophagocytosis, decreased natural killer cell function, increased soluble interleukin-2 receptor) were also applied to all patients [4]. Results 153 patients (55.6% male) were identified. Patient diagnoses included: infections (29.4%), rheumatological (17.0%) and malignancies (17.0%). A diagnosis of HLH/MAS was made by the treating clinical team in 39.9% and considered in a further 16.3%. Using all available data, 30/153 (19.6%) met ≥5/8 criteria and 93.3% of these patients were diagnosed with HLH/MAS by the treating team. 56 (36.6%) met ≥4/5 criteria and 33 (58.9%) of these were diagnosed with HLH/MAS by clinicians. HLH/MAS was not documented as being considered in the differential in 23.2%. Of 23 patients with sJIA, 82.6% met MAS classification criteria and 89.5% of these were diagnosed with MAS by the treating clinicians. Overall mortality was 32.7% (50/153) and was 27.9% (17/61) in patients diagnosed with HLH/MAS during their admission. Conclusion Although HEF is highly specific for HLH/MAS, the diagnosis was only made or considered in just over half of paediatric patients with this laboratory result. Increased awareness of this potentially-lethal condition is likely to lead to earlier treatment and reduced mortality. References [1] Allen CE, et al. 2008;50:1227-35. [2] Henter JI, et al. 2007;48:124-31. [3] Ravelli A, et al. 2016;75:481-9. [4] Davi S, et al. 2014;66:2871-80. Disclosure of Interests Ethan Sen: None declared, Beverley Almeida: None declared, Louise Moran: None declared, Charlene Foley: None declared, Nagla Abdelrahman: None declared, Rosie Close: None declared, Ema-Louise Long: None declared, Joshua Bennett: None declared, Jason Palman: None declared, Catriona Anderson: None declared, Kirsty McLellan: None declared, Samundeeswari Deepak: None declared, Kathy Gallagher: None declared, Peter Bale: None declared, Kamran Mahmood: None declared, Clare Pain: None declared, Flora McErlane: None declared, Athimalaipet Ramanan Consultant for: AbbVie, UCB, Sobi, Eli Lilly, Speakers bureau: Speaker fees/honoraria from Abbvie, SOBI, Eli Lilly and UCB, Speakers bureau: AbbVie, UCB, Sobi, Eli Lilly, Rachel Tattersall: None declared

Mesenchymal stem cells (MSCs) are powerful immunomodulators that regulate the diverse functions of immune cells involved in allogeneic reactions, such as T cells and natural killer (NK) cells, through cell-cell contact or secreted factors. Exosomes secreted by MSCs may be involved in their regulatory functions, providing new therapeutic tools. Here, we showed that fetal liver (FL) MSC-derived exosomes inhibit proliferation, activation, and cytotoxicity of NK cells. Exosomes bearing latency associated peptide (LAP), TGFβ, and thrombospondin 1 (TSP1), a regulatory molecule for TGFβ, induced downstream TGFβ/Smad2/3 signaling in NK cells. The inhibition of TGFβ, using a neutralizing anti-TGFβ antibody, restored NK proliferation, differentiation, and cytotoxicity, demonstrating that FL-MSC-derived exosomes exert their inhibition on NK cell function via TGFβ. These results suggest that FL-MSC-derived exosomes regulate NK cell functions through exosome-associated TGFβ.

The following study on natural immunology in schizophrenic patients aims at elucidating differential effects of psychopathological status and neuroleptic treatment. Natural killer (NK-) cell activity and antibody dependent cellular cytotoxity (ADCC) were tested in 24 adolescent schizophrenic patients and compared to 27 adult schizophrenics and healthy controls. Twelve adolescent patients were tested before and after 2 weeks on neuroleptic treatment. Age or psychopathological status did not have a significant impact on NK-activity or ADCC. There were no significant general effects resulting from neuroleptic treatment on NK-activity detectable in patients tested before and during treatment. However, there was a significant negative correlation between the differences of NK-activity (before and during treatment) and the NK-activity before treatment.

In the attempt of purging the HIV-1 reservoir through the “shock-and-kill” strategy, it is important to select latency-reversing agents (LRAs) devoid of deleterious effects on the antiviral function of immune effector cells. Here, we investigated two LRAs with PKC agonist activity, prostratin (PRO) and bryostatin-1 (BRY), for their impact on the function of natural killer (NK) cells, the major effectors of innate immunity whose potential in HIV-1 eradication has emerged in recent clinical trials. Using NK cells of healthy donors, we found that exposure to either PRO or BRY potently activated NK cells, resulting in upmodulation of NKG2D and NKp44 activating receptors and matrix metalloprotease-mediated shedding of CD16 receptor. Despite PRO and BRY affected NK cell phenotype in the same manner, their impact on NK cell function was diverse and showed considerable donor-to-donor variation. Altogether, in most tested donors, the natural cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) of NK cells were either improved or maintained by PRO, while both activities were impaired by BRY. Moreover, we analyzed the effect of these drugs on the capacity of treated NK cells to kill autologous latently infected CD4+ T cells reactivated via the same treatment. First, we found that PRO but not BRY increased upmodulation of the ULBP2 ligand for NKG2D on reactivated p24+ cells. Importantly, we showed that clearance of reactivated p24+ cells by NK cells was enhanced when both targets and effectors were exposed to PRO but not to BRY. Overall, PRO had a superior potential compared with BRY as to the impact on key NK cell functions and on NK-cell-mediated clearance of the HIV-1 reservoir. Our results emphasize the importance of considering the effects on NK cells of candidate “shock-and-kill” interventions. With respect to combinative approaches, the impact on NK cells of each LRA should be re-evaluated upon combination with a second LRA, which may have analogous or opposite effects, or with immunotherapy targeting NK cells. In addition, avoiding co-administration of LRAs that negatively impact ADCC activity by NK cells might be essential for successful application of antibodies or vaccination to “shock-and-kill” strategies.

Complement receptor 3 (CR3) is expressed abundantly on natural killer (NK) cells; however, whether it plays roles in NK cell-dependent tumor surveillance is largely unknown. Here, we show that CR3 is an important negative regulator of NK cell function, which has negative impact on tumor surveillance. Mice deficient in CR3 (CD11b−/− mice) exhibited a more activated NK phenotype and had enhanced NK-dependent tumor killing. In a B16-luc melanoma-induced lung tumor growth and metastasis model, mice deficient in CR3 had reduced tumor growth and metastases, compared with WT mice. In addition, adaptive transfer of NK cells lacking CR3 (into NK-deficient mice) mediated more efficient suppression of tumor growth and metastases, compared with the transfer of CR3 sufficient NK cells, suggesting that CR3 can impair tumor surveillance through suppression of NK cell function. In vitro analyses showed that engagement of CR3 with iC3b (classical CR3 ligand) on NK cells negatively regulated NK cell activity and effector functions (i.e. direct tumor cell killing, antibody-dependent NK-mediated tumor killing). Cell signaling analyses showed that iC3b stimulation caused activation of Src homology 2 domain-containing inositol-5-phosphatase-1 (SHIP-1) and JNK, and suppression of ERK in NK cells, supporting that iC3b mediates negative regulation of NK cell function through its effects on SHIP-1, JNK, and ERK signal transduction pathways. Thus, our findings demonstrate a previously unknown role for CR3 in dysregulation of NK-dependent tumor surveillance and suggest that the iC3b/CR3 signaling is a critical negative regulator of NK cell function and may represent a new target for preserving NK cell function in cancer patients and improving NK cell-based therapy.

The effects of negatively-charged air conditions were analyzed as one of the approaches to improve health and quality of life. We previously reported that the use of a charcoal coating and application of an electric voltage yielded predominantly negatively-charged particles in an experimental room, and that 2.5 hours of living in these conditions caused a slight activation of the immune system (slight elevation of serum interleukin (IL)-2), regulated blood flow, and stabilized the autonomic nervous system when compared with control conditions (no dominance of negatively-charged particles). In this study, we expanded the previous study and placed 15 subjects in negatively-charged air conditions for two weeks during the night and analyzed various biological parameters. Although individual biological reactions differed from subject to subject, natural killer (NK) cell activity increased significantly following living in negatively-charged air conditions. Taken together, the results of the previous investigation and those of this study show that repeated elevation of IL-2 (although it immediately returned to the baseline level) causes chronic and recurrent stimulation to NK cells and results in the steady activation of NK cells. Negatively-charged air particles may be a good tool to improve health and quality of life.

CRACC is a self-associating member of the signaling lymphocytic activation molecule family that is expressed on cells of the immune system, including natural killer cells and activated T cells. Here we examine the function and mechanism of action of CRACC using several complementary approaches, including the generation of a CRACC-deficient mouse. Our results demonstrate that CRACC positively regulated natural killer cell functions by a mechanism dependent on the adaptor EAT-2 but not the related adaptor SAP. However, in the absence of EAT-2, CRACC potently inhibited natural killer cell function. CRACC was also inhibitory in T cells, which are typically devoid of EAT-2. Thus, CRACC can exert activating or inhibitory influences on cells of the immune system depending on cellular context and the availability of effector proteins.

The present review summarizes the diversity of killer cell immunoglobulin-like receptors and their complex interactions with self human leukocyte antigen class I molecules that control natural killer cell function. Further, a working model has been developed illustrating the potential impact of variable killer cell immunoglobulin-like receptor-human leukocyte antigen interactions on the outcome of solid organ transplants in view of current knowledge from basic and clinical research.In addition to restraining natural killer cell function, the interaction of inhibitory receptors with cognate human leukocyte antigen class I ligands has been recently shown to set the functional threshold for natural killer cells. Therefore, the number and type of inhibitory killer cell immunoglobulin-like receptor-human leukocyte antigen class I interactions in the recipient, as well as the type of human leukocyte antigen class I ligands expressed on the allograft, can determine the degree of natural killer cell alloreactivity and have potential impact in transplant outcome.Natural killer cells can respond to allografts. The strength of that response is likely determined by the number and type of inhibitory killer cell immunoglobulin-like receptor-human leukocyte antigen class I ligand combinations in the recipient. Understanding the interactions of these intrinsic immunogenetic factors in patients and donors could have important implications on solid organ transplantation.

Natural killer (NK) cells participate in the immune response against infection and cancer. An emerging body of epidemiological data supports that circadian homeostasis may constitute a factor risk for cancer development. Physiological rhythms under circadian control persist in the absence of light entrainment and ultimately rely on a molecular clock. We have previously shown that NK cell cytolytic activity follows a daily rhythm and that NK cells enriched from light-entrained rats present 24-h oscillations of clock genes, cytolytic factors, and cytokines. To investigate whether these oscillations are under a genuine circadian control, we assessed the daily expression of clock genes (Per1, Per2, Clock, and Bmal1), a clock-controlled gene (Dbp), cytolytic factors (granzyme B and perforin), and cytokines (IFN-gamma and TNF-alpha) in NK cells enriched from rats maintained in constant darkness (DD). In addition, we investigated whether the disruption of the NK cell clock by RNA interference (RNAi) affects the expression of cytolytic factors and cytokines. Persistent 24-h oscillations were found in the expression levels of clock genes, cytolytic factors, and cytokines in NK cells enriched from DD rats. In addition, RNAi-mediated Per2 knockdown caused a significant decrease of granzyme B and perforin levels in the rat derived NK cell line RNK16. Taken together, these results provide evidence supporting that NK cell function is under circadian regulation.

Purpose of review Interleukin-18 (IL-18) has potent immunomodulatory effects. It is the only cytokine with a unique capacity to induce T helper 1 or T helper 2 polarization, depending on the immunologic context. Serum levels of IL-18 are increased in many human diseases and it has been implicated in the pathogenesis of several immune-mediated processes. Some of the recent key advances in the immunobiology of IL-18 are discussed in this review. Recent findings Recent data from several laboratories have shed light on the structure of IL-18; the signaling cascades that are initiated; and its role on modulating T cells, dendritic cells, and natural killer cell function. Several new reports have expanded and delineated the role of IL-18 in a multitude of diseases, but only recent advances in the role of IL-18 in three disease processes (acute graft-versus-host disease, insulin-dependent diabetes, and sepsis), where it appears to play paradoxic roles are discussed. Summary Although emerging data shed more light on the complex role of IL-18 in immune reactions, they also pose more questions. Given the pleiotropic, complex, and at times paradoxic effects of IL-18 in various disease processes, better understanding of its immunobiology might lead to the development of IL-18 and/ or its antagonists as therapeutic agents against immune-mediated diseases.

In the present work, we studied the effects of two titanocenes, biscyclopentadienyldichlorotitanium IV, (DDCT) and its derivative, biscyclopentadienylditiocianatetitanium IV (BCDT), on the activity of natural killer (NK) cells in Ehrlich ascites tumour (EAT)-bearing BALB/c mice. In order to investigate a more direct effect of these compounds on NK cell function, we performed experiments with severe combined immunodeficiency (SCID) mice, which exhibit a normal NK cell response in the absence of T and B cells. The treatment consisted of intraperitoneal (i.p.) administration of 15 mg/kg/day of DDCT for 2 days or 10 mg/kg/day of BCDT for 3 days. In addition, to verify whether the effects produced by the titanocenes were compound specific or related to a direct antitumour effect, we also investigated the effects of a 3-day treatment with 100 mg/kg of cyclophosphamide cyclophosphamide on NK cell activity. Our results demonstrated that, in BALB/c and SCID mice, NK cell function declined to subnormal levels after inoculation of the tumour. In these animals, although treatment with DDCT and BCDT significantly enhanced NK cell function, only DDCT restored NK cell activity to normal values in all stages studied. Conversely, treatment with cyclophosphamide reduced NK cell function in nontumour bearing SCID mice and was also unable to restore the decreased NK activity of tumour-bearing SCID mice, thus demonstrating that the enhancement of NK cell function by titanocenes is compound specific. The same effect of cyclophosphamide was observed with BALB/c mice. In the present study, the up-modulatory effects of these two compounds on NK cell function reveal a new aspect of the mechanism of antitumoural action of titanocenes.

Type 1 and type 2 diabetes mellitus are associated with an increased risk of viral infections and certain tumors. Natural killer (NK) cells appear to have a central role in the immune defense against

Several guanosine analogues were synthesized in the pyrazolo[3,4-d]pyrimidine ring system with various substituents at the 3-position. The new analogues prepared here include the CH3 (2-amino-3-methyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13a), the phenyl (2-amino-3-phenyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13b), and the NH2 (3,6-diamino-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)- one, 17) substituted derivatives. These new agents, as well as several other 3-substituted derivatives including H, Br, OCH3, COOH, and oxo, were evaluated for their ability to potentiate certain murine immune functions relative to the known active agent 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (4, 7-thia-8-oxoguanosine). The biological evaluation included the (1) ex vivo determination of increased natural killer cell function and (2) in vivo antiviral protection against a lethal challenge of Semliki Forest virus. The 3-unsubstituted (5a) and the 3-bromo (5c) derivatives were found to be the most active immunopotentiators in this series.

Probiotics are bacteria, but sometimes fungi, which when taken by the oral route may give some health benefits. The most compelling evidence for beneficial effects of probiotics is in the prevention and reduction in the duration of symptoms related to gut infectious disease. There is also evidence to show that some specific probiotics are beneficial in Clostridium difficile diarrhoea in the elderly. As further and better controlled clinical studies have appeared, some specific probiotics also appear to have beneficial effects in perhaps preventing and reducing the duration of symptoms due to acquired upper respiratory tract infections. In an attempt to explain these effects, attention has turned to the effects of some specific probiotics on the immune system. There is evidence that some specific probiotics can alter monocyte and natural killer cell function in the blood. Evidence is also accumulating that taking some specific probiotics can boost antibody responses to oral and systemically administered vaccines. The effect when shown is modest and is not always seen in different studies to all vaccines, but there is enough of a trend to make the area worthy of further investigation, particularly to tease out the mechanisms involved.

As discussed in Part 1 of this series, HIV infection alters the function of the immune system. These alterations include declines in CD4-positive lymphocyte counts, disturbances in the function of the CD4-positive lymphocyte, diminished delayed-type hypersensitivity (DTH) skin test responses and cell-mediated immune responses, phenotypic changes in lymphocytes, and changes in cytoxic T-lymphocyte and natural killer cell function. Although highly active antiretroviral therapy (HAART) has dramatically improved CD4-positive lymphocyte counts and quality of life, there have been unforeseen consequences of immune reconstitution. For example, cytomegalovirus (CMV) and hepatitis C flares have been observed in HAART-treated patients coinfected with HIV and CMV and hepatitis C (HCV). Part 2 of this series will examine the clinical consequences of immune reconstitution in persons with HIV infection.

The clinical utility and capacity to evaluate immunologic function has evolved significantly over the past few decades. This chapter summarizes screening methods and more sophisticated approaches to assess the immune system when there is a suspicion of an immune deficiency.

Normal pigmentation is a complex biological process and in the human, at least 127 different genes have been identified (Bennett and Lamoreaux 2003). Colour loci are the genetic loci in which mutations can affect pigmentation of the hair, skin, and/or eyes.

Natural killer (NK) cell activity of peripheral blood lymphocytes was evaluated in a group of 13 patients with classical Kaposi’s sarcoma (KS). All patients had a normal T4/T8 ratio, and the disease was confined to the skin of the lower extremities. A group of 5 healthy subjects served as controls. NK cell function was significantly decreased in patients as compared to controls. Our result is similar to that found in another group of patients with AIDS-related KS with lymphadenopathy and an abnormal T4/T8 ratio. This suggests that decreased NK cell function is not a result of a progressive process and might be directly involved in the development of KS.

2B4, NTB-A and CRACC are members of the recently defined family of SLAM-related receptors. Here we review the role of these receptors for the regulation of Natural Killer cell function and describe the current knowledge about the signal transduction of these receptors. Finally, we critically analyze some controversial data about the function of 2B4 in mouse and man.

In a previous study, we demonstrated that subchronic exposure to pure, linearly polarized 60 Hz magnetic fields (MFs) at flux densities ranging from 0.002 to 1.0 mT induced a modest but statistically significant and reproducible suppression of NK cell activity in young adult B6C3F(1) mice. NK cell activity in mice declines with age and is known to be suboptimal in older animals. The present study was designed to determine if the same MF exposure regimens will suppress NK cell activity in mature (i.e. more than 1 year old) animals. Extending our previous findings, a modest suppressive effect of MFs on NK cell activity in B6C3F(1) mice was found when subchronic exposure was initiated in animals held in quarantine for 1 year prior to exposure. These data demonstrate that MF exposure suppresses NK cell activity in both young and mature adult B6C3F(1) mice. However, because chronic exposure to the same MF parameters used in the NK function studies does not increase the incidence of neoplasia in B6C3F(1) mice, this statistically significant inhibition of NK cell function appears to be of limited biological significance.

Natural killer cells are now recognized as major effectors of innate resistance to protozoan parasites. The principal mechanism by which they control the growth of these pathogens is indirect, involving cytokine production rather than cytolytic activity. Recent studies have identified a series of positive and negative signals provided by cytokines and cellular interactions which regulate protozoa-induced natural killer cell function.

Natural killer cells (NK cells) are a subset of peripheral blood lymphocytes that mediate non-major histocompatibility complex-restricted cytotoxicity of foreign target cells. The "gold standard" assay for NK cell activity has been the chromium release assay. This method is not easily performed in the clinical laboratory because of difficulties with disposal of radioactive and hazardous materials, short reagent half-lives, expense, and difficulties with assay standardization. We describe a flow cytometric assay for the clinical measurement of NK cell activity. This study compared the chromium release assay and the flow cytometric assay by using clinically relevant specimens. There were no significant differences between the two assays in the measurement of lytic activity for 17 peripheral blood specimens or in reproducibility in repeated samplings of healthy individuals. We also established a normal range of values for NK activity in healthy adults and identified a small cluster of individuals who have exceptionally high or low levels of NK activity. The flow cytometric assay was validated by testing specimens from subjects expected to have abnormally low levels of NK activity (pregnant women) and specimens from healthy individuals in whom the activity of NK cells was enhanced by exposure to interleukin-2 or alpha interferon. Treatment with these agents was associated with a significant increase in NK activity. These results confirm and extend those of others, showing that the flow cytometric assay is a viable alternative to the chromium release assay for measuring NK cell activity.

Summary The natural killer (NK) cell function was examined in the peripheral blood mononuclear cells of 14 patients with moderate or severe atopic dermatitis. There were significantly impaired NK cell responses in the atopic patients as compared to the control group. This impairment showed a negative correlation with log IgE concentration in the scrum. These findings prompt consideration of a relationship between decreased NK cell activity and the familiar enhanced susceptibility to viral infections in patients with atopic dermatitis.

In the present study, 28 hemophiliacs substituted continuously and 5 hemophiliacs who had received almost no blood products were investigated. Cells of OKT 3+, OKT 4+, and OKT 8+ subsets were counted. Percoll separated fractions of peripheral blood mononuclear cells were examined by morphological criteria and were tested for NK cell activity. We found that the NK cell activity of both groups of hemophiliacs was decreased on testing Ficoll separated cells or low density Percoll separated cells. Normal NK cell activity was found in medium density cells of hemophiliacs. Two possible explantations are discussed: first, the NK cell activity may be suppressed in hemophiliacs and secondly, there may be a block in maturation of NK cell activity. It is unlikely that chronic substitution by blood products counts for these alterations. The possible role of chronic infections is discussed.

The percentage and absolute number of lymphocytes and Leu 7+ cells were significantly lower in HD even in active stages. There was no significant difference in the percentage of LGL between the three groups (control, active HD, inactive HD), however, because of differences in counts of lymphocytes the absolute number of LGL was significantly lower in HD even in the active group than that in healthy controls. The absolute count of LGL and Leu 7+ cells in patients in remission was significantly higher than that in active HD. Natural cytotoxicity against K-562 cells was also significantly lower in active patients in comparison with controls, while the percentage of cytotoxicity was slightly but not significantly higher in patients in remission than that in the active group. A positive correlation was observed between all the three examined parameters both in controls and in patients with active and inactive HD.

Human Chediak-Higashi syndrome (CHS) is a rare, recessively inherited disease with multiple clinical symptoms including increased susceptibility to infection, diluted pigmentation, and giant lysosomes in many tissues (Blume and Wolff, 1972). Other defects, including decreased fusion of lysosomes with phagosomes (Root et al., 1972; Stossel et al., 1912), decreased bactericidal capacity (Root et al, 1972), decreased chemotaxis (Clark and Kimball, 1971), platelet storage disease (Buchanan and Handin, 1976; G. J. Boxer et al., 1977), and defective natural killer cell function (Roder, 1979; Roder and Duwe, 1979; Roder et al., 1979), have more recently been described. Homozygous carriers of the disease suffer from repeated attacks by infectious organisms, often enter an advanced lymphoproliferative phase, and as a result rarely survive their teen years.

By using mice with naturally occurring defects, we have shown that an intact macrophage system is crucial to survival with the pathogenic protozoan Trypanosoma rhodesiense, since a defect in these cells decreased survival by half. Deficiencies in natural killer cell function or complement levels had no effect on survival. However, the capacity to survive trypanosomiasis was not related to the levels of parasitemia achieved during infection.

The natural killer cell activity was studied in 41 children with mild, moderate and severe atopic dermatitis (AD) and in 37 controls. The natural killer cell function of lymphocytes was reduced in atopic children (mean +/- SD 21.92 +/- 6.18% vs. 43.87 +/- 5.80%; p less than 0.0001). This decrease was not related to the IgE serum level. A negative correlation was found between natural killer cell activity and the clinical severity of AD (r = 0.73; p less than 0.001). Natural killer cell function was re-evaluated after 9 months in 27 children during a quiescent phase of AD; it was still low, but to a lesser degree (27.66 +/- 5.42%, in the quiescent phase, vs. 43.87 +/- 5.80, controls; p less than 0.0001). The reduced natural killer cell activity seems related to the disease activity.

SummaryThe RAG endonuclease generates DNA double strand breaks during antigen receptor gene assembly, an essential process for B- and T-lymphocyte development. However, a recent study reveals that RAG endonuclease activity affects natural killer cell function, demonstrating that such double strand breaks, and the responses they elicit, may have broad cellular effects.