Natural killer cell enumeration and function in HIV-infected and high-risk uninfected adolescents

This is the first report of natural killer cell enumeration and function in HIV-infected and high-risk uninfected adolescents. We examined the association of demographic characteristics of this cohort with three outcomes: CD16+ cell absolute count, lytic units per peripheral blood mononuclear cell (PBMC), and lytic units per natural killer (NK) cell. We also examined the association of CD4, CD38, and antiretroviral therapy (ART) use with these outcomes in the subset of HIV-infected adolescents. Adolescents participating in an on-going longitudinal study (the REACH study) were sampled for CD16+ cell count and NK function. This cross-sectional analysis was performed on 412 subjects with NK cell data available. HIV-positive males had higher numbers of CD3-/CD16+/CD56+ NK cells than HIV-positive females. However, for the HIV-negative subjects, we did not observe a gender-related effect for absolute NK cell numbers. Gender, however, was a significant covariate for the analysis, using lytic units per PBMC as the unit of measurement, with males showing higher values than females. Age was not a predictive covariate for any of the three assessments of NK cell number and function examined. Our observations concerning the HIV-positive individuals indicate that reduced CD4+ T cell counts were associated with decreased circulating CD3-/CD16+/CD56+ NK cells. We also observed an association between elevation of CD8+/CD38+/DR+ lymphocytes and lower NK lytic units per PBMC. The results of our multivariate models indicate that there is a reduced number of NK cells and reduced lytic units per PBMC in patients receiving single or multidrug antiretroviral therapy. There are changes in circulating NK cell number and function in HIV-infected adolescents, in comparison with high-risk HIV-negative adolescents. The data suggest that these changes may occur early in the course of HIV disease but that quantitative changes continue to occur with advancing depletion of the CD4+ T cell pool.     

Co-morbid medical and psychiatric illness and substance abuse in HCV-infected and uninfected veterans

Comorbidities may affect the decision to treat chronic hepatitis C virus (HCV) infection. We undertook this study to determine the prevalence of these conditions in the HCV-infected persons compared with HCV-uninfected controls. Demographic and comorbidity data were retrieved for HCV-infected and -uninfected subjects from the VA National Patient Care Database using ICD-9 codes. Logistic regression was used to determine the odds of comorbid conditions in the HCV-infected subjects. HCV-uninfected controls were identified matched on age, race/ethnicity and sex. We identified 126 926 HCV-infected subjects and 126 926 controls. The HCV-infected subjects had a higher prevalence of diabetes, anaemia, hypertension, chronic obstructive pulmonary disease (COPD)/asthma, cirrhosis, hepatitis B and cancer, but had a lower prevalence of coronary artery disease and stroke. The prevalence of all psychiatric comorbidities and substance abuse was higher in the HCV-infected subjects. In the HCV-infected persons, the odds of being diagnosed with congestive heart failure, diabetes, anaemia, hypertension, COPD/asthma, cirrhosis, hepatitis B and cancer were higher, but lower for coronary artery disease and stroke. After adjusting for alcohol and drug abuse and dependence, the odds of psychiatric illness were not higher in the HCV-infected persons. The prevalence and patterns of comorbidities in HCV-infected veterans are different from those in HCV-uninfected controls. The association between HCV and psychiatric diagnoses is at least partly attributable to alcohol and drug abuse and dependence. These factors should be taken into account when evaluating patients for treatment and designing new intervention strategies.     

Impaired natural killer cell function in systemic lupus erythematosus

Immune regulation requires clonal expansion of regulatory T cells which is dependent on the presence of interleukin-2 (IL-2). Previously, both natural killer (NK) cell function and IL-2 production were found to be depressed in systemic lupus erythematosus (SLE). This study was designed to determine the relationship between IL-2 production and NK cell activity in SLE. NK activity as determined by a standard 4-hour ⁵¹Cr-release assay was impaired in SLE (11.0 ± 5.1 lytic units/10⁷ cells) compared with controls (25.1 ± 7.1 lytic units/10⁷ cells) (P < 0.05). IL-2 production was induced with concanavalin A and phorbol ester and quantitated using the IL-2 dependent cell line HT-2. IL-2 production was impaired in only 1 SLE patient, despite concomitant abnormalities in NK function in the SLE group as a whole. Moreover, in patients with impaired NK activity, incubation of lymphocytes with exogenous IL-2 did not restore NK activity to normal levels. These findings demonstrate that impaired NK activity in SLE is independent of IL-2 production and that defects in IL-2 production in SLE may not be as common as previously reported.     

Relationship between custodial status and psychosocial problems among cocaine-abusing parents initiating substance abuse treatment

Using the Addiction Severity Index and Brief Symptom Inventory, drug use and psychosocial problems are compared between 93 custodial and 125 non-custodial mothers and fathers initiating outpatient treatment for cocaine dependence. Compared to non-custodial parents, custodial parents experienced more severe current cocaine and alcohol problems, including spending more money on cocaine and alcohol, as well as using more cocaine and being intoxicated on more days. Non-custodial parents demonstrated more psychological distress, more prior history of alcohol problems, and greater current employment and legal problems than custodial parents. Suggestions are made for differential treatment plans based on these findings.     

Human papillomavirus infection and abnormal cytology of the anus in HIV-infected and uninfected adolescents

OBJECTIVE: To examine the prevalence of and risk for anal human papillomavirus (HPV) infection and abnormal anal cytology in sexually active adolescents. DESIGN: Prevalence data from adolescents aged 13-18 years with and without HIV infection and with a history of high-risk sexual behavior. METHODS: HPV DNA was detected using amplification techniques. Abnormal anal cytology was defined as atypical squamous cell of undetermined significance or worse. RESULTS: Prevalence of anal HPV infection was similar in HIV-infected [28/58 (48%)] and uninfected [9/25 (36%)] boys (P = 0.3). but greater in HIV-infected [59/183 (59%)] than in uninfected [11/82 (13%)] girls (P < 0.001). Perianal warts were a risk for anal HPV in both boys [odds ratio (OR), 15.5; 95% confidence interval (CI), 1.6-149] and girls (OR, 9.9; 95% CI, 1.9-51.3). In subjects without anal warts, HIV infection was significant for girls (OR, 2.3; 95% CI, 1.1-4.9) and homosexual/bisexual orientation was significant for boys (OR, 5.2; 95% CI, 1.3-20.6). Abnormal anal cytology was more common among boys [32/77 (41.6%)] than girls [38/230 (16.5%)] (P < 0.001) and in addition to anal HPV, independent risk factors were positive HIV status in boys (OR, 6.5; 95% CI, 1.5-11.9) and number of partners within the past 3 months in girls (OR, 4.2; 95% CI, 1.5-11.9). CONCLUSIONS: Strong risk factors for abnormal anal cytology were HIV infection and anal HPV in boys and anal HPV and higher number of sexual partners for girls. The results suggest that anal cytology screening should be considered in HIV infected homosexual/bisexual males.     

Music therapy induced alternations in natural killer cell count and function

The effects of music therapy on natural killer (NK) cell count and activity (NKCA) were studied in 19 persons. Alzheimer's disease, cerebrovessel disease and Parkinson's disease subjects were assigned to a music therapy. Blood samples were drawn at rest and after completion of music therapy. Music therapy did not change the number of circulating lymphocytes. The percentage of NK cells increased during music therapy, along with an increase in the NK cell activity. The proportion of T cells, CD4 and CD8 did not change significantly during music therapy. One hour after the music therapy session, plasma adrenaline increased but cortisol and noradrenalin did not change. The results indicate that music therapy can significantly increase NK cell count and activity. The change in NK cell and function were independent of neuro-degenerative diseases.     

Impact of victimization on substance abuse treatment outcomes for adolescents in outpatient and residential substance abuse treatment

This paper considers whether victimization moderates adolescents' outcomes in substance abuse treatment. Adolescents (N=975) in outpatient and residential settings were assessed at intake, three, six, nine, and 12 months. Differential outcomes by gender and degree of victimization were analyzed. Dependent variables were marijuana use and substance-related problems. The residential sample reported higher baseline marijuana use and victimization. Both samples significantly reduced marijuana use and associated problems during treatment. Victimization was significantly related to more substance-related problems at intake and follow-up. More severe trauma histories in residential females were associated with significantly greater persistence in substance-related problems post-discharge.     

过敏性紫癜患者红细胞免疫功能与NK细胞活性的变化

目的 探讨红细胞免疫及天然杀伤细胞（ＮＫＣ）在过敏性紫癜（ＨＳＰ）发病中的可能作用。方法 红细胞免疫采用郭峰法测定２２例ＨＳＰ患者,红细胞Ｃ３ｂ受体花环率（ＲＢＣ－Ｃ３ｂＲＲ）,与免疫复合物受体花环率（ＲＢＣ－ＩＣＲ）,流式细胞仪与单克隆抗体（ＣＤ１６）测定ＮＫ细胞的活性。并与２０名正常体检儿童对照。结果 ＨＳＰ患者ＲＢＣ－Ｃ３ｂＲＲ及ＮＫＣ活性低于正常对照组（Ｐ〈０．０１）,ＲＢＣ－ＩＣＲ高于正     

HLA-C and HLA-E reduce antibody-dependent natural killer cell-mediated cytotoxicity of HIV-infected primary T cell blasts

OBJECTIVE: To determine whether the presence of HLA-C and HLA-E on HIV-infected cells modulates autologous natural killer (NK) cells from implementing antibody-dependent cell-mediated cytotoxicity (ADCC) of HIV-infected cells. DESIGN: The capability of HLA-C and HLA-E to control NK cell killing of HIV-infected autologous T cells coated with anti-gp120 monoclonal antibody was determined by blocking the interaction between the inhibitory receptors on NK cells and the MHC class I molecules on infected cells. METHODS: Phytohemagglutinin-treated CD4 T cells were infected in vitro with HIV-1. Infected cells were separated from uninfected cells by removal of CD4 T cells. Infected cells were labeled with chromium-51, treated with a cocktail of four different monoclonal antibodies against HIV gp120, and co-cultured with freshly isolated autologous NK cells that were incubated with or without anti-CD159a, anti-CD158a, and CD158b, or all three antibodies combined. Killing of the HIV-infected cells by NK cells was assessed in a 4 h cytotoxic assay. RESULTS: When the interaction between NK cell inhibitory receptors (i.e., CD158a, CD158b, and CD159a) and MHC class I molecules (i.e., HLA-C and HLA-E) on HIV-infected autologous T cells was blocked, a drastic increase in killing of anti-gp120-coated HIV-infected cells by NK cells was observed. CONCLUSION: These studies indicate that the presence of HLA-C and HLA-E molecules on HIV-infected cells may facilitate evasion of NK-mediated killing of antibody-coated HIV-infected cells.     

Enhanced natural killer cell activity is found in exposed uninfected recipients of hepatitis C‐contaminated blood

A minority of injecting drug users, termed exposed uninfected, are resistant to hepatitis C (HCV) infection despite repeated low‐dose exposures. We identify for the first time a cohort of blood recipients who remained uninfected despite large‐dose exposure to HCV‐contaminated blood and characterize immune factors that may confer protection. Of 1340 blood recipients from the English Look Back database who were transfused HCV‐contaminated blood, we identified 8 who remained uninfected. In these 8 exposed uninfecteds, we characterized their natural killer (NK) cell populations and HCV‐specific T‐cell responses. Findings were compared with 10 spontaneous resolvers of HCV infection, 10 patients with chronic HCV infection and 10 healthy controls. Exposed uninfecteds had significantly greater numbers of NK cells with the activating receptor NKp30+ on CD56^bright and CD56^dim subsets compared with other groups (P < .05). Following interleukin‐2 activation, NK cells of exposed uninfecteds had enhanced cytotoxicity that positively correlated with NKp30 expression (P = .02). Differences in NKp80 and KIR2DL3 expression were also observed. HCV‐specific T‐cell responses were observed in some exposed uninfecteds but of low amplitude. Exposure without infection following transfusion of HCV‐contaminated blood is a very rare phenomenon and suggests a high level of resistance to infection. Enhanced NK cell activation and killing, with weak HCV‐specific T‐cell responses, were observed many years after exposure in uninfected recipients and may contribute to protection from HCV acquisition, although additional protective factors are being sought in this important cohort.     

The natural killer cell cytotoxic function is modulated by HIV-1 accessory proteins

Natural killer (NK) cells' major role in the control of viruses is to eliminate established infected cells. The capacity of NK cells to kill virus-infected cells is dependent on the interactions between ligands on the infected cell and receptors on the NK cell surface. Because of the importance of ligand-receptor interactions in modulating the NK cell cytotoxic response, HIV has developed strategies to regulate various NK cell ligands making the infected cell surprisingly refractory to NK cell lysis. This is perplexing because the HIV-1 accessory protein Vpr induces expression of ligands for the NK cell activating receptor, NKG2D. In addition, the accessory protein Nef removes the inhibitory ligands HLA-A and -B. The reason for the ineffective killing by NK cells despite the strong potential to eliminate infected cells is due to HIV-1 Vpu's ability to down modulate the co-activation ligand, NTB-A, from the cell surface. Down modulation of NTB-A prevents efficient NK cell degranulation. This review will focus on the mechanisms through which the HIV-1 accessory proteins modulate their respective ligands, and its implication for NK cell killing of HIV-infected cells.     

Personality dimensions and substance misuse: relationships in adolescents, mothers and fathers.

The research addressed the question of whether relationships exist between personality dimensions, antisocial behavior, and alcohol or other substance misuse (AOSM) in adolescents and in their fathers and mothers, who often also have histories of AOSM. One hundred male adolescents (mean age 15.8 years) entering a residential treatment center for youths with AOSM, their mothers (n = 88, mean age 39.4 years), their fathers (n = 36, mean age 44.9 years), and community controls (n = 100 adolescents, mean age 16.5 years; n = 96 mothers, mean age 43.8 years; n = 87 fathers, mean age 45.9 years) were recruited. All participants completed a personality questionnaire and were interviewed on several measures, including structured interviews for psychopathology and substance misuse. The findings indicated that novelty seeking (NS), one of the personality dimensions, was significantly correlated with substance misuse in adolescent probands, adolescent controls, and proband fathers and mothers, but not in control fathers and mothers. Regression analyses that included conduct disorder (CD) or antisocial personality disorder (APD) symptoms indicated that both NS and CD or APD symptoms made significant contributions to the prediction of substance misuse in treatment group probands and in their fathers and mothers. The findings further suggest that NS and antisocial behaviors contribute independently to substance misuse in severely impaired adolescents and their fathers, but not in their mothers.     

Impaired natural killer cell function in hemophiliacs with or without continuous substitution

Summary 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.     

Lymphokine-activated killer cell and natural killer cell activities in patients with systemic sclerosis

Objective. To determine the ability of T lymphocytes and natural killer (NK) cells from patients with systemic sclerosis (SSc) to respond to cytokines and to generate immune effector cells. Methods. The numbers and percentages of peripheral blood T and NK cells were examined by 2-color flow cytometry, and NK and lymphokine-activated killer (LAK) cell function were measured in 4-hour ⁵¹Cr-release assays, in 34 patients with SSc. The patients were categorized into 3 subgroups: 10 had diffuse cutaneous disease of ≤3 years disease duration, 11 had diffuse cutaneous SSc of >3 years duration, and 13 had limited cutaneous disease. Results. Baseline and activated NK and T cell numbers and NK activity were normal in SSc patients. However, mean LAK activity was significantly depressed in all SSc subgroups. Conclusion. Decreased LAK cell function, despite normal numbers of circulating T and NK cells, indicates that SSc patients have poor ability to produce effector cells in response to interleukin-2.     

The abstinence phobias: links between substance abuse and anxiety

This paper presents a new model to explain the observed relationship between anxiety and substance abuse. Specifically, the concept of "abstinence phobias," common across psychoactive substances, is developed. The evidence needed to support this concept is outlined, and relevant data from studies of opiate, alcohol, and tobacco dependences are reviewed. Parallel data obtained from the treatment of obesity are discussed. It is concluded that the abstinence phobia merits further study; clinical implications are also considered.     

Lymphokine-activated killer cell and natural killer cell activities in patients with systemic sclerosis.

OBJECTIVE. To determine the ability of T lymphocytes and natural killer (NK) cells from patients with systemic sclerosis (SSc) to respond to cytokines and to generate immune effector cells. METHODS. The numbers and percentages of peripheral blood T and NK cells were examined by 2-color flow cytometry, and NK and lymphokine-activated killer (LAK) cell function were measured in 4-hour 51Cr-release assays, in 34 patients with SSc. The patients were categorized into 3 subgroups: 10 had diffuse cutaneous disease of less than or equal to 3 years disease duration, 11 had diffuse cutaneous SSc of greater than 3 years duration, and 13 had limited cutaneous disease. RESULTS. Baseline and activated NK and T cell numbers and NK activity were normal in SSc patients. However, mean LAK activity was significantly depressed in all SSc subgroups. CONCLUSION. Decreased LAK cell function, despite normal numbers of circulating T and NK cells, indicates that SSc patients have poor ability to produce effector cells in response to interleukin-2.     

Impaired intrahepatic natural killer cell cytotoxic function in chronic hepatitis C virus infection

Hepatitis C virus (HCV) persistence in the host results from inefficiencies of innate and adaptive immune responses. Most studies addressing the role of innate immunity concentrated on peripheral blood (PB) natural killer (NK) cells, whereas only limited information is available on intrahepatic (IH) NK cells. We therefore examined phenotypic and functional features of IH and PB NK cells in paired liver biopsy and venous blood samples from 70 patients with chronic HCV infection and 26 control persons subjected to cholecystectomy for gallstones as controls. Ex vivo isolated IH NK cells from HCV-infected patients displayed unique phenotypic features, including increased expression of NKp46-activating receptor in the face of reduced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and cluster of differentiation (CD) 107a expression, which resulted in impaired degranulation compared with controls. To gain insights into the effect of HCV on NK cells, we exposed peripheral blood mononuclear cells (PBMCs) from patients and healthy donors to cell-culture-derived HCV (HCVcc) and measured NK cell degranulation, TRAIL, and phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2) expression. Exposure of PBMCs to HCVcc significantly boosted NK degranulation, pERK1/2, and TRAIL expression in healthy donors, but not in patients with chronic HCV infection, a defect that was completely reversed by interferon-alpha. Purified NK cells showed a minimal, though significant, increase in degranulation and TRAIL expression, both in patients and controls, after exposure to HCVcc. Conclusions: These findings indicate dysfunctional IH NK cell cytotoxicity associated with TRAIL down-regulation in chronic HCV infection, which may contribute to virus persistence. PB NK cell impairment upon exposure to HCVcc suggests the existence of an accessory cell-dependent NK cell lytic defect in chronic HCV infection predominantly involving the TRAIL pathway. (HEPATOLOGY 2012;56:841-849).     

Risk factors for serious alcohol and drug use: the role of psychosocial variables in predicting the frequency of substance use among adolescents

Reviews of the psychosocial risk factors of adolescent alcohol and drug use suggest that the highest risks can be summarized as: 1) psychological functioning, 2) family environment, 3) peer relationships, and 4) stressful life events. The purpose of this study is to describe the relationships among the most common risk factors among a clinical sample (n = 214) and to determine the collective importance of these risk factors on problems with substance use. Collectively, these risk factors were most effective in explaining alcohol use and binge drinking and marijuana use, which were the most frequent types of substance use in this sample. Antisocial peers and delinquent behavior were the strongest predictors of substance use. Implications are that treatment programs target different psychosocial factors depending on the substance being used, and put extra effort on understanding and altering the relationship between an adolescent's choice of peers and their own attitudes toward delinquency and drug use.