The burden of non-communicable diseases and mortality in people living with HIV (PLHIV) in the pre-, early- and late-HAART era.

OBJECTIVES: To estimate the burden of non-communicable diseases (NCDs) and mortality among PLHIV in the pre-, early- and late-HAART (highly active antiretroviral therapy) era. METHODS: We conducted a cohort study using population-based Danish medical registries including all adult HIV-infected residents of the Central Denmark Region during 1985-2017. For each HIV patient, we selected 10 comparisons from the background population matched by age, sex and municipality of residence. Based on hospital-related diagnoses we estimated the prevalence and incidence of specific NCD at diagnosis and at 5 and 10 years. RESULTS: We identified 1043 PLHIV and 10 430 matched comparisons. PLHIV had lower socioeconomic status and more were born outside western Europe. At HIV diagnosis, 21.9% of PHLIV vs. 18.2% of non-HIV individuals had at least one NCD, increasing to 42.2% vs. 25.9% after 10 years. PLHIV had higher prevalence and cumulative incidence of alcohol abuse, chronic obstructive pulmonary disease (COPD), ischaemic heart disease, mental disorders, renal and liver disease, but no increased risk of diabetes mellitus. Only PLHIV in the age groups 41-50 and > 51 years had an increased incidence of osteoporosis. From the pre- to the late-HAART era, 10-year mortality among PLHIV decreased from 45.5% to 9.4% but continued at more than twice that of uninfected comparisons. However, in the late-HAART era, the mortality of PLHIV who were alive 2 years after HIV diagnosis was approaching that of comparisons. CONCLUSIONS: Even in the late-HAART era, PLHIV have an excess mortality, which may be attributable to several NCDs being more prevalent among PLHIV. The prevalence rates of ischaemic heart disease, diabetes, osteoporosis and renal disease tend to increase over calendar time. Therefore, improvement of survival and quality of life of PLHIV neets strategies to reduce the risk of developing NCDs, including avoiding toxic antiretroviral therapy and lifestyle changes.

Identification and Characterization of a Nationwide Danish Adult Common Variable Immunodeficiency Cohort.

In this study, we identified all adults living in Denmark diagnosed with common variable immunodeficiency (CVID) and characterized them according to clinical presentation and EUROclass classification. Using a retrospective, cross-sectional design, possible CVID patients were identified in the Danish National Patient Register and Centers in Denmark treating patients with primary immunodeficiencies. The CVID diagnosis was verified by review of medical records. One-hundred-seventy-nine adults with CVID were identified. This corresponds to a prevalence of 1:26,000. The median age at onset of symptoms was 29 years with no sex difference. The median age at diagnosis was 40 years. Males were diagnosed earlier with a peak in the fourth decade of life, whereas females were diagnosed later with a peak in the sixth decade. The median diagnostic delay was seven years. Recurrent sinopulmonary infections were seen in 92.7% of the patients. The prevalence of non-infectious complications was similar to that of previously reported cohorts: bronchiectasis (35.8%), splenomegaly (22.4%), lymphadenopathy (26.3%), granulomatous inflammation (3.9%) and idiopathic thrombocytopenic purpura (14.5%). Non-infectious complications were strongly associated with B cell phenotype, with all having a reduced number of isotype-switched memory B cells. One-hundred-seventy (95%) were treated with immunoglobulin replacement therapy, primarily administered subcutaneously. According to international guidelines, diagnostic evaluation was inadequate in most cases. This study emphasizes the need for improved diagnostic criteria and more awareness of CVID as a differential diagnosis. Diagnosis and management of CVID patients is a challenge requiring specialists with experience in the field of PID.

Utilization of psychotropic drugs prescribed to persons with and without HIV infection: a Danish nationwide population-based cohort study.

OBJECTIVES: The objective was to estimate the utilization of psychotropic drugs in HIV-infected individuals compared with that in the background population. METHODS: Using data obtained from the Danish HIV Cohort Study and the Danish National Prescription Registry, we analysed aggregated data on redeemed prescription of psychotropic drugs during 1995-2009. We primarily focused our analyses on HIV-infected individuals with no history of injecting drug use (IDU) or hepatitis C virus (HCV) infection. Drug utilization was expressed as defined daily doses per 1000 person-days (DDD/1000PD). The utilization rate ratio (URR) was calculated as utilization in the HIV-infected cohort compared with that in the comparison cohort. We estimated longitudinal trends in utilization and potential associations with HIV and exposure to highly active antiretroviral therapy (HAART), especially efavirenz. RESULTS: During 1995-2009, 54.5% of the HIV-infected cohort (3615 non-IDU/non-HCV-infected HIV-infected individuals) and 29.2% of the comparison cohort (32 535 individuals) had at least one prescription of a psychotropic drug. HIV infection was associated with a URR of 1.13 for antipsychotics, 1.76 for anxiolytics, 4.42 for hypnotics and sedatives, and 2.28 for antidepressants. Antidepressants were confined primarily to men who have sex with men (MSM). Older age, more recent calendar time, and increased time after HIV diagnosis were associated with increased drug utilization. However, no association with exposure to HAART or efavirenz was found. CONCLUSIONS: HIV-infected individuals had a higher utilization of psychotropic drugs than the background population, which was not confined to individuals with a history of IDU or HCV infection. This emphasizes the need to focus on diagnosis of, and appropriate psychopharmacological interventions for, mental disorders in this population.

No change in viral set point or CD4 cell decline among antiretroviral treatment-naïve, HIV-1-infected individuals enrolled in the Danish HIV Cohort Study in 1995-2010.

OBJECTIVES: Recent studies have reported faster progression of HIV infection than anticipated based on results from earlier studies. The aim of the present study was to examine if the virulence of HIV-1 infection changed in the period 1995-2010 among chronically HIV-infected individuals in Denmark. METHODS: We included all patients registered in the Danish HIV Cohort Study, who were diagnosed in 1995-2009, had a CD4 count > 100 cells/µL at diagnosis and had at least two CD4 measurements prior to initiation of antiretroviral therapy (ART). Changes in viral set point and rate of CD4 cell decline from enrolment until the initiation of ART by calendar year of HIV diagnosis were analysed. Time to first CD4 count < 350 cells/µL was compared among patients diagnosed in 1995-2000, 2001-2005 and 2006-2010. RESULTS: We followed 1469 HIV-infected patients for a total of 5783 person-years. The median viral set point was 4.27 log10 HIV-1 RNA copies/mL [interquartile range (IQR) 3.58-4.73 log10 copies/mL]. The median CD4 cell decline per year was 57 cells/µL (IQR 10-139 cells/µL). In analyses adjusted for age, gender, origin, route of transmission and CD4 count at diagnosis, there were no associations between year of diagnosis and viral set point or CD4 cell decline. Time to first CD4 count < 350 cells/µL did not change in the study period [incidence rate ratio (IRR) 0.90 (95% confidence interval (CI) 0.76-1.06) for 2001-2005 and 1.09 (95% CI 0.79-1.34) for 2006-2010 compared with 1995-2000]. CONCLUSIONS: We found no evidence of changing trends in viral set point, CD4 cell decline or time to CD4 count < 350 cells/µL during the period 1995-2010 in a cohort of chronically HIV-infected individuals.

Major but differential decline in the incidence of Staphylococcus aureus bacteraemia in HIV-infected individuals from 1995 to 2007: a nationwide cohort study*.

OBJECTIVES: Incidence rates (IRs) of Staphylococcus aureus bacteraemia (SAB) are known to be higher in HIV-infected individuals than in the general population, but have not been assessed in the era of highly active antiretroviral therapy. METHODS: From 1 January 1995 to 31 December 2007, all Danish HIV-infected individuals (n=4871) and population controls (n=92 116) matched on age and sex were enrolled in a cohort and all cases of SAB were registered. IRs and risk factors were estimated using time-updated Poisson regression analysis. RESULTS: We identified 329 cases of SAB in 284 individuals, of whom 132 individuals were infected with HIV and 152 were not [crude IR ratio (IRR) 24.2; 95% confidence interval (CI) 19.5-30.0, for HIV-infected vs. non-HIV-infected individuals]. Over time, IR declined for HIV-infected individuals (IRR 0.40). Injecting drug users (IDUs) had the highest incidence and the smallest decline in IR, while men who have sex with men (MSM) had the largest decline over time. Among HIV-infected individuals, a latest CD4 count <100 cells/µL was the strongest independent predictor of SAB (IRR 10.2). Additionally, HIV transmission group was associated with risk of SAB. MSM were more likely to have hospital-acquired SAB, a low CD4 cell count and AIDS at the time of HIV acquisition compared with IDUs. CONCLUSIONS: We found that the incidence of SAB among HIV-infected individuals declined during the study period, but remained higher than that among HIV-uninfected individuals. There was an unevenly distributed burden of SAB among HIV transmission groups (IDU>MSM). Low CD4 cell count and IDU were strong predictors of SAB among HIV-infected individuals.

Causes of death among Danish HIV patients compared with population controls in the period 1995-2008.

PURPOSE: To compare the mortality and causes of death in human immunodeficiency syndrome (HIV) patients with the background population. METHODS: All adult HIV patients treated in Danish HIV centers from 1995 to 2008 and 14 controls for each HIV patient were included. Age-adjusted mortality rates (MR) and mortality rate ratios (MRR) were estimated using direct standardization and Poisson regression analyses. Up to four contributory causes of death for each person were included in analyses of cause-specific MR. RESULTS: A total of 5,137 HIV patients and 71,918 controls were followed for 37,838 and 671,339 person-years (PY), respectively. Among non-injection drug use (IDU) HIV patients, the acquired immune deficiency syndrome (AIDS)-related MR/1,000 PY declined dramatically from 122.9 [95 % confidence interval (CI) 106.8-141.4] in 1995 to 5.0 (95 % CI 3.1-8.1) in 2008. The non-AIDS-related MR did not change substantially from 6.9 (95 % CI 3.8-12.5) to 5.6 (95 % CI 3.6-8.8). The MR of unnatural causes declined from 6.9 (95 % CI 3.8-12.5) to 2.7 (95 % CI 1.4-5.1). The MRR of infections declined from 46.6 (95 % CI 19.6-110.9) to 3.3 (95 % CI 1.6-6.6). The MRR of other natural causes of death remained constant. CONCLUSIONS: After the introduction of highly active antiretroviral therapy (HAART), the AIDS-related mortality has decreased substantially, but the long-term exposure to HIV and HAART has not translated into increasing mortality from malignancy, cardiovascular, and hepatic diseases.

HIV and risk of venous thromboembolism: a Danish nationwide population-based cohort study.

OBJECTIVE: The association between HIV infection and the risk of venous thromboembolism (VTE) is controversial. We examined the risk of VTE in HIV-infected individuals compared with the general population and estimated the impact of low CD4 cell count, highly active antiretroviral therapy (HAART) and injecting drug use (IDU). METHODS: We identified 4333 Danish HIV-infected patients from the Danish HIV Cohort Study and a population-based age- and gender-matched comparison cohort of 43,330 individuals. VTE diagnoses were extracted from the Danish National Hospital Registry. Cumulative incidence curves were constructed for time to first VTE. Incidence rate ratios (IRRs) and impact of low CD4 cell count and HAART were estimated by Cox regression analyses. Analyses were stratified by IDU, adjusted for comorbidity and disaggregated by overall, provoked and unprovoked VTE. RESULTS: The 5-year risk of VTE was 8.0% [95% confidence interval (CI) 5.78-10.74%] in IDU HIV-infected patients, 1.5% (95% CI 1.14-1.95%) in non-IDU HIV-infected patients and 0.3% (95% CI 0.29-0.41%) in the population comparison cohort. In non-IDU HIV-infected patients, adjusted IRRs for unprovoked and provoked VTE were 3.42 (95% CI 2.58-4.54) and 5.51 (95% CI 3.29-9.23), respectively, compared with the population comparison cohort. In IDU HIV-infected patients, the adjusted IRRs were 12.66 (95% CI 6.03-26.59) for unprovoked VTE and 9.38 (95% CI 1.61-54.50) for provoked VTE. Low CD4 cell count had a minor impact on these risk estimates, while HAART increased the overall risk (IRR 1.93; 95% CI 1.00-3.72). CONCLUSION: HIV-infected patients are at increased risk of VTE, especially in the IDU population. HAART and possibly low CD4 cell count further increase the risk.

Abacavir and risk of myocardial infarction in HIV-infected patients on highly active antiretroviral therapy: a population-based nationwide cohort study.

OBJECTIVE: The aim of the study was to examine whether exposure to abacavir increases the risk for myocardial infarction (MI). DESIGN, SETTING AND SUBJECTS: This was a prospective nationwide cohort study which included all Danish HIV-infected patients on highly active antiretroviral therapy (HAART) from 1995 to 2005 (N = 2952). Data on hospitalization for MI and comorbidity were obtained from Danish medical databases. Hospitalization rates for MI after HAART initiation were calculated for patients who used abacavir and those who did not. We used Cox's regression to compute incidence rate ratios (IRR) as a measure of relative risk for MI, while controlling for potential confounders (as separate variables and via propensity score) including comorbidity. MAIN OUTCOME: Relative risk of hospitalization with MI in abacavir users compared with abacavir nonusers. RESULTS: Hospitalization rates for MI were 2.4/1000 person-years (PYR) [95% confidence interval (CI) 1.7-3.4] for abacavir nonusers and 5.7/1000 PYR (95% CI 4.1-7.9) for abacavir users. The risk of MI increased after initiation of abacavir [unadjusted IRR = 2.22 (95% CI 1.31-3.76); IRR adjusted for confounders = 2.00 (95% CI 1.10-3.64); IRR adjusted for propensity score = 2.00 (95% CI 1.07-3.76)]. This effect was also observed among patients initiating abacavir within 2 years after the start of HAART and among patients who started abacavir as part of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen. CONCLUSIONS: We confirmed the association between abacavir use and increased risk of MI. Further studies are needed to control for potential confounding not measured in research to date.

A study on the role of protein kinase C and intracellular calcium in the activation of superoxide generation.

Accumulating evidence indicates that protein kinase C plays an essential role in the activation of NADPH oxidase. In the present study, the correlation between superoxide generation, intracellular calcium, activation of purified protein kinase C and stabilized membrane-bound protein kinase C was studied. Phorbol 12-myristate 13-acetate (PMA) and 1-deacyl-2-acetyl-rac-glycerol (OAG) were found to induce equal activation of purified protein kinase C and translocation of protein kinase C to the membrane fraction, but differed significantly in their ability to induce superoxide generation. Intracellular calcium was varied using calcium ionophores and increasing the intracellular calcium concentration to more than 1 microM was found to induce increased superoxide generation in maximally OAG-stimulated cells; this contrasted to maximally PMA-stimulated leukocytes. Ionomycin and A23187 were both found to induce a translocation of protein kinase C to the membrane fraction. This translocation was highly dependent upon extracellular calcium. In contrast, PMA- and OAG-induced translocation of protein kinase C was not dependent upon extracellular calcium. In conclusion, our results indicate that although PMA, OAG and calcium ionophores seem to activate protein kinase C in human polymorphonuclear leukocytes these activators differ in their ability to induce superoxide generation.

Protein kinase C activity in activated human T-lymphocytes stimulated by interleukin-2.

Interleukin-2 and phorbol 12-myristate 13-acetate (PMA) are shown to induce DNA-synthesis in human T-lymphocytes activated with phytohaemagglutinin. However, whereas PMA induced a rapid and persistent translocation of protein kinase C from cytosol to particulate fraction, no translocation was observed upon stimulation with interleukin-2. Treatment with PMA for 72 h caused a slow down-regulation of protein kinase C activity to less than 10% of unstimulated T-lymphocytes and was mainly located in the particulate fraction. In contrast, stimulation with phytohaemagglutinin increased the total cellular protein kinase C activity by approx. 100% but with an unaltered subcellular distribution. However, interleukin-2-induced DNA synthesis in PMA- and phytohaemagglutinin-stimulated T-lymphocytes was comparable. Further, maximal DNA synthesis was shown to be dependent on the continuous presence of interleukin-2. These results indicate that interleukin-2-induced proliferation of activated human T-lymphocytes can occur without a translocation of protein kinase C from the cytosol to the particulate fraction and that interleukin-2 most likely functions as a progression factor.

Ca2+ and phorbol ester activation of protein kinase C at intracellular Ca2+ concentrations and the effect of TMB-8.

A calcium-activated, phospholipid-dependent protein kinase (protein kinase C) was purified to near homogeneity from human polymorphonuclear leukocytes and shown to be identical to bovine protein kinase C. The Ca2+ activation of the enzyme was studied and the Ca2+ concentrations required to activate the enzyme were compared to free cytosolic Ca2+ concentrations in resting and activated polymorphonuclear leukocytes. The free calcium concentrations in the cytosol and in the enzyme assay mixture were determined using the calcium indicator quin 2. The enzyme activity was almost totally dependent upon phosphatidylserine and could be strongly activated by Ca2+ concentrations in the micromolar range, but was not activated by phosphatidylserine at Ca2+ concentrations corresponding to the intracellular free Ca2+ concentration under resting conditions. However, at similar Ca2+ concentrations (less than 2.5 X 10(-7) M) the enzyme was highly activated by phorbol 12-myristate 13-acetate (PMA) or diolein in the presence of phosphatidylserine. It was demonstrated that PMA stimulation of human polymorphonuclear leukocytes did not induce any increase in the level of the intracellular free calcium concentration. It was concluded that PMA activation of protein kinase C occurred independently of a rise in the intracellular Ca2+ concentration. K0.5 (half-maximal activation) for the PMA activation of purified protein kinase C was shown to be equivalent to the K0.5 for PMA stimulation of superoxide (O-2) production in human polymorphonuclear leukocytes, suggesting that protein kinase C is involved in activation of the NADPH oxidase. The presumed intracellular Ca2+ antagonist TMB-8 inhibited the PMA-induced superoxide production, but neither by an intracellular Ca2+ antagonism nor by a direct inhibition of protein kinase C activity.

Membrane-associated protein kinases in phorbol ester-activated human polymorphonuclear leukocytes.

Membrane-associated protein kinases in human polymorphonuclear leukocytes were studied. In unstimulated polymorphonuclear leukocytes the protein kinase C was predominantly present in the cytosol but in phorbol 12-myristate 13-acetate- (PMA-) activated cells a time and dose-dependent translocation of the kinase to the particulate fraction occurred. Two new protein kinase activities also appeared in the particulate fraction upon PMA activation. The one had a Mr of 40,000 and its activity was independent of phospholipids. The other (Mr 90,000) as partially activated by phospholipids, but separated from protein kinase C on DEAE-cellulose chromatography.

Membrane-associated protein kinase C activity in superoxide-producing human polymorphonuclear leukocytes.

Protein kinase C activity was studied in superoxide-producing human polymorphonuclear leukocytes. Using equivalent cell concentrations, superoxide production and particulate fraction-associated protein kinase C activity increased in parallel in phorbol 12-myristate 13-acetate (PMA), oleoyl-acetyl-glycerol (OAG), opsonized zymosan, and A23187-activated leukocytes. Also, an increase in particulate fraction-associated phospholipid-independent kinase activity was observed upon stimulation with these activators. In contrast, in formyl-methionyl-leucine-phenylalanine (FMLP)-activated cells the increase in superoxide production was only accompanied by an increase in particulate fraction-associated protein kinase C activity if the cells were pretreated with cytochalasin B. Purified protein kinase C activity was stimulated by OAG and PMA, whereas no stimulation was observed using A23187 or opsonized zymosan. It is suggested that the activation induced in human neutrophils by PMA, OAG, opsonized zymosan, and A23187 involves a tight membrane association of phospholipid-dependent and -independent protein kinase activity. This contrasts to FMLP-activated neutrophils, in which a membrane-bound form is only observed after pretreatment with cytochalasin B.

Acute acalculous cholecystitis in a patient with primary Epstein-Barr virus infection: a case report and literature review.

Epstein-Barr Virus (EBV) infection can lead to infectious mononucleosis syndrome with the typical symptoms of fever, pharyngitis, and lymphadenopathy. Self-limited mild to moderate elevation of liver enzymes and hepatosplenomegaly are common. However, cholecystitis is not usually considered part of a primary EBV infection and ultrasound scan (USS) of the liver and gallbladder is not routinely performed. Acute acalculous cholecystitis (AAC) caused by etiologies other than primary EBV infection is often associated with severe illness and antibiotic treatment and surgery may be needed. We present a case with primary EBV infection and AAC and a literature review. Our patient was a 34-year-old woman with clinical, biochemical and serological signs of primary EBV infection (lymphocytes 7.6×10˄9/l, monocytes 2.6×10˄9/l, positive early antigen IgM test and 14 days later positive early antigen IgG test). During admission, increasing liver function tests indicated cholestasis (alanine aminotransferase 61 U/l, alkaline phosphatase 429 U/l and bilirubin 42µmol/l). USS revealed a thickened gallbladder wall indicating cholecystitis but no calculus. All other microbiological tests were negative. The literature search identified 26 cases with AAC and acute EBV infection; 25 cases involved females. Sore throat was not predominant (six reported this), and all cases experienced gastrointestinal symptoms. Our and previous published cases were not severely ill and recovered without surgical drainage. In conclusion primary EBV infection should be considered in cases of AAC, especially in young women. In cases associated with EBV infection neither administration of antibiotics nor surgical drainage may be indicated.

Dental modifications and tool use in the western Great Basin.

Nondietary function is an important concern in the study of the human dentition and its role in adaptation. The purpose of the present investigation is to describe and interpret a pattern of dental wear in the anterior dentition of precontact hunter-gatherers that inhabited the western Great Basin. These data are discussed in light of ethnographic documentation as a means by which the archaeological record is linked with associated behavior of the representative populations. A series of 171 dentitions from a group of archaeological localities was examined. Of 1,931 teeth observed, 16 of these showed narrow (0.4-2.0 mm) transverse grooves located on the midocclusal surfaces of anterior teeth. The grooves were restricted in occurrence to five older adult males. Documentation of prehistoric and historic western Great Basin aboriginal populations indicates an adaptation that involves use of plant materials in the production of a variety of utilitarian objects, such as fish nets, basketry, funerary bags, fowling bags, and rope. In postcontact contexts, the anterior dentition has been shown to play an important role in the preparation of materials used for the production of this equipment. It seems most likely, then, that the grooves observed herein resulted directly from the use of the dentition as part of the tool assemblage for the production of other tools.

Activation of human T lymphocytes by phorbol-12,13-dibutyrate and ionomycin.

The calcium ionophore ionomycin and the phorbol ester phorbol-12,13-dibutyrate (PDBu) are shown to have a synergistic effect upon interleukin 2 (IL-2) production, interleukin 2 receptor expression, and T-lymphocyte proliferation. The proliferative response was inhibited by addition of a monoclonal antibody directed against the IL-2R (Tac antigen) demonstrating that PDBu and ionomycin induce T-cell growth through an IL-2-dependent autocrine pathway. Sequential stimulation with PDBu and ionomycin failed to induce IL-2 production, IL-2R expression, and consequently proliferation of the T cells, indicating that T-cell activation requires simultaneous activation of protein kinase C (PKC) and elevation of cytosolic calcium. Exposure of T cells to both agents for different times resulted in IL-2 production, IL-2R expression, and proliferation in proportion to the duration of incubation with at least 4 h required for maximal T-cell activation. Further, in the presence of PDBu maximal T-cell activation was found to require stimulation with ionomycin for 4 h, indicating that a sustained increase in free cytoplasmic calcium of several hours' duration is essential for T-cell activation. In contrast T cells incubated with ionomycin were induced to produce IL-2 and express IL-2Rs upon brief exposure to PDBu with a 2-h incubation period being sufficient for maximal T-cell activation. Thus transient activation of PKC seems to be sufficient for activation of the IL-2 gene and IL-2R gene. However, maximal T-cell activation requires activation of PKC for at least 2 h.

Determination of interleukin-2 (IL-2) and soluble IL-2 receptors (S-IL-2R) in serum and cerebrospinal fluid does not discriminate purulent and aseptic meningitis.

Elevated levels of soluble interleukin-2 receptors (S-IL-2R) but not interleukin-2 (IL-2) activity were found in sera from patients with aseptic meningitis, purulent meningitis, and meningism. Elevated levels of S-IL-2R in serum was also observed in 4/4 patients with bacterial pneumonia and 2/2 patients with infectious mononucleosis. The inflammation of the meninges was only reflected by an increase in S-IL-2R in cerebrospinal fluid (CSF) in 1/14 patients with aseptic meningitis and 3/10 patients with purulent meningitis. Further, IL-2 activity was only demonstrated in CSF from 2 patients with aseptic meningitis and 3 patients with purulent meningitis. In conclusion, neither S-IL-2R nor IL-2 in serum or CSF seem to have any value in the diagnosis of or discrimination between purulent meningitis and aseptic meningitis. Further, the elevation of S-IL-2R in serum is not specific for infections primarily fought by cytotoxic T-lymphocytes such as viral infections, but seems merely to reflect an unspecific activation of the immune system.

Induction of high-affinity interleukin 2 receptors on human T lymphocytes. The role of calcium and protein kinase C.

The relationship between free cytoplasmic calcium, activation of protein kinase C (PKC) and expression of high-affinity interleukin 2 receptors (HA-IL-2R) on human T lymphocytes was studied. Induction of HA-IL-2R by phytohaemagglutinin (PHA) was associated with an increase in free cytoplasmic calcium and a transient increase in membrane-associated PKC. However, whereas addition of EGTA inhibited induction of receptors by PHA, addition of the PKC-inhibitor H7 did not. 12-o-tetradecanoyl-phorbol-13-acetate (PMA) and 1-oleoyl-2-acetyl-rac-glycerol (OAG) were both found to activate and translocate PKC. However, only PMA induced expression of HA-IL-2R. Not surprisingly, the effect of PMA was independent of extracellular calcium, but was inhibited by H7. Furthermore, a correlation between the number of HA-IL-2R and free cytoplasmic calcium upon stimulation with ionomycin was observed. Associated with the rise in intracellular calcium, the ionophore caused a slight increase in membrane-associated PKC. Also, addition of H7 inhibited expression of HA-IL-2R. Finally, OAG and ionomycin acted synergistically on expression of HA-IL-2R. In conclusion, induction of HA-IL-2R requires at least two different signals and neither activation of PKC nor an increase in free cytoplasmic calcium is sufficient. However, these two signals may act synergistically. There is evidence for both a PKC- and calcium-independent pathway.

Protein kinase C subtypes in human T lymphocytes.

As contradictory results have previously been published on protein kinase C subtypes in human T lymphocytes, we made comparable studies on protein kinase C subtypes in human lymphocytes and in rat brain. In accordance with results published by Shearman et al. [16] we found that human T lymphocytes only contain type II = beta and type III = alpha protein kinase C.