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T cell proliferation and T helper (TH) cells that make IL-17 (TH17 cells) and IFN-γ (TH1 cells) have been shown to be inhibited by 1,25(OH)2D3. Previous work has shown that immune-mediated diseases, where TH1 and TH17 cells are pathogenic, are ameliorated with 1,25(OH)2D3 treatment. Paradoxically, infectious diseases that require TH1 and TH17 responses for host resistance are unaffected by 1,25(OH)2D3 treatment. Resting T cells are not responsive to vitamin D because they do not express the vitamin D receptor (VDR) until late after activation. T cells activated following an infection help clear the infection, and since the antigen is eliminated, vitamin D is not needed to dampen the immune response. Conversely, in immune-mediated disease, there is chronic T cell activation, and in this scenario, vitamin D and 1,25(OH)2D3 are critical for inhibiting T cell proliferation and cytokine production. Vitamin D is a late regulator of T cell function and acts to turn off T cells. This paper will review these data. [ABSTRACT FROM AUTHOR]

Introduction: CD4/CD8 ratio is a marker of immune activation in HIV infection and has been associated with neurocognitive performance during chronic infection, but little is known about the early phases. The aim of this study was to examine the relationship between blood CD4/CD8 ratio and central nervous system endpoints in primary HIV infection (PHI) before and after antiretroviral treatment (ART). Methods: This was a retrospective analysis of the Primary Infection Stage CNS Events Study (PISCES) cohort. We longitudinally assessed blood and cerebrospinal fluid (CSF) markers of inflammation, immune activation and neuronal injury, and neuropsychological testing performance (NPZ4, an average of three motor and one processing speed tests, and a summarized total score, NPZ11, including also executive function, learning and memory) in ART‐naïve participants enrolled during PHI. Spearman correlation and linear mixed models assessed the relationships between the trajectory of CD4/CD8 ratio over time and neurocognitive performance, blood and CSF markers of immune activation and neuronal injury. Results: In all, 109 PHI participants were enrolled. The mean CD4/CD8 ratio decreased with longer time from infection to starting treatment (p < 0.001). Every unit increase in NPZ4 score was independently associated with a 0.15 increase in CD4/CD8 ratio (95% CI: 0.002–0.29; p = 0.047), whereas no correlation was found between CD4/CD8 ratio and NPZ11. Among the cognitive domains, only a change in processing speed was correlated with CD4/CD8 ratio over time (p = 0.03). The trajectory of the CD4/CD8 ratio was negatively correlated with change in CSF neurofilament light chain (p = 0.04). Conclusions: The trajectory of CD4/CD8 ratio was independently associated with motor/psychomotor speed performance, suggesting that immune activation is involved in brain injury during the early stages of the infection. [ABSTRACT FROM AUTHOR]

In the last decade, there has been a tremendous development of technologies focused on analysing various molecular attributes in single cells, with an ever‐increasing number of parameters becoming available at the DNA, RNA and protein levels. Much of this progress has involved cells in suspension, but also in situ analysis of tissues has taken great leaps. Paralleling the development in the laboratory, and because of increasing complexity, the analysis of single‐cell data is also constantly being updated with new algorithms and analysis platforms. Our immune system shares this complexity, and immunologists have therefore been in the forefront of this technological development. These technologies clearly open new avenues for immunology research, maybe particularly within autoimmunity where the interaction between the faulty immune system and the thymus or the target organ is important. However, the technologies currently available can seem overwhelming and daunting. The aim of this review is to remedy this by giving a balanced overview of the prospects of using single‐cell analysis in basal and clinical autoimmunity research, with an emphasis on endocrine autoimmunity. [ABSTRACT FROM AUTHOR]

Aim Successful pregnancy requires balanced regulation of immune cells at the feto-maternal interface. Systemic monitoring of the immune system cannot precisely outline local immune status in the uterus. In this survey, endometrial immune milieu was investigated using a non-invasive method of analysis of menstrual blood (MB). The results were compared with peripheral blood (PB). Method PB and MB of healthy fertile women ( n = 15) were collected simultaneously on the second day of their menstrual cycle. T and natural killer T cell subpopulations were immunophenotyped by flow cytometry. Results Among examined cell populations, the frequency of CD4 + Foxp3+, CD4 + Foxp3 + CD25-, CD4 + Foxp3 + CD25+ and IL17+ T cells ( P = 0.022, 0.028, 0.017 and 0.005, respectively) and TCRαβ+, CD45RO+, CD16-, IFNγ + and IL17+ NKT (CD56 + CD3+) cells ( P = 0.010, 0.037, 0.038, 0.015 and 0.021, respectively) were significantly higher in MB compared with PB. Conversely, PB contained a higher percentage of CD16+ T cells ( P = 0.025) in comparison with MB. Conclusion MB contains cells of an inflammatory and anti-inflammatory nature, implying the existence of finely tuned cell homeostasis during menstruation. Our results imply that MB could be viewed as an easy-to access specimen for monitoring endometrial immune cells, especially those that have preferential endometrial localization. [ABSTRACT FROM AUTHOR]

Objectives The role of Th17 cells and associated cytokines was investigated in oral lichen planus. Material and methods 14 consecutive patients with oral lichen planus were investigated. For biological studies, tissues were taken from reticular or erosive lesions and from normal oral mucosa (controls) of the same patient. mRNA expression for IL-17F, IL-17A, MCP-1, IL-13, IL-2, IL-10, IL-1β, RANTES, IL-4, IL-12B, IL-8, IFN-γ, TNF-α, IL-1α, IL-18, TGF-β1, IL-23R, IL-7, IL-15, IL-6, MIG, IP-10, LTB, VEGF, IL-5, IL-27, IL-23A, GAPDH, PPIB, Foxp3, GATA3, and RORC was measured using the QuantiGene 2.0. Results Results showed that Th17-type and Th0-type molecules' mRNAs, when compared with results obtained from tissue controls, were increased in biopsies of erosive lesions, whereas Th2-type molecules' mRNAs were increased in reticular lesions. When the CD4+ T-cell clones, derived from oral lichen planus tissues and tissue controls, were analyzed, a higher prevalence of Th17 (confirmed by an increased CD161 expression) and Th0 CD4+ T clones was found in erosive lesions, whereas a prevalence of Th2 clones was observed in reticular lesions. Conclusions Our data suggest that Th17, Th0, and Th2 cells, respectively, may have a role in the pathogenesis of erosive and reticular oral lichen planus. [ABSTRACT FROM AUTHOR]

Background Major surgery suppresses the cell-mediated immune response in children and adults. Data on preoperative and postoperative T-cell counts in pediatric surgical patients and their relationship to health-care-associated infection ( HAI) are not yet known. Methods A prospective observational study was carried out in a level III multidisciplinary neonatal and pediatric intensive care unit. Before and after, and in the first 3 days after surgery, lymphocyte subsets in peripheral blood were measured in 28 neonates and infants on flow cytometry. HAI were classified according to CDC/ NHSN criteria. Results Six out of 28 neonates and infants (21.4%) developed HAI (group I- HAI), while 22 out of 28 (78.6%) remained infection free (group II-non- HAI). In group I with HAI, the preoperative median cytotoxic T-lymphocyte ( CD8-T-cell) level was found to be below normal, and remained very low throughout the study period. In addition, the median and interquartile CD8 T-cell range (358 cells/μ L; 304-424 cells/μ L) were twice as low compared to group II without HAI (822 cells/μ L; 522-933 cells/μ L; P = 0.013). No differences were found between the two groups with regard to patient demographics and clinical data. Conclusion Neonates and infants who underwent a major surgical procedure and who had a very low preoperative CD8 T-cell level, developed HAI postoperatively. [ABSTRACT FROM AUTHOR]

Introduction We aimed to determine the antibody responses and effect on viral load of the AS03-adjuvanted pandemic H1N1 vaccine in HIV-infected patients. Method A total of 121 HIV-infected patients and 138 healthy subjects were enrolled in a prospective, open-label study. Healthy subjects received one dose and HIV-infected patients two doses of the AS03-adjuvanted split influenza A/09/ H1N1 vaccine ( Pandemrix®; GlaxoSmithKline, Brentford, United Kingdom.) at an interval of 3-4 weeks. The study was extended in 2010/2011 for 66 patients. Geometric mean titres ( GMTs), seroprotection rates (post-vaccination titre ≥1:40) and HIV-1 RNA levels were measured before and 4 weeks after immunization. Results After two immunizations, the seroprotection rate (94.2 vs. 87%, respectively) and GMT (376 vs. 340, respectively) in HIV-infected patients were as high as in healthy subjects after one dose, regardless of CD4 cell count. Four weeks after immunization, HIV RNA was detected in plasma samples from 40 of 68 (58.0%) previously aviraemic patients [median 152 HIV-1 RNA copies/m L; interquartile range ( IQR) 87-509 copies/m L]. Subsequent measures indicated that HIV RNA levels had again declined to <20 copies/m L in most patients (27 of 34; 79.4%). Following (nonadjuvanted) influenza immunization in 2010/2011, HIV RNA levels only slightly increased (median final level 28 copies/m L) in three of 66 (4.5%) previously aviraemic patients, including two of 25 (8%) patients in whom an increase had been elicited by AS03-adjuvanted vaccine the year before. Conclusion Most HIV-infected patients developed seroprotection after two doses of AS03-adjuvanted pandemic vaccine. A transient effect on HIV RNA levels was observed in previously aviraemic patients. A booster dose of the nonadjuvanted influenza vaccine containing the A/09/ H1N1 strain the following year did not reproduce this finding, indicating a non-antigen-specific adjuvant effect. [ABSTRACT FROM AUTHOR]

Objectives Antiretroviral therapy reduces mortality and morbidity in HIV-infected individuals most markedly when initiated early, before advanced immunodeficiency has developed. Late presentation for diagnosis and care remains a significant challenge. To guide public health interventions effectively it is crucial to describe the factors associated with late presentation. Methods Case surveillance data for all individuals newly diagnosed with HIV infection in Germany in the years 2001-2010 and data for the years 1999-2010 from the German Clinical Surveillance of HIV Disease ( ClinSurv) cohort study, a large multicentre observational study, were analysed. Factors associated with late presentation ( CD4 count < 350 cells/ μL or clinical AIDS) were assessed using descriptive statistics and multivariable logistic regression methods. Results Among 22 925 eligible patients in the national surveillance database, 49.5% were late presenters for HIV diagnosis. Among 6897 treatment-naïve patients in the ClinSurv cohort, 58.1% were late presenters for care. Late presenters for care were older (median 42 vs. 39 years for early presenters), more often heterosexuals from low-prevalence countries (18.1% vs. 15.5%, respectively) and more often migrants (18.2% vs. 9.7%, respectively; all P < 0.005). The probability of late presentation was >65% throughout the observation period in migrants. The probability of late presentation for care clearly decreased in men who have sex with men ( MSM) from 60% in 1999 to 45% in 2010. Conclusions In Germany, the numbers of late presenters for HIV diagnosis and care remain high. The probability of late presentation for HIV diagnosis seems to be particularly high for migrants. These results argue in favour of targeted test promotion rather than opt-out screening. Late presentation for care seems to be an additional problem after HIV diagnosis. [ABSTRACT FROM AUTHOR]

Background Early diagnosis of HIV infection is important for the individual and for disease control. A consensus was recently reached among European countries on definitions of timing of presentation for care: 'Late presentation' refers to entering care with a CD4 count <350 cells/μL or an AIDS-defining event, regardless of the CD4 count. Presentation with 'advanced HIV disease' is a subset having a CD4 count <200 cells/μL and also includes all who have an AIDS-defining event regardless of CD4 count. This study examines timing of presentation in New Zealand from 2005 to 2010. Methods Since 2005, information on the initial CD4 cell count has been requested on all people newly diagnosed with HIV infection through antibody testing in New Zealand. Excluded in this analysis were those previously diagnosed overseas or for an immigration medical. Results A CD4 cell count was provided for 606 (80.3%) of the 755 newly diagnosed adults. Overall, 50.0% were 'late presenters' and 32.0% had 'advanced HIV disease'. Compared with men who have sex with men ( MSM), people heterosexually infected were more likely to present late. 'Late presentation' and presentation with 'advanced HIV disease' were significantly more common among older MSM. Māori and Pacific MSM were more likely to present with 'advanced HIV disease'. Compared with European MSM, the age-adjusted relative risks for Māori and Pacific MSM were 2.1 [95% confidence interval ( CI) 1.4-3.2] and 2.5 (95% CI 1.2-5.0), respectively. Conclusions The high proportion of people presenting late reflects inadequate levels of HIV testing. The lower proportion of late presentations among MSM compared with those heterosexually infected may be explained by a higher proportion of recent locally acquired infections together with different testing patterns. [ABSTRACT FROM AUTHOR]

Objective The aim of the study was to compare the yields of newly diagnosed cases of HIV infection and advanced immunodeficiency between individuals attending a mobile HIV counselling and testing (HCT) service as participants in a population-based HIV seroprevalence survey and those accessing the same service as volunteers for routine testing. Methods The study was conducted in a peri-urban township within the Cape Metropolitan Region, South Africa. Survey participants (recruited testers) were randomly selected, visited at home and invited to attend the mobile HCT service. They received 70 South African Rand food vouchers for participating in the survey, but could choose to test anonymously. The yield of HIV diagnoses was compared with that detected in members of the community who voluntarily attended the same HIV testing facility prior to the survey and did not receive incentives (voluntary testers). Results A total of 1813 individuals were included in the analysis (936 recruited and 877 voluntary testers). The prevalence of newly diagnosed HIV infection was 10.9% [95% confidence interval (CI) 9.0-13.1%] among recruited testers and 5.0% (3.7-6.7%) among voluntary testers. The prevalence of severe immune deficiency (CD4 count ≤200 cells/μL) among recruited and voluntary testers was 17.8% (10.9-26.7%) and 4.6% (0.0-15.4%), respectively. Linkage to HIV care in recruited testers with CD4 counts ≤350 cells/μL was 78.8%. Conclusion Compared with routine voluntary HCT, selection and invitation in combination with incentives doubled the yield of newly diagnosed HIV infections and increased the yield almost fourfold of individuals needing antiretroviral therapy. This may be an important strategy to increase community-based HIV diagnosis and access to care. [ABSTRACT FROM AUTHOR]

Objectives The aim of the study was to determine whether combination antiretroviral therapy (cART) with high central nervous system penetration-effectiveness (CPE) rank (neurocART) is associated with increased survival benefit compared with non-neurocART. Methods Prospective data were examined for HIV-positive patients in the Asia Pacific HIV Observational Database who had commenced cART. CPE rank was calculated using the 2010 rankings process. NeurocART status was assigned to regimens with a CPE rank of 8 or more. Survival was analysed using Cox proportional hazards models with covariates updated at changes in cART regimen and with deaths up to 90 days after regimen cessation attributed to that regimen. Sensitivity analyses were conducted to examine the robustness of analysis assumptions. Results Among 5882 patients, 308 deaths occurred. The hazard ratio (HR) for neurocART use was 0.89 ( P=0.35) when data were stratified by cohort and adjusted for age, mode of HIV exposure, hepatitis B virus coinfection, AIDS-defining illness, CD4 count (cells/μL) and regimen count. Sensitivity analyses showed similar nonsignificant results. We also examined a composite endpoint of AIDS-defining illness or death (HR=0.93; P=0.61), baseline regimen as neurocART (HR=0.95; P=0.69), CPE category ( P=0.71) and prior neurocART duration ( P=0.16). No association between CD4 cell count and neurocART use was observed ( P=0.52). Conclusions Our findings do not show a significant overall survival benefit associated with neurocART compared with cART. The potential benefit associated with neurocART in terms of prevention of neurocognitive impairment did not translate into an improvement in overall survival in this population. These findings were limited by the low incidence of associated mortality. Further studies and more extensive data are needed to address these limitations. [ABSTRACT FROM AUTHOR]

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Background and Objectives Bacterial pneumonia still contributes to morbidity/mortality in HIV infection despite effective combination antiretroviral therapy (cART). Evaluation of Subcutaneous Interleukin-2 in a Randomized International Trial (ESPRIT), a trial of intermittent recombinant interleukin-2 (rIL-2) with cART vs. cART alone (control arm) in HIV-infected adults with CD4 counts ≥300 cells/mL, offered the opportunity to explore associations between bacterial pneumonia and rIL-2, a cytokine that increases the risk of some bacterial infections. Methods Baseline and time-updated factors associated with first-episode pneumonia on study were analysed using multivariate proportional hazards regression models. Information on smoking/pneumococcal vaccination history was not collected. Results IL-2 cycling was most intense in years 1-2. Over ≈ 7 years, 93 IL-2 [rate 0.67/100 person-years (PY)] and 86 control (rate 0.63/100 PY) patients experienced a pneumonia event [hazard ratio (HR) 1.06; 95% confidence interval (CI) 0.79, 1.42; P = 0.68]. Median CD4 counts prior to pneumonia were 570 cells/mL (IL-2 arm) and 463 cells/μL (control arm). Baseline risks for bacterial pneumonia included older age, injecting drug use, detectable HIV viral load (VL) and previous recurrent pneumonia; Asian ethnicity was associated with decreased risk. Higher proximal VL (HR for 1 log10 higher VL 1.28; 95% CI 1.11, 1.47; P < 0.001) was associated with increased risk; higher CD4 count prior to the event (HR per 100 cells/mL higher 0.94; 95% CI 0.89, 1.0; P = 0.04) decreased risk. Compared with controls, the hazard for a pneumonia event was higher if rIL-2 was received o180 days previously (HR 1.66; 95% CI 1.07, 2.60; P = 0.02) vs. ≥180 days previously (HR 0.98; 95% CI 0.70, 1.37; P = 0.9). Compared with the control group, pneumonia risk in the IL-2 arm decreased over time, with HRs of 1.41, 1.71, 1.16, 0.62 and 0.84 in years 1, 2, 3-4, 5-6 and 7, respectively. Conclusions Bacterial pneumonia rates in cART-treated adults with moderate immunodeficiency are high. The mechanism of the association between bacterial pneumonia and recent IL-2 receipt and/or detectable HIV viraemia warrants further exploration. [ABSTRACT FROM AUTHOR]

Aldehydes that are produced following the breakdown of ethanol (acetaldehyde) and lipid peroxidation of membranes (malondialdehyde) have been shown to bind (adduct) proteins. Additionally, these two aldehydes can combine (MAA) on nonsyngeneic and syngeneic proteins to initiate numerous immune responses to the unmodified part of the protein in the absence of an adjuvant. Therefore, these studies provide a potential mechanism for the development of antigen-specific immune responses resulting in liver damage should syngeneic liver proteins be adducted with MAA. This study sought to test whether MAA-modified syngeneic liver cytosolic proteins administered daily in the absence of adjuvant into C57BL/6 mice abrogates tolerance to initiate a MAA-induced autoimmune-like hepatitis. In mice immunized with MAA-modified cytosols, there was an increase in liver damage as assessed by aspartate aminotransferase/alanine aminotransferase levels that correlated with liver pathology scores and the presence of the pro-fibrotic factors, smooth muscle actin, TGF-β, and collagen. IgG antibodies and T-cell proliferative responses specific for cytosolic proteins were also detected. Pro-inflammatory cytokines were produced in the livers of animals exposed to MAA-modified cytosols. Finally, transfer of immunized T cells to naïve animals caused biochemical and histological evidence of liver damage. These data demonstrate that a disease with an autoimmune-like pathophysiology can be generated in this animal model using soluble MAA-modified syngeneic liver cytosols as the immunogen. These studies provide insight into potential mechanism(s) that the metabolites of alcohol may play in contributing to the onset of an autoimmune-like disease in patients with alcoholic liver disease. [ABSTRACT FROM AUTHOR]