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1.  Soluble Major Histocompatibility Complex Class I-Related Chain B Molecules Are Increased and Correlate With Clinical Outcomes During Rhinovirus Infection in Healthy Subjects 
Chest  2014;146(1):32-40.
BACKGROUND:
Surface major histocompatibility complex class I-related chain (MIC) A and B molecules are increased by IL-15 and have a role in the activation of natural killer group 2 member D-positive natural killer and CD8 T cells. MICA and MICB also exist in soluble forms (sMICA and sMICB). Rhinoviruses (RVs) are the major cause of asthma exacerbations, and IL-15 levels are decreased in the airways of subjects with asthma. The role of MIC molecules in immune responses in the lung has not been studied. Here, we determine the relationship between MICA and MICB and RV infection in vitro in respiratory epithelial cells and in vivo in healthy subjects and subjects with asthma.
METHODS:
Surface MICA and MICB, as well as sMICA and sMICB, in respiratory epithelial cells were measured in vitro in response to RV infection and exposure to IL-15. Levels of sMICA and sMICB in serum, sputum, and BAL were measured and correlated with blood and bronchoalveolar immune cells in healthy subjects and subjects with asthma before and during RV infection.
RESULTS:
RV increased MICA and MICB in vitro in epithelial cells. Exogenous IL-15 upregulated sMICB levels in RV-infected epithelial cells. Levels of sMICB molecules in serum were increased in healthy subjects compared with subjects with stable asthma. Following RV infection, airway levels of sMIC are upregulated, and there are positive correlations between sputum MICB levels and the percentage of bronchoalveolar natural killer cells in healthy subjects but not subjects with asthma.
CONCLUSIONS:
RV infection induces MIC molecules in respiratory epithelial cells in vitro and in vivo. Induction of MICB molecules is impaired in subjects with asthma, suggesting these molecules may have a role in the antiviral immune response to RV infections.
doi:10.1378/chest.13-2247
PMCID: PMC4077410  PMID: 24556715
2.  Evolution of cardiovascular risk factors and ischemic heart disease in an elderly urban Romanian population over the course of 1 year 
Background
Romania has some of the highest mortality figures in the world attributable to ischemic heart disease and stroke among both men and women.
Objectives
To assess the changes in cardiovascular risk factors and ischemic heart disease in a group of subjects over 65 years of age during 1 year in an urban community of Romania.
Materials and methods
We studied 515 subjects (264 women and 251 men) with a mean age of 73.41±6.44 years, followed up over the course of 1 year in order to determine the changes that occurred in cardiovascular risk factors and in the evolution of ischemic heart disease. At the beginning and after 1 year, we determined the following parameters: anthropometric measurements, blood pressure, smoking status, lipid profile (total cholesterol, triglycerides, high-density lipid cholesterol, low-density lipid cholesterol), fasting plasma glucose, and the presence of ischemic heart disease.
Results
There were no differences between the first and second assessments concerning the incidence of smoking (12.3% versus (vs) 12.5%), obesity (25% vs 26%), diabetes mellitus (19% vs 22.9%), or hypertension (88.2% vs 92.2%). Statistically significant differences were recorded regarding dyslipidemia (40.6% vs 30.3%, P<0.001). Cholesterol median values decreased (204 mg/dL vs 194 mg/dL, P=0.003), while median concentrations of plasma glucose increased (101 mg/dL vs 105 mg/dL, P<0.05). At the same time, we noted a higher incidence of ischemic heart disease (51.65% vs 63%).
Conclusion
Our data show that in subjects over 65 years of age, cardiovascular disease occurs more often in women, but with certain features that should be taken into account. In addition, we point out the importance of reducing cardiovascular risk factors. However, we should not expect a major decrease or improvement in cardiovascular risk factors with such a short follow-up. Such results will be achieved only through long-term interventions.
doi:10.2147/CIA.S53987
PMCID: PMC3848471  PMID: 24348025
evolution; cardiovascular risk factors; ischemic heart disease
3.  Correction: The Role of IL-15 Deficiency in the Pathogenesis of Virus-Induced Asthma Exacerbations 
PLoS Pathogens  2012;8(4):10.1371/annotation/43a4a197-1739-4561-8b8d-b13cd6d7009f.
doi:10.1371/annotation/43a4a197-1739-4561-8b8d-b13cd6d7009f
PMCID: PMC3321056
4.  RSV-Induced Bronchial Epithelial Cell PD-L1 Expression Inhibits CD8+ T Cell Nonspecific Antiviral Activity 
Respiratory syncytial virus (RSV) is a major cause of bronchiolitis in infants. It is also responsible for high morbidity and mortality in the elderly. Programmed death ligands (PD-Ls) on antigen-presenting cells interact with receptors on T cells to regulate immune responses. The programmed death receptor-ligand 1/programmed death receptor 1 (PD-L1-PD-1) pathway is inhibitory in chronic viral infections, but its role in acute viral infections is unclear. We hypothesized that bronchial epithelial cell (BEC) expression of PD-Ls would inhibit local effector CD8+ T cell function. We report that RSV infection of primary human BECs strongly induces PD-L1 expression. In a co-culture system of BECs with purified CD8+ T cells, we demonstrated that RSV-infected BECs increased CD8+ T cell activation, proliferation, and antiviral function. Blocking PD-L1 on RSV-infected BECs co-cultured with CD8+ T cells enhanced CD8+ T cell IFN-γ, IL-2, and granzyme B production. It also decreased the virus load of the BECs. Based on our findings, we believe therapeutic strategies that target the PD-L1-PD-1 pathway might increase antiviral immune responses to RSV and other acute virus infections.
doi:10.1093/infdis/jiq020
PMCID: PMC3086441  PMID: 21148500
5.  The Role of IL-15 Deficiency in the Pathogenesis of Virus-Induced Asthma Exacerbations 
PLoS Pathogens  2011;7(7):e1002114.
Rhinovirus infections are the major cause of asthma exacerbations. We hypothesised that IL-15, a cytokine implicated in innate and acquired antiviral immunity, may be deficient in asthma and important in the pathogenesis of asthma exacerbations. We investigated regulation of IL-15 induction by rhinovirus in human macrophages in vitro, IL-15 levels in bronchoalveolar lavage (BAL) fluid and IL-15 induction by rhinovirus in BAL macrophages from asthmatic and control subjects, and related these to outcomes of infection in vivo. Rhinovirus induced IL-15 in macrophages was replication-, NF-κB- and α/β interferon-dependent. BAL macrophage IL-15 induction by rhinovirus was impaired in asthmatics and inversely related to lower respiratory symptom severity during experimental rhinovirus infection. IL-15 levels in BAL fluid were also decreased in asthmatics and inversely related with airway hyperresponsiveness and with virus load during in vivo rhinovirus infection. Deficient IL-15 production in asthma may be important in the pathogenesis of asthma exacerbations.
Author Summary
We previously reported deficiency in interferon production in asthma, which correlated with disease severity and viral load during experimental rhinovirus infection. Here we show that macrophages produce IL-15 upon rhinovirus infection and that IFN-β plays an important role in IL-15 production. In asthmatic subjects, there is a deficiency in rhinovirus-induced production of IL-15 by macrophages, which indicates immunodeficiency in asthma is surprisingly broad, also involving IL-15, an important cytokine that bridges innate and acquired immunity. These results show that IFN-β therapy in asthma exacerbations could be effective not only due to direct anti-viral effects of IFN-β, but also by inducing IL-15 production. We also show induction of IFN-β and IL-15 to be NF-kB dependent, an important finding which has implications for NF-kB inhibitor drug development programmes as these drugs have potential to worsen rather than improve asthma exacerbation severity, by further enhancing deficiencies of IL-15 and IFN-β. This study investigating the role of IL-15 in rhinovirus infection and asthma has also major implications in other diseases, for example pandemic influenza, where asthma is a major risk factor for severe disease and death, and COPD and cystic fibrosis where IFN-β deficiency is also present.
doi:10.1371/journal.ppat.1002114
PMCID: PMC3136447  PMID: 21779162
6.  The role of macrophage IL-10/innate IFN interplay during virus-induced asthma 
Reviews in Medical Virology  2014;25(1):33-49.
Activation through different signaling pathways results in two functionally different types of macrophages, the pro-inflammatory (M1) and the anti-inflammatory (M2). The polarization of macrophages toward the pro-inflammatory M1 phenotype is considered to be critical for efficient antiviral immune responses in the lung.
Among the various cell types that are present in the asthmatic airways, macrophages have emerged as significant participants in disease pathogenesis, because of their activation during both the inflammatory and resolution phases, with an impact on disease progression. Polarized M1 and M2 macrophages are able to reversibly undergo functional redifferentiation into anti-inflammatory or pro-inflammatory macrophages, respectively, and therefore, macrophages mediate both processes.
Recent studies have indicated a predominance of M2 macrophages in asthmatic airways. During a virus infection, it is likely that M2 macrophages would secrete higher amounts of the suppressor cytokine IL-10, and less innate IFNs. However, the interactions between IL-10 and innate IFNs during virus-induced exacerbations of asthma have not been well studied.
The possible role of IL-10 as a therapy in allergic asthma has already been suggested, but the divergent roles of this suppressor molecule in the antiviral immune response raise concerns. This review attempts to shed light on macrophage IL-10–IFNs interactions and discusses the role of IL-10 in virus-induced asthma exacerbations. Whereas IL-10 is important in terminating pro-inflammatory and antiviral immune responses, the presence of this immune regulatory cytokine at the beginning of virus infection could impair the response to viruses and play a role in virus-induced asthma exacerbations.
doi:10.1002/rmv.1817
PMCID: PMC4316183  PMID: 25430775

Results 1-6 (6)