Ahra Kim

Reverse signaling through the costimulatory ligand CD137L in epithelial cells is essential for natural killer cell-mediated acute tissue inflammation

Renal ischemia-reperfusion injury (IRI) after kidney transplantation is a major cause of delayed graft function. Even though IRI is recognized as a highly coordinated and specific process, the pathways and mechanisms through which the innate response is activated are poorly understood. In this study, we used a mouse model of acute kidney IRI to examine whether the interactions of costimulatory receptor CD137 and its ligand (CD137L) are involved in the early phase of acute kidney inflammation caused by IRI. We report here that the specific expressions of CD137 on natural killer cells and of CD137L on tubular epithelial cells (TECs) are required for acute kidney IRI. Reverse signaling through CD137L in TECs results in their production of the chemokine (C-X-C motif) receptor 2 ligands CXCL1 and CXCL2 and the subsequent induction of neutrophil recruitment, resulting in a cascade of proinflammatory events during kidney IRI. Our findings identify an innate pathogenic pathway for renal IRI involving the natural killer cell–TEC–neutrophil axis, whereby CD137–CD137L interactions provide the causal contribution of epithelial cell dysregulation to renal IRI. The CD137L reverse signaling pathway in epithelial cells therefore may represent a good target for blocking the initial stage of inflammatory diseases, including renal IRI.

TLR2 Signaling in Tubular Epithelial Cells Regulates NK Cell Recruitment in Kidney Ischemia–Reperfusion Injury

Damage-associated molecular patterns released from damaged kidney cells initiate postischemic inflammation, an essential step in the progression of kidney ischemia–reperfusion injury (IRI). However, the mechanism that coordinates this highly specific process in ischemic kidneys remains to be clarified. Previously, we demonstrated that CD137 from NK cells specifically stimulates CD137 ligand (CD137L) on tubular epithelial cells (TECs) such that TECs produced the high CXCR2 chemokine levels required for neutrophil chemotaxis. We report in the present study that endogenous TLR2 ligands released from ischemic TECs induce CCR5 chemokine expression, which is critical to promoting NK cell recruitment. By implanting CD137L−/− TECs into the kidney capsule of TLR2−/− mice, we further showed that TLR2-mediated NK cell recruitment is an uncoupled event that can occur independently of CD137L signaling in TECs, which is responsible for recruiting neutrophils. Therefore, our findings identify TECs as both a target for kidney damage and also as a master regulator that actively modulates stepwise signaling, leading to the initiation and amplification of acute sterile inflammation that inflicts kidney IRI. Being clinically important, the signaling pathway of innate receptors in epithelial cells may therefore be a good target to block acute sterile inflammation resulting from tissue damage, including kidney IRI.

Protection induced by virus-like particles containing Toxoplasma gondii microneme protein 8 against highly virulent RH strain of Toxoplasma gondii infection

Toxoplasma gondii (T. gondii) microneme protein 8 (MIC8) represents a novel, functional distinct invasion factor. In this study, we generated virus-like particles (VLPs) targeting Toxoplasma gondii MIC8 for the first time, and investigated the protection against highly virulent RH strain of T. gondii in a mouse model. We found that VLP vaccination induced Toxoplasma gondii-specific IgG and IgG1 antibody responses in the sera. Upon challenge infection with RH strain of T. gondii tachyzoites, vaccinated mice showed a significant increase of both IgG antibodies in sera and IgA antibodies in feces compared to those before challenge, and a rapid expansion of both germinal center B cell (B220+, GL7+) and T cell (CD4+, CD8+) populations. Importantly, intranasally immunized mice showed higher neutralizing antibodies and displayed no proinflammatory cytokine IFN-γ in the spleen. Mice were completely protected from a lethal challenge infection with the highly virulent T. gondii (RH) showing no body weight loss (100% survival). Our study shows the effective protection against T. gondii infection provided by VLPs containing microneme protein 8 of T. gondii, thus indicating a potential T. gondii vaccine candidate.

Effects of self-reported sensitivity and road-traffic noise levels on the immune system

Sensitivity to noise, particularly road traffic noise, can increase cortisol levels and result in changes in immune system biomarkers. Therefore, continuous exposure to noise can have an effect on immune function, hormonal levels, and cardiovascular function, leading to hypertension and stress. The purpose of this study was to investigate the changes in stress-and immune system-related biomarkers according to the self-reported sensitivity to noise and exposure to road traffic noise, to ultimately determine the potential effects of noise on health. A survey was conducted through questionnaire (ISO/TS 15666) sent to 172 female subjects in Korea, including 128 from Ulsan and 44 from Seoul. The average noise level was calculated, and blood samples were collected for measurements of cortisol levels, Natural killer (NK) / Natural killer T (NKT) cell populations, and NK cell activity (through measurements of interleukin-12 (IL-12) and interferon-gamma (INF-γ) concentrations). Multivariate linear regression analysis of the measured biomarkers according to the road traffic noise level and self-reported noise sensitivity was conducted adjusting for the effects of age, alcohol status, smoking status, regular exercise, and residence period. IL-12 levels increased, whereas the NKT cell population decreased with increasing noise levels. The results further suggested that cortisol levels are more influenced by the subject’s sensitivity to noise than to the level of chronic road traffic noise. Therefore, noise appears to have the largest effect on IL-12 levels as well as the population and activity of NKT cells. In conclusion, our results suggest that low-level road traffic noise and sensitivity to noise can affect health by causing changes in the immune response through mechanisms other than increased cortisol.

Protection induced by virus-like particle vaccine containing tandem repeat gene of respiratory syncytial virus G protein

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract illness in infants, young children and the elderly. However, there is no licensed vaccine available against RSV infection. In this study, we generated virus-like particle (VLP) vaccine and investigated the vaccine efficacy in a mouse model. For VLP vaccines, tandem gene (1–780 bp) for V1 VLPs and tandem repeat gene (repeated 450–780 bp) for V5 VLPs were constructed in pFastBacTM vectors, respectively. Influenza matrix protein 1 (M1) was used as a core protein in the VLPs. Notably, upon challenge infection, significantly lower virus loads were measured in the lung of mice immunized with V1 or V5 VLPs compared to those of naïve mice and formalin-inactivated RSV immunized control mice. In particular, V5 VLPs immunization showed significantly lower virus titers than V1 VLPs immunization. Furthermore, V5 VLPs immunization elicited increased memory B cells responses in the spleen. These results indicated that V5 VLP vaccine containing tandem repeat gene protein provided better protection than V1 VLPs with significantly decreased inflammation in the lungs. Thus, V5 VLPs could be a potential vaccine candidate against RSV.

Environmental and Body Concentrations of Heavy Metals at Sites Near and Distant from Industrial Complexes in Ulsan (Korea)

Background Industrial pollution may affect the heavy metal body burden of people living near industrial complexes. We determined the average concentrations of atmospheric heavy metals in areas close to and distant from industrial complexes in Korea, and the body concentrations of these heavy metals in residents living near and distant from these facilities. Methods The atmospheric data of heavy metals (lead and cadmium) were from the Regional Air Monitoring Network in Ulsan. We recruited 1,148 participants, 872 who lived near an industrial complex (“exposed” group) and 276 who lived distant from industrial complexes (“non-exposed” group), and measured their concentrations of blood lead, urinary cadmium, and urinary total mercury. Results The results showed that atmospheric and human concentrations of heavy metals were higher in areas near industrial complexes. In addition, residents living near industrial complexes had higher individual and combined concentrations (cadmium + lead + mercury) of heavy metals. Conclusion We conclude that residents living near industrial complexes are exposed to high concentrations of heavy metals, and should be carefully monitored.

Perinatal factors and the development of childhood asthma

BACKGROUND Perinatal factors are suspected to have a significant impact on the development of asthma; however, sufficiently powered studies have not been performed to investigate this issue. OBJECTIVE To evaluate whether perinatal factors and other risk factors have an independent or combined effect on the development of asthma. METHODS This study involved 3,770 children (mean age 9.1 years, range 5.68-12.16 years; 51.9% boys) who were enrolled in the Elementary School Student Cohort (2009-2014) in Ulsan University Hospital (Ulsan, Korea). Subjects were divided into an asthma group (n = 514) and a non-asthma group (n = 3,256). RESULTS Multivariate analyses showed that early life (within first week) oxygen therapy (adjusted odds ratio [aOR] 1.864, 95% confidence interval [CI] 1.156-3.004) and breastfeeding (aOR 0.763, 95% CI 0.606-0.960) were 2 significant perinatal factors influencing the development of asthma. Environmental tobacco smoke (aOR 1.634, 95% CI 1.298-2.058) and parental allergic disease (aOR 1.882, 95% CI 1.521-2.328) also were identified as risk factors. Using subgroup analyses, combined effects on asthma development were observed between perinatal factors (early life oxygen therapy and breastfeeding) and other risk factors (vicinity to major roadway [traffic-related air pollution], environmental tobacco smoke, parental allergic disease, and atopy). CONCLUSION Early life oxygen therapy and breastfeeding were identified as 2 important perinatal factors influencing the development of asthma. Furthermore, these factors showed combined effects with other risk factors (environmental tobacco smoke, traffic-related air pollution, parental allergic disease, and atopy) on the development of asthma.

Correlation between Allergic Rhinitis Prevalence and Immune Responses of Children in Ulsan: A Case-control Study

*Department of Occupational & Environmental Medicine, University of Ulsan College of Medicine, Korea **Environmental Health Center, University of Ulsan College of Medicine, Korea ABSTRACTObjectives: This study aims to investigate the correlations between the prevalence of allergic rhinitis (AR) andcytokines among elementary school children in an industrial city, Ulsan, South Korea, and to identify majorenvironmental risk factors associated with AR prevalence. Methods: We conducted a case-control study in June 2009 and February 2010 in order to evaluate therelationship between AR and related cytokines. Data on physician-treated prevalence over the past 12 monthsand potential risk factors for AR were compiled through a questionnaire from a survey of 339 schoolchildrenliving in different urban environments. Logistic regression analysis was carried out with propensity scorematched data (n=180) to assess the influences of cytokines (IL-13, IL-33, IL-4 and IL-5) on AR prevalence andto determine which environmental factors affected AR.Results: In univariate analysis, the AR prevalence was influenced by family history of AR (mother andsiblings), environmental factors (odor condition and irritated symptoms of air pollution), and indoorallergens (D. farinae and D. pteronyssinus). The t-test demonstrated that eosinophils, Immunoglobulin E(IgE), and interleukins (IL-13 and IL-5) were statistically significantly different according to treatment ofallergic rhinitis over the preceeding 12 months. The results of the multiple logistic regression analysisshowed that a statistically significant association between several factors (such as irritated symptoms of airpollution (OR 4.075, CI 1.735-9.568), IL-13 (OR 0.825, CI 0.734-0.928), odor condition (OR 2.409, CI0.908-6.389), and AR history of siblings (OR 2.217, CI 0.999-4.921)) and the prevalence of AR was foundafter adjusting for confounders. Conclusion: These results suggest that AR prevalence is significantly associated with cytokine level, geneticbackground, and outdoor environmental factors. Although living in a polluted area and genetic background cancontribute to an increased risk of childhood AR, cytokine level should be considered as an important factor inthe treatment of AR in the last 12 months.Keywords: Allergic rhinitis, case-control study, cytokine, environmental risk factors, propensity scorematching