Eosinophil and T Cell Markers Predict Functional Decline in COPD Patients

BACKGROUND. The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, asingle measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. METHODS. Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (ΔFEV1 % predicted = 4.7 ± 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (ΔFEV1 % predicted = -16.0 ± 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. RESULTS AND DISCUSSION. Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). CONCLUSION. These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.National Heart, Lung, and Blood Institute (NO1-HR-96140, NO1-HR-96141-001, NO1-HR-96144, NO1-HR-96143; NO1-HR-96145; NO1-HR-96142, R01HL086936-03); The Flight Attendant Medical Research Institute; the Jo-Ann F. LeBuhn Center for Chest Diseas

Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis

Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; however, the role of central nervous system (CNS) cells remains unclear. We investigated the effect of the risk variant, rs7665090G, located near NFKB1, on astrocytes. We demonstrated that chromatin is accessible at the risk locus, a prerequisite for its impact on astroglial function. The risk variant was associated with increased NF-κB signaling and target gene expression, driving lymphocyte recruitment, in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates and lesion sizes. Thus, our study establishes a link between genetic risk for MS (rs7665090G) and dysfunctional astrocyte responses associated with increased CNS access for peripheral immune cells. MS may therefore result from variant-driven dysregulation of the peripheral immune system and of the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation

Acinetobacter baumannii Infection Inhibits Airway Eosinophilia and Lung Pathology in a Mouse Model of Allergic Asthma

Allergic asthma is a dysregulation of the immune system which leads to the development of Th2 responses to innocuous antigens (allergens). Some infections and microbial components can re-direct the immune response toward the Th1 response, or induce regulatory T cells to suppress the Th2 response, thereby inhibiting the development of allergic asthma. Since Acinetobacter baumannii infection can modulate lung cellular and cytokine responses, we studied the effect of A. baumannii in modulating airway eosinophilia in a mouse model of allergic asthma. Ovalbumin (OVA)-sensitized mice were treated with live A. baumannii or phosphate buffered saline (PBS), then intranasally challenged with OVA. Compared to PBS, A. baumannii treatment significantly reduced pulmonary Th2 cytokine and chemokine responses to OVA challenge. More importantly, the airway inflammation in A. baumannii-treated mice was strongly suppressed, as seen by the significant reduction of the proportion and the total number of eosinophils in the bronchoalveolar lavage fluid. In addition, A. baumannii-treated mice diminished lung mucus overproduction and pathology. However, A. baumannii treatment did not significantly alter systemic immune responses to OVA. Serum OVA-specific IgE, IgG1 and IgG2a levels were comparable between A. baumannii- and PBS-treated mice, and tracheobronchial lymph node cells from both treatment groups produced similar levels of Th1 and Th2 cytokines in response to in vitro OVA stimulation. Moreover, it appears that TLR-4 and IFN-γ were not directly involved in the A. baumannii-induced suppression of airway eosinophilia. Our results suggest that A. baumannii inhibits allergic airway inflammation by direct suppression of local pulmonary Th2 cytokine responses to the allergen

Association between genetic variants of IL-1beta, IL-6 and TNF-alpha cytokines and cognitive performance in the elderly general population of the MEMO-study

This study is to investigate the associations between specific polymorphisms in three cytokine genes and domains of cognitive functioning in a population based study in the elderly. In a cross-sectional study of 369 community dwelling elderly subjects we examined the relationships between the polymorphisms IL-1beta-1418C-->T, IL-6-572G-->C and TNF-alpha-308G-->A and the cognitive function domains memory, processing speed and motor function using an extensive neuropsychological test battery. Linear regression models were used in the analysis and results adjusted for multiple comparisons. A significant association between the IL-1beta-1418C-->T polymorphism and memory performance was found with carriers of the T allele (dominant model) having worse memory performance than those with the C allele. In addition, a significant association between the TNF-alpha-308G-->A polymorphism and processing speed was observed, indicating better performance for heterozygous or homozygous carriers of the A allele. These results remained significant after adjustment for known confounders of cognitive function and additional Bonferroni correction for multiple comparisons. Our study provides first results on detrimental effects of the IL-1beta-1418C-->T polymorphism on memory performance and neuroprotective effects of the TNF-alpha-308G-->A polymorphism on processing speed in elderly individuals. Further research is needed to prospectively examine changes in cognitive performance in relation to cytokine genotypes.Bernhard T. Baune, Gerald Ponath, Matthias Rothermundt, Olaf Riess, Harald Funke, Klaus Berge

Association between IL-8 cytokine and cognitive performance in an elderly general population - The MEMO-Study

ObjectivesTo investigate the associations between circulating cytokines and specific neuropsychological domains of cognitive functioning (memory, processing speed and motor function) and general cognitive function (MMSE) in healthy elderly individuals.MethodsIn a cross-sectional study of 369 community dwelling elderly subjects, we examined the relationship between serum IL-1beta, sIL-4R, IL-6, IL-8, IL-10, IL-12 and TNF-alpha concentrations and cognitive performance using an extensive standardized and validated cognitive test battery assessing memory, word fluency, perceptual/cognitive speed, attention and executive functioning, and motor speed.ResultsMultivariate analysis adjusted for various confounders and Bonferroni correction for multiple comparisons demonstrated that increased serum concentrations of IL-8 were associated with poor performance in the memory and speed domains and in motor function. No significant associations were found between the remaining cytokines and domains of cognitive functioning. Global cognitive functioning, as measured with MMSE, was not associated with any cytokine.ConclusionsThis study suggests an association between circulating IL-8 concentrations and cognitive dysfunction in the elderly. An interaction between this cytokine and glial cells may help explain the pathophysiological mechanisms leading to cognitive impairment in our study group.Bernhard T. Baune, Gerald Ponath, Jonathan Golledge, Gerald Varga, Volker Arolt, Matthias Rothermundt, Klaus Berge