Faculty Bibliography

The interaction of Mycobacterium tuberculosis (MTB) with the immune system is mediated by cytokine and chemokine responses of macrophages and/or dendritic cells. Chemokine (C-C motif) ligand 18 (CCL18) and interleukin (IL)-10 are major factors secreted by phagocytes, postulated to recruit naive T lymphocytes and inhibit pro-inflammatory cells. Our study investigated the role of CCL18 and IL-10 in an in vitro model of infection by MTB in human macrophages. CD14(+) monocytes, obtained from the peripheral blood of eight healthy donors, differentiated in monocyte-derived macrophages (MDM) with monocyte-colony stimulating factor (100 ng/ml) for 6 days, were stimulated in vitro with lipopolysaccharide (LPS) (1 microg/ml) and with heat killed MTB Hv37Ra (multiplicity of infection 1:5) for 24 h. Alveolar macrophages from five healthy donors were infected with MTB Hv37RA. CCL18 protein and mRNA were detected by enzyme-linked immunosorbent assay (ELISA) and real-time PCR, IL-10 levels by ELISA. Stimulation of MDM with LPS or MTB led to a significant increase in CCL18 protein (control 2.67 +/- 0.46 ng/ml, LPS 4.05 +/- 0.56 ng/ml, with MTB 6.70 +/- 1.59 ng/ml, n = 5, P < 0.05) and specific mRNA levels (control 0.09 +/- 0.01, LPS 0.24 +/- 0.11, with MTB 0.34 +/- 0.08 CCL18/Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), n = 3, P < 0.05). A significant increase of the production of CCL18 was observed in infected alveolar macrophages. IL-10 levels increased from 38.52 +/- 26.38 pg/ml in control cells to 1129.32 +/- 235.00 and 974.25 +/- 164.46 pg/ml in LPS and MTB treated cells, respectively (P < 0.05). Up-regulation of CCL18 and IL-10 in macrophages by MTB may be involved in the recruitment of naive T cells in association with local suppressive immunity against intracellular pathogens. This could represent a mechanism of tolerance during the early phases of infection

The microbes that persistently colonize their vertebrate hosts are not accidental (1). Although highly numerous and diverse, there is specificity by site and substantial conservation between individuals. The genus Helicobacter includes spiral, highly motile, urease-positive, gram-negative bacteria that colonize the stomach in many mammals. Each mammal has one or more dominant Helicobacter species and they are highly, if not exclusively, host species-specific (2). Such observations are consistent with the hypothesis that when ancestral mammals diverged from reptiles about 150 million years ago, they contained ancestral helicobacters, which then diverged as their hosts changed. According to this hypothesis, helicobacters represent ancestral biota (flora) in the mammalian stomach. The human-adapted strain is H. pylori (3), which has not been reproducibly observed in any animals other than humans and other primates (3)

Human exposure to air pollutants, including ambient particulate matter, has been proposed as a mechanism for the rise in allergic disorders. Diesel exhaust particles, a major component of ambient particulate matter, induce sensitization to neoallergens, but the mechanisms by which sensitization occur remain unclear. We show that diesel exhaust particles upregulate thymic stromal lymphopoietin in human bronchial epithelial cells in an oxidant-dependent manner. Thymic stromal lymphopoietin induced by diesel exhaust particles was associated with maturation of myeloid dendritic cells, which was blocked by anti-thymic stromal lymphopoietin antibodies or silencing epithelial cell-derived thymic stromal lymphopoietin. Dendritic cells exposed to diesel exhaust particle-treated human bronchial epithelial cells induced Th2 polarization in a thymic stromal lymphopoietin-dependent manner. These findings provide new insight into the mechanisms by which diesel exhaust particles modify human lung mucosal immunity

BACKGROUND: Microbial exposures have been suggested to confer protection from allergic disorders and reduced exposures to gastrointestinal microbiota have been proposed as an explanation for the increase in asthma prevalence. Since the general prevalence of Helicobacter pylori has been decreasing, we hypothesized that H. pylori serostatus would be inversely related to the presence of asthma. METHODS: Adults were recruited to participate in the New York University (NYU)/Bellevue Asthma Registry in New York City. Adult asthma cases (N = 318) and controls (N = 208) were identified and serum IgG antibodies to H. pylori whole cell antigens or the immunodominant CagA antigen were measured. RESULTS: As expected, the asthma cases and controls differed with respect to atopy and lung function. Seropositivity to H. pylori or CagA antigen was present in 47.1% of the total case and control study population. Asthma was inversely associated with CagA seropositivity (OR = 0.57, 95% CI = 0.36-0.89). Median age of onset of asthma (doctor's diagnosis) was older (21 years) among individuals with CagA+ strains than among H. pylori- individuals (11 years) (p = 0.006). CONCLUSION: These data are consistent with the hypothesis that colonization with CagA+ H. pylori strains is inversely associated with asthma and is associated with an older age of asthma onset in an urban population. The data suggest H. pylori as a marker for protection

RATIONALE: Following collapse of the World Trade Center (WTC), individuals reported new-onset respiratory symptoms. Despite symptoms, spirometry often revealed normal airway function. However, bronchial wall thickening and air trapping were seen radiographically in some subjects. We hypothesized that symptomatic individuals following exposure to WTC dust may have functional abnormalities in distal airways not detectable with routine spirometry. METHODS: One hundred seventy-four subjects with respiratory symptoms and normal spirometry results were evaluated. Impedance oscillometry (IOS) was performed to determine resistance at 5 Hz, 5 to 20 Hz, and reactance area. Forty-three subjects were also tested for frequency dependence of compliance (FDC). Testing was repeated after bronchodilation. RESULTS: Predominant symptoms included cough (67%) and dyspnea (65%). Despite normal spirometry results, mean resistance at 5 Hz, 5 to 20 Hz, and reactance area were elevated (4.36 +/- 0.12 cm H(2)O/L/s, 0.86 +/- 0.05 cm H(2)O/L/s, and 6.12 +/- 0.50 cm H(2)O/L, respectively) [mean +/- SE]. Resistance and reactance normalized after bronchodilation. FDC was present in 37 of 43 individuals with improvement after bronchodilation. CONCLUSIONS: Symptomatic individuals with presumed WTC dust/fume exposure and normal spirometry results displayed airway dysfunction based on the following: (1) elevated airway resistance and frequency dependence of resistance determined by IOS; (2) heterogeneity of distal airway function demonstrated by elevated reactance area on oscillometry and FDC; and (3) reversibility of these functional abnormalities to or toward normal following administration of a bronchodilator. Since spirometry results were normal in all subjects, these abnormalities likely reflect dysfunction in airways more distal to those evaluated by spirometry. Examination of distal airway function when spirometry results are normal may be important in the evaluation of subjects exposed to occupational and environmental hazards

This study investigated whether self-reported damage, dust, and odors in homes near the World Trade Center (WTC) after September 11, 2001, were related to increased rates of respiratory symptoms among residents and if multiple sources of exposure were associated with greater health risk. We mailed questionnaires to homes within 1.5 km of the WTC site (affected area) and in upper Manhattan (control area). Surveys asked about respiratory symptoms, unplanned medical visits, physician diagnoses, medication use, and conditions in the home after 9/11. Adverse home conditions were associated with new-onset (i.e., began after 9/11) and persistent (i.e., remained 1 year after 9/11) upper and lower respiratory symptoms in the affected area (Cumulative Incidence Ratios [CIRs] 1.20-1.71). Residents reporting longer duration of dust/odors or multiple sources of exposure had greater risk for symptoms compared to those reporting shorter duration and fewer sources. These data suggest that WTC-related contamination in the home after 9/11 was associated with new and persistent respiratory symptoms among residents living near the site. While we cannot eliminate potential biases related to self-reported data, we took strategies to minimize their impact, and the observed effects are biologically plausible