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Biomedical subjects

Lee S Newman

Publications and source records attributed to Lee S Newman.

At least 19 recordsLinked to original sources
PubMed2006

Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis.

Sarcoidosis is an enigmatic disease with a pathology similar to that of tuberculosis. We detected Th-1 immune responses to Mycobacterium tuberculosis ESAT-6 and KatG peptides from peripheral blood mononuclear cells from 15/26 sarcoidosis, 1/24 purified-protein-derivative-negative (PPD-) (P < 0.0001, Fisher's exact test), and 7/8 PPD-positive (PPD+) subjects (P = 0.21). This finding provides immunologic links between mycobacteria and systemic sarcoidosis.

Adult↗
PubMed2006

Beryllium-induced TNF-alpha production is transcription-dependent in chronic beryllium disease.

Beryllium (Be)-antigen presentation to Be-specific CD4(+) T cells from the lungs of patients with chronic beryllium disease (CBD) results in T cell proliferation and TNF-alpha secretion. We tested the hypothesis that Be-induced, CBD bronchoalveolar lavage (BAL) T cell, transcription-dependent, TNF-alpha secretion was accompanied by specific transcription factor upregulation. After 6 h of Be stimulation, CBD BAL cells produced a median of 883 pg/ml TNF-alpha (range, 608-1,275 pg/ml) versus 198 pg/ml (range, 116-245 pg/ml) by unstimulated cells. After 12 h CBD BAL cells produced a median of 2,963 pg/ml (range, 99-9,424 pg/ml) TNF-alpha versus 55 pg/ml (range, 0-454) by unstimulated cells. Using real-time RT-PCR, Be-stimulated TNF-alpha production at 6 h was preceded by a 5-fold increase in TNF-alpha pre-mRNA copy number:beta-actin copy number (Be median ratio 0.21; unstimulated median ratio 0.04). The median ratio of mature TNF-alpha mRNA:beta-actin mRNA was upregulated 1.4-fold (Be median ratio 0.17; unstimulated median ratio 0.12). Be exposure in the presence of the transcription inhibitor pentoxifylline (PTX) decreased CBD BAL cell TNF-alpha pre-mRNA levels > 60%, whereas treatment with the mRNA splicing inhibitor 2-aminopurine (2AP) decreased levels 40% relative to Be exposure alone. PTX treatment decreased mature TNF-alpha mRNA levels 50% while 2AP decreased levels > 80%, relative to Be exposure alone. Beryllium exposure specifically upregulated transcription factors AP-1 and NF-kappaB. The data suggest that Be exposure induces transcription-dependent TNF-alpha production, potentially due to upregulation of specific transcription factors.

Adult↗
PubMed2006

Characterization of endotoxin and mouse allergen exposures in mouse facilities and research laboratories.

OBJECTIVES: Researchers and technicians who use mice in research are exposed to complex mixtures containing mouse allergen, endotoxin and particulates from animals, bedding and feed. The particle characteristics of these different exposures, and whether they are encountered together or separately, are important to better understand their adjuvant and allergic effects. Endotoxin and mouse allergen are derived from the same animal source, but have different physicochemical attributes. It is not known if airborne exposures to these agents are correlated in the laboratory animal workplace. METHODS: Side-by-side personal and area samples for airborne endotoxin (52), mouse allergen (46) and total particulates (43) were obtained in the animal facility and laboratories of a medical research institution. Animal handlers and researchers reported time spent on work tasks with mice, symptoms upon exposure to mice and mouse sensitization was determined by skin test or RAST. RESULTS: Mean airborne endotoxin exposure was highest during mouse experiments in the animal facility at 960 pg m(-3), peaked at 3125 pg m(-3), and ranged from 46 to 678 pg m(-3) with work in mouse rooms and research labs. Mouse allergen concentrations were highest during direct mouse work and background in research labs (mean 63-68 ng m(-3), range 41-271 ng m(-3)), but were undetectable during mouse research performed under a hood. Endotoxin and mouse allergen concentrations were correlated during direct research with mice and mouse care activities. Particle counts were low, typically < 1 cm(-3), varied widely, and exhibited peaks and valleys during different work tasks. From 80-90% of particles were < 1 microm in aerodynamic diameter during background measurements. The contribution of respirable particles 1-5 microm in size increased to 25-30% during mouse care and mouse research activities, but we found no association between any particle size and endotoxin or mouse allergen concentrations. Animal handlers and researchers in the mouse facility were exposed to the highest daily endotoxin concentrations, whereas researchers working with mice in the mouse facility and in laboratories were exposed to the highest daily mouse allergen concentrations. CONCLUSIONS: These findings suggest that endotoxin and mouse allergen are co-exposures during mouse handling and research, and that control of exposure peaks may be necessary to limit allergic disease in the laboratory animal workplace.

Air Pollutants, Occupational↗
PubMed2006

Mycobacterial antigens may be important in sarcoidosis pathogenesis.

PURPOSE OF REVIEW: To describe the most recent epidemiologic, molecular and immunologic literature related to the role of infectious antigens in sarcoidosis pathogenesis, with a focus upon Mycobacterium and Proprionibacterium species. RECENT FINDINGS: Recent studies of successful molecular analysis for and humoral immunity to mycobacterial antigens from sarcoidosis patients have renewed interest in a potential role of mycobacteria in sarcoidosis. One study provided molecular and immunologic evidence for mycobacteria among sarcoidosis subjects from the United States. These studies, while preliminary, provide the groundwork for more in-depth studies of the potential role of mycobacteria in sarcoidosis pathogenesis. Proprionibacteria have also been proposed as a cause of sarcoidosis; a study of the detection of Proprionibacterium species nucleic acids throughout the lung of sarcoidosis and control subjects, however, suggests that these organisms are less likely to be causal. SUMMARY: While the studies to date do not fulfill Koch's postulates, they do add further support to the hypothesis that infectious antigens, particularly those from mycobacteria, may have a causal role in some sarcoidosis cases. In future studies that purport to show an association of microbial antigen(s) with sarcoidosis, investigation of genetic risk factors contributing to risk will be important, in order to explain why some patients are found to have an association with microbial antigens and others are not.

Antigens, Bacterial↗
PubMed2006

Comparison of sarcoidosis phenotypes among affected African-American siblings.

STUDY OBJECTIVE: To test the hypothesis that sibling pairs, who share genes and environmental exposures, might have similar phenotypic expressions of sarcoidosis beyond what would be expected by chance alone. DESIGN: Multicenter family study with study subjects recruited from 11 clinical centers. SUBJECTS: Subjects were African-American sibling pairs with sarcoidosis. Sarcoidosis and organ pattern involvement were defined according to specific criteria. Fifteen different organ systems were evaluated. RESULTS: For full-sibling pairs, ocular involvement was found in both siblings more often than expected by chance alone (p < 0.05), but the concordance was weak (kappa = 0.18). When analyzing full-sibling and half-sibling pairs, ocular and liver involvement showed a significant concordance between sibling pairs (p < 0.05), but again the agreement was poor (kappa = 0.16 for both). Concordance in pulmonary function change over time was also weak. Clinical outcomes of sibling pairs were not significantly correlated except for whether treatment was prescribed, and this level of agreement was poor (kappa = 0.14 for full-sibling and half-sibling pairs; kappa = 0.15 for full-sibling pairs only). Modeling phenotypic expression in sibling pairs using logistic regression did show that the presence of ocular and liver sarcoidosis in the first affected sibling conferred a statistically significant increased risk to the second affected sibling for having those organs involved (odds ratio [OR], 3; 95% confidence interval [CI], 1.7 to 5.4 for ocular; OR, 3.3; 95% CI, 1.5 to 7.4 for liver). CONCLUSIONS: The phenotypic features and clinical outcomes of sarcoidosis in sibling pairs show minimal concordance, with the possible exception that the presence of ocular or liver involvement in the first sibling with a diagnosis of sarcoidosis makes involvement of these organs more likely in other affected siblings.

Adult↗
PubMed2005

Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response.

Beryllium exposure can lead to the development of beryllium-specific CD4+ T cells and chronic beryllium disease (CBD), which is characterized by the presence of lung granulomas and a CD4+ T cell alveolitis. Studies have documented the presence of proliferating and cytokine-secreting CD4+ T cells in blood of CBD patients after beryllium stimulation. However, some patients were noted to have cytokine-secreting CD4 T cells in blood in the absence of beryllium-induced proliferation, and overall, the correlation between the 2 types of responses was poor. We hypothesized that the relative proportion of memory T cell subsets determined antigen-specific proliferation. In most CBD patients, the majority of beryllium-specific CD4+ T cells in blood expressed an effector memory T cell maturation phenotype. However, the ability of blood cells to proliferate in the presence of beryllium strongly correlated with the fraction expressing a central memory T cell phenotype. In addition, we found a direct correlation between the percentage of beryllium-specific CD4+ T(EM) cells in blood and T cell lymphocytosis in the lung. Together, these findings indicate that the functional capability of antigen-specific CD4+ T cells is determined by the relative proportion of memory T cell subsets, which may reflect internal organ involvement.

Aged↗
PubMed2005

Beryllium-stimulated reactive oxygen species and macrophage apoptosis.

Beryllium (Be), the etiologic agent of chronic beryllium disease, is a toxic metal that induces apoptosis in human alveolar macrophages. We tested the hypothesis that Be stimulates the formation of reactive oxygen species (ROS) which plays a role in Be-induced macrophage apoptosis. Mouse macrophages were exposed to 100 microM BeSO4 in the absence and presence of the catalytic antioxidant MnTBAP (100 microM). Apoptosis was measured as the percentage of TUNEL+ and caspase-8+ cells. ROS production was measured by flow cytometry using the fluorescence probes, dihydroethidine (DHE) and dichlorofluorescein diacetate (DCFH-DA). Be-exposed macrophages had increased TUNEL+ cells (15+/-1% versus controls 1+/-0.2%, P<0.05) and increased caspase-8+ cells (18.7+/-2% versus controls 1.8+/-0.4%, P<0.05). Be-induced caspase-8 activation, and a 4-fold increase in ROS formation, was ameliorated by exposure to MnTBAP. Hydrogen peroxide (30 microM) exposure potentiated Be-induced caspase-8 activation, and was also attenuated by MnTBAP. Our data are the first to demonstrate that Be stimulates macrophage ROS formation which plays an important role in Be-induced macrophage apoptosis.

Animals↗
PubMed2005

Frequency of beryllium-specific, TH1-type cytokine-expressing CD4+ T cells in patients with beryllium-induced disease.

BACKGROUND: Beryllium sensitization is caused by exposure to beryllium in the workplace. A subset of beryllium-sensitized (BeS) subjects progress to chronic beryllium disease (CBD), a disorder characterized by a CD4+ T-cell alveolitis and granulomatous inflammation. Whether biomarkers are present in blood that would allow separation of CBD from beryllium sensitization without invasive pulmonary procedures is unknown. OBJECTIVE: The aim of this study was to determine whether the quantity of beryllium-specific T cells in blood of patients with CBD differs from that found in BeS subjects. METHODS: Beryllium-induced T-cell proliferation and T H 1-type cytokine secretion were determined in blood cells from 33 patients with CBD and 18 BeS subjects. RESULTS: We demonstrate here that patients with CBD have a significantly elevated number of IFN-gamma-producing and IL-2-producing beryllium-specific CD4+ T cells in blood compared with both BeS and normal control subjects. In contrast, no difference in beryllium-induced proliferation of blood T cells was seen between BeS patients and patients with CBD. Compared with the blood beryllium lymphocyte proliferation test, which detected beryllium-induced proliferation in 65% of BeS patients and patients with CBD, ELISPOT analysis detected IFN-gamma secretion in 80% of these subjects. Higher numbers of beryllium-specific cells in blood were also associated with the extent of alveolar inflammation, as measured by both bronchoalveolar lavage white blood cell and lymphocyte counts. CONCLUSION: The frequency of beryllium-specific T cells in the blood of beryllium-exposed subjects may be a useful biomarker that helps discriminate between beryllium sensitization and progression to CBD.

Adult↗
PubMed2005

Secondary ion mass spectroscopy demonstrates retention of beryllium in chronic beryllium disease granulomas.

OBJECTIVE: We hypothesized that beryllium (Be) might persist in lung granulomas in patients with chronic beryllium disease (CBD). METHODS: A total of 33 Be-exposed ceramics workers underwent transbronchial biopsy. They were classified based on histopathology and Be-lymphocyte proliferation test as CBD or other categories. Lung tissue sections were analyzed using secondary ion mass spectroscopy. RESULTS: Be was detected in the lungs of all Be-exposed groups. Be levels were increased within the granulomas of patients with CBD compared with the Be levels outside granulomas. Notably, Be was detectable in the lungs of CBD patients who had ceased exposure to Be an average of 9 years previously. CONCLUSIONS: Be was detected in the lungs of all Be-exposed subjects, with the highest levels of persistent Be inside CBD lung granulomas. Be antigen persistence may help explain the chronicity of this granulomatous disorder.

Adult↗
PubMed2005

Lung fibrosis in plutonium workers.

There have been few systematic studies of the non-malignant health effects of alpha-particle radiation in humans. Animal studies and a report on plutonium-exposed workers from Russia suggest an association between high doses to the lung from plutonium exposure and the development of fibrotic lung disease. Prompted by a case of lung fibrosis in a retired plutonium worker, we tested the hypothesis that plutonium inhalation increases the risk for developing chest radiograph abnormalities consistent with pulmonary fibrosis. We conducted a retrospective study of nuclear weapons workers that included estimating absorbed doses to the lung with an internal dosimetry model. Our study population consisted of 326 plutonium-exposed workers with absorbed lung doses from 0 to 28 Sv and 194 unexposed workers. We compared the severity of chest radiograph interstitial abnormalities between the two groups using the International Labour Organization profusion scoring system. There was a significantly higher proportion of abnormal profusion scores among plutonium-exposed workers (17.5%) than among unexposed workers (7.2%), P < 0.01. Lung doses of 10 Sv or greater conferred a 5.3-fold risk (95% CI 1.2-23.4) of having an abnormal chest X ray consistent with pulmonary fibrosis when compared with unexposed individuals after controlling for the effects of age, smoking and asbestos exposure. This study shows that plutonium may cause lung fibrosis in humans at absorbed lung doses above 10 Sv.

Adult↗
PubMed2005

A sarcoidosis genetic linkage consortium: the sarcoidosis genetic analysis (SAGA) study.

BACKGROUND: Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the United States of America, African Americans have a higher sarcoidosis incidence and suffer greater morbidity than Caucasians. METHODS: A sarcoidosis genetic linkage study consortium was established to recruit African-American affected sib pair (ASP) families to identify chromosomal regions that may harbor sarcoidosis susceptibility genes and to determine if environmental factors modify any genetic effects. RESULTS: We successfully met our goal of enrolling 359 ASPs using a multifaceted recruitment approach. In the total 559 sib pairs that were enrolled, genetic analyses revealed incorrectly specified relationships that required reclassification or removal from the analysis dataset of 10.4% of reported full and 1.4% of reported half sib pairs. The final study sample comprised 415 full and 104 half sib pairs with complete data. This included 338 ASPs. Within sib pairs, affection status was not associated with sex. Only 15 per cent of the 229 families had three or more affected sibs, but they contributed 42 per cent of the ASP total. CONCLUSIONS: The SAGA study experience should provide useful lessons and information to serve others in conducting genetic studies of complex diseases in African-American families.

Black or African American↗
PubMed2005

Pulmonary and psychosocial findings at enrollment in the ACCESS study.

AIM: To assess lung involvement and the association of demographic and psychosocial factors with respiratory health in 736 persons with sarcoidosis at enrollment in A Case Control Etiologic Study of Sarcoidosis (ACCESS). METHODS: 736 patients with biopsy diagnosis of sarcoidosis within 6 months of enrollment were studied at 10 US centers. Lung involvement was evaluated by chest radiography, spirometry and dyspnea questionnaire. Demographics, number of involved extrathoracic organ systems, comorbidities, and health-related quality of life (HRQL) were assessed. RESULTS: 95% of patients had lung involvement. 8% were Scadding Stage 0, 40% I, 37% II, 10% III, and 5% IV 51% reported dyspnea. Increasing radiographic lung stage was associated with decreasing Forced Vital Capacity (FVC) (p < 0.01). Patients with higher stages had more airways obstruction and dyspnea. 46% of cases and 27% of controls had Center for Epidemiologic Studies Depression Scale (CES-D) scores of 9 or greater, (p < 0.001). Age > or = 40, African-American race, body mass index > or = 30kg/m2, and CES-D scores > 9 were associated with decreased FVC and greater dyspnea. Impaired spirometry and greater dyspnea were associated with poorer quality of life. CONCLUSION: A "global" approach to the sarcoidosis patient, including careful assessment of dyspnea and health related quality of life, as well as of lung function and radiographic changes, and any extrathoracic involvement, is important, not only in management of the individual patient, but should also prove beneficial in assessing outcomes in clinical trials in the future.

Adult↗
PubMed2004

Beryllium sensitization progresses to chronic beryllium disease: a longitudinal study of disease risk.

The blood beryllium lymphocyte proliferation test is used in medical surveillance to identify both beryllium sensitization and chronic beryllium disease. Approximately 50% of individuals with beryllium sensitization have chronic beryllium disease at the time of their initial clinical evaluation; however, the rate of progression from beryllium sensitization to chronic beryllium disease is unknown. We monitored a cohort of beryllium-sensitized patients at 2-year intervals, using bronchoalveolar lavage and repeated transbronchial lung biopsies to determine progression to chronic beryllium disease as evidenced by granulomatous inflammation in lung tissue. Fifty-five individuals with beryllium sensitization were monitored with a range of 2 to 5 clinical evaluations. Disease developed in 17 sensitized individuals (31%) within an average follow-up period of 3.8 years (range, 1.0-9.5 years). Thirty-eight of the 55 (69%) remained beryllium sensitized without disease after an average follow-up time of 4.8 years (range, 1.7-11.6 years). Progressors were more likely to have worked as machinists. We found no difference in average age, sex, race or ethnicity, smoking status, or beryllium exposure time between those who progressed to chronic beryllium disease and those who remained sensitized without disease. We conclude that beryllium sensitization is an adverse health effect in beryllium-exposed workers and merits medical follow-up.

Adult↗
PubMed2004

A case control etiologic study of sarcoidosis: environmental and occupational risk factors.

Past research suggests that environmental factors may be associated with sarcoidosis risk. We conducted a case control study to test a priori hypotheses that environmental and occupational exposures are associated with sarcoidosis. Ten centers recruited 706 newly diagnosed patients with sarcoidosis and an equal number of age-, race-, and sex-matched control subjects. Interviewers administered questionnaires containing questions regarding occupational and nonoccupational exposures that we assessed in univariable and multivariable analyses. We observed positive associations between sarcoidosis and specific occupations (e.g., agricultural employment, odds ratio [OR] 1.46, confidence interval [CI] 1.13-1.89), exposures (e.g., insecticides at work, OR 1.52, CI 1.14-2.04, and work environments with mold/mildew exposures [environments with possible exposures to microbial bioaerosols], OR 1.61, CI 1.13-2.31). A history of ever smoking cigarettes was less frequent among cases than control subjects (OR 0.62, CI 0.50-0.77). In multivariable modeling, we observed elevated ORs for work in areas with musty odors (OR 1.62, CI 1.24-2.11) and with occupational exposure to insecticides (OR 1.61, CI 1.13-2.28), and a decreased OR related to ever smoking cigarettes (OR 0.65, CI 0.51-0.82). The study did not identify a single, predominant cause of sarcoidosis. We identified several exposures associated with sarcoidosis risk, including insecticides, agricultural employment, and microbial bioaerosols.

Adolescent↗
PubMed2004

Beryllium-ferritin: lymphocyte proliferation and macrophage apoptosis in chronic beryllium disease.

A beryllium (Be)-ferritin adduct containing 270 pm of Be stimulated proliferation of bronchoalveolar lavage (BAL) lymphocytes from subjects with chronic beryllium disease (CBD) at concentrations 5-6 logs lower than the amounts of beryllium sulfate (BeSO4) needed to induce proliferation. We observed increased apoptotic CBD BAL macrophages after exposure to both BeSO4 (50 +/- 6%, mean +/- SEM, P <0.05 versus unstimulated controls) and Be-ferritin (40 +/- 2%), whereas only 2.0 +/- 0.2% of BAL lymphocytes underwent activation-induced cell death. Be-ferritin also induced apoptosis in BAL macrophages from subjects with Be sensitization (25 +/- 3%) and in the H36.12j hybrid macrophage cell line (15 +/- 2%). Be-ferritin induced lung macrophage CD95 (Fas) expression and the activation of intracellular caspase-3, -8 and -9. Thus, lung macrophages take up Be-ferritin, delivering physiologically relevant levels of Be that promote Be antigen presentation and macrophage apoptosis. Be-ferritin thereby serves as a "Trojan Horse," triggering proliferation of Be-ferritin-specific CBD BAL T cells. We hypothesize that Be-ferritin exposure may result in persistent antigen exposure inducing Be-specific T cell clonal expansion and T cell helper type 1-type cytokine production and potentially explains the chronicity of CBD and its development years after environmental Be exposure has ceased.

Adult↗
PubMed2004

Beryllium-induced tumor necrosis factor-alpha production by CD4+ T cells is mediated by HLA-DP.

Beryllium (Be) presentation to CD4+ T cells from patients with chronic beryllium disease (CBD) results in T cell activation, and these Be-specific CD4+ T cells undergo clonal proliferation and T-helper 1-type cytokine production. In exposed workers, genetic susceptibility to this granulomatous disorder is associated with particular HLA-DPB1 alleles. We hypothesized that these HLA-DP molecules could mediate Be-stimulated tumor necrosis factor-alpha (TNF-alpha) messenger RNA (mRNA) and protein production. Using intracellular cytokine staining, we found that treatment with an anti-HLA-DP, but not anti-HLA-DR, monoclonal antibody inhibited Be-stimulated TNF-alpha expression in lung CD3+ CD4+ T cells. This monoclonal antibody also blocked Be-specific T cell proliferation, increased production of TNF-alpha mature-mRNA transcripts, and increased TNF-alpha protein production by Be-stimulated CBD peripheral blood mononuclear cells and bronchoalveolar lavage (BAL) cells. The Be-stimulated upregulation of TNF-alpha mature-mRNA levels with TNF-alpha protein production was a unique property of CBD BAL cells, and did not occur in BAL cells from Be-sensitized patients without CBD, or sarcoidosis BAL cells. This study identifies HLA-DP as a regulatory component in the activation of T cell receptors on Be-specific CD4+ T cells from CBD patients resulting in proliferation and proinflammatory cytokine production.

Antibodies, Monoclonal↗