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1.  Occupational Causes of Sarcoidosis 
Purpose of review
Sarcoidosis, the multiorgan, granulomatous disease of unknown etiology, remains mysterious. Several important investigations in the past two years add to accumulating evidence for both occupational and environmental causes of granulomatous inflammation.
Recent findings
This review considers the most recent studies that contribute to the hypothesis that sarcoidosis occurs when individuals are exposed to foreign antigens and to inorganic particulates that promote inflammation. Major recent findings, such as those emerging from the study of World Trade Center responders, the study of nanoparticles, and cases of work-associated sarcoidosis support the probability that occupational, as well as environmental, exposures to inflammatory stimuli trigger sarcoidosis-like illness. Major recent studies of microbially-rich indoor environments, including moldy indoor workplaces and mycobacterially-contaminated settings, contribute to the evidence that a variety of microbial antigens serve as targets for the hypersensitivity immune response in an inflammatory milieu.
Summary
There is increasing evidence that sarcoidosis can occur in workplace settings in which there is exposure to both foreign antigens and inorganic triggers of inflammation that promote an exuberant granulomatous immune response. It is likely that sarcoidosis has more than one cause.
doi:10.1097/ACI.0b013e3283515173
PMCID: PMC4196683  PMID: 22314258
Sarcoidosis; Occupation; Granuloma; Nanoparticle; World Trade Center
3.  Birth Outcomes and Maternal Residential Proximity to Natural Gas Development in Rural Colorado 
Environmental Health Perspectives  2014;122(4):412-417.
Background: Birth defects are a leading cause of neonatal mortality. Natural gas development (NGD) emits several potential teratogens, and U.S. production of natural gas is expanding.
Objectives: We examined associations between maternal residential proximity to NGD and birth outcomes in a retrospective cohort study of 124,842 births between 1996 and 2009 in rural Colorado.
Methods: We calculated inverse distance weighted natural gas well counts within a 10-mile radius of maternal residence to estimate maternal exposure to NGD. Logistic regression, adjusted for maternal and infant covariates, was used to estimate associations with exposure tertiles for congenital heart defects (CHDs), neural tube defects (NTDs), oral clefts, preterm birth, and term low birth weight. The association with term birth weight was investigated using multiple linear regression.
Results: Prevalence of CHDs increased with exposure tertile, with an odds ratio (OR) of 1.3 for the highest tertile (95% CI: 1.2, 1.5); NTD prevalence was associated with the highest tertile of exposure (OR = 2.0; 95% CI: 1.0, 3.9, based on 59 cases), compared with the absence of any gas wells within a 10-mile radius. Exposure was negatively associated with preterm birth and positively associated with fetal growth, although the magnitude of association was small. No association was found between exposure and oral clefts.
Conclusions: In this large cohort, we observed an association between density and proximity of natural gas wells within a 10-mile radius of maternal residence and prevalence of CHDs and possibly NTDs. Greater specificity in exposure estimates is needed to further explore these associations.
Citation: McKenzie LM, Guo R, Witter RZ, Savitz DA, Newman LS, Adgate JL. 2014. Birth outcomes and maternal residential proximity to natural gas development in rural Colorado. Environ Health Perspect 122:412–417; http://dx.doi.org/10.1289/ehp.1306722
doi:10.1289/ehp.1306722
PMCID: PMC3984231  PMID: 24474681
4.  Phytotechnologies – Preventing Exposures, Improving Public Health 
Phytotechnologies have the potential to reduce the amount and/or toxicity of deleterious chemicals/agents, and thereby, prevent human exposures to hazardous substances. As such, phytotechnologies are a tool for primary prevention within the context of public health. Research advances demonstrate that phytotechnologies can be uniquely tailored for effective exposure prevention for a variety of applications. In addition to exposure prevention, phytotechnologists have advanced the use of plants as sensors to delineate environmental contaminants and potential exposures. The applications presented in this paper are at various stages of development and are presented in a framework to reflect how phytotechnologies can help meet basic public health needs for access to clean water, air, and food resources. As plant-based technologies can often be integrated into communities at minimal cost and with low infrastructure needs, their use in improving environmental quality can be applied broadly to minimize potential contaminant exposure. These natural treatment systems concurrently provide ecosystem services of notable value to communities and society. In the future, integration and coordination of phytotechnology activities with public health research will allow technology development that focuses on prevention of environmental exposures. Such an approach will lead to an important role of phytotechnologies in providing sustainable solutions to environmental exposure challenges that improve public health and potentially reduce the burden of disease.
PMCID: PMC3954606  PMID: 23819283
phytotechnologies; sustainability; exposure prevention; primary prevention; public health; airborne pollution; water contamination; food safety; developing countries
5.  Beryllium-Specific CD4+ T Cells in Blood as a Biomarker of Disease Progression 
Background
CD4+ T cells are responsible for the progressive lung damage seen in patients with chronic beryllium disease (CBD), a granulomatous lung disorder in which antigen-specific, Th1-type cytokine-secreting T cells have been characterized. Compared to beryllium (Be)-sensitized subjects, an increased number of Be-responsive T cells are present in the blood of CBD patients.
Objective
The aim of this study was to determine whether the number of Be-specific T cells in blood predicted the development of CBD in a cohort of Be-exposed subjects.
Methods
Using IFN-γ ELISPOT and proliferation-based assays, we determined the frequency and proliferative capacity of Be-responsive T cells in blood.
Results
Compared with the Be lymphocyte proliferation test which detected an abnormal Be-induced proliferative response in 11 of 260 (4.2%) workers from a Be-machining facility, IFN-γ ELISPOT detected a sensitization rate of 10% (χ2 = 55.7; P < 0.0001). A significant positive correlation was also noted between the number of Be-responsive CD4+ T cells in blood and lung of CBD patients. Importantly, the transition from Be sensitization to CBD was associated with an increased number of antigen-specific T cells in blood.
Conclusion
These findings have important implications for Be-induced disease and potentially other immune-mediated disorders, suggesting that the frequency of antigen-specific T cells in blood can serve as a noninvasive biomarker to predict disease development and severity of the Be-specific CD4+ T cell alveolitis.
Clinical implications
These findings suggest that the number of Be-responsive T cells in the circulation can serve as a biomarker of disease progression and as an estimate of the severity of Be-induced lung inflammation.
doi:10.1016/j.jaci.2011.08.022
PMCID: PMC3205205  PMID: 21943943
Human; Lung; CD4-Positive T-Lymphocytes; Beryllium; Cytokines; Granuloma; ELISPOT
6.  Risk of Chronic Beryllium Disease by HLA-DPB1 E69 Genotype and Beryllium Exposure in Nuclear Workers 
Rationale: Beryllium sensitization (BeS) and chronic beryllium disease (CBD) are determined by at least one genetic factor, a glutamic acid at position 69 (E69) of the HLA-DPB1 gene, and by exposure to beryllium. The relationship between exposure and the E69 genotype has not been well characterized.
Objectives: The study goal was to define the relationship between beryllium exposure and E69 for CBD and BeS.
Methods: Workers (n = 386) from a U.S. nuclear weapons facility were enrolled into a case–control study (70 BeS, 61 CBD, and 255 control subjects). HLA-DPB1 genotypes were determined by sequence-specific primer-polymerase chain reaction. Beryllium exposures were reconstructed on the basis of worker interviews and historical exposure measurements.
Measurements and Main Results: Any E69 carriage increased odds for CBD (odds ratio [OR], 7.61; 95% confidence interval [CI], 3.66–15.84) and each unit increase in lifetime weighted average exposure increased the odds for CBD (OR, 2.27; 95% CI, 1.26–4.09). Compared with E69-negative genotypes, a single E69-positive *02 allele increased the odds for BeS (OR, 12.01; 95% CI, 4.28–33.71) and CBD (OR, 3.46; 95% CI, 1.42–8.43). A single non-*02 E69 allele further increased the odds for BeS (OR, 29.54; 95% CI, 10.33–84.53) and CBD (OR, 11.97; 95% CI, 5.12–28.00) and two E69 allele copies conferred the highest odds for BeS (OR, 55.68; 95% CI, 14.80–209.40) and CBD (OR, 22.54; 95% CI, 7.00–72.62).
Conclusions: E69 and beryllium exposure both contribute to the odds of CBD. The increased odds for CBD and BeS due to E69 appear to be differentially distributed by genotype, with non-*02 E69 carriers and E69 homozygotes at higher odds than those with *02 genotypes.
doi:10.1164/rccm.201002-0254OC
PMCID: PMC3136994  PMID: 21471109
berylliosis; genetics; case–control studies; occupational exposure; HLA-DP antigens
7.  Sulfasalazine and Mesalamine Modulate Beryllium-Specific Lymphocyte Proliferation and Inflammatory Cytokine Production 
Occupational exposure to beryllium (Be) results in Be sensitization (BeS) that can progress to pulmonary granulomatous inflammation associated with chronic Be disease (CBD). Be-specific lymphocytes are present in the blood of patients with BeS and in the blood and lungs of patients with CBD. Sulfasalazine and its active metabolite, mesalamine, are clinically used to ameliorate chronic inflammation associated with inflammatory bowel disease. We tested whether sulfasalazine or mesalamine could decrease Be-stimulated peripheral blood mononuclear cell (PBMC) proliferation in subjects with CBD and BeS and Be-induced cytokine production in CBD bronchoalveolar lavage (BAL) cells. CBD (n = 25), BeS (n = 12) and healthy normal control (n = 6) subjects were enrolled and ex vivo proliferation and cytokine production were assessed in the presence of Be and sulfasalazine or mesalamine. Be-stimulated PBMC proliferation was inhibited by treatment with either sulfasalazine or mesalamine. Be-stimulated CBD BAL cell IFN-γ and TNF-α cytokine production was decreased by treatment with sulfasalazine or mesalamine. Our data suggest that both sulfasalazine and mesalamine interfere with Be-stimulated PBMC proliferation in CBD and BeS and dampens Be-stimulated CBD BAL cell proinflammatory cytokine production. These studies demonstrate that sulfasalazine and mesalamine can disrupt inflammatory pathways critical to the pathogenesis of chronic granulomatous inflammation in CBD, and may serve as novel therapy for human granulomatous lung diseases.
doi:10.1165/rcmb.2009-0150OC
PMCID: PMC2951876  PMID: 19901345
granulomatous inflammation; IFN-γ; TNF-α; lymphocyte proliferation; berylliosis
8.  Beryllium Lymphocyte Proliferation Test Surveillance Identifies Clinically Significant Beryllium Disease 
Background
Workplace surveillance identifies chronic beryllium disease (CBD) but it remains unknown over what time frame mild CBD will progress to a more severe form.
Methods
We examined physiology and treatment in 229 beryllium sensitization (BeS) and 171 CBD surveillance-identified cases diagnosed from 1982 to 2002. Never smoking CBD cases (81) were compared to never smoking BeS patients (83) to assess disease progression. We compared CBD machinists to non-machinists to examine effects of exposure.
Results
At baseline, CBD and BeS cases did not differ significantly in exposure time or physiology. CBD patients were more likely to have machined beryllium. Of CBD cases, 19.3% went on to require oral immunosuppressive therapy. At 30 years from first exposure, measures of gas exchange were significantly worse and total lung capacity was lower for CBD subjects. Machinists had faster disease progression as measured by pulmonary function testing and gas exchange.
Conclusions
Medical surveillance for CBD identifies individuals at significant risk of disease progression and impairment with sufficient time since first exposure.
doi:10.1002/ajim.20736
PMCID: PMC3063521  PMID: 19681064
beryllium; chronic beryllium disease; medical surveillance
9.  Genome Sequence of the Plant Growth Promoting Endophytic Bacterium Enterobacter sp. 638 
PLoS Genetics  2010;6(5):e1000943.
Enterobacter sp. 638 is an endophytic plant growth promoting gamma-proteobacterium that was isolated from the stem of poplar (Populus trichocarpa×deltoides cv. H11-11), a potentially important biofuel feed stock plant. The Enterobacter sp. 638 genome sequence reveals the presence of a 4,518,712 bp chromosome and a 157,749 bp plasmid (pENT638-1). Genome annotation and comparative genomics allowed the identification of an extended set of genes specific to the plant niche adaptation of this bacterium. This includes genes that code for putative proteins involved in survival in the rhizosphere (to cope with oxidative stress or uptake of nutrients released by plant roots), root adhesion (pili, adhesion, hemagglutinin, cellulose biosynthesis), colonization/establishment inside the plant (chemiotaxis, flagella, cellobiose phosphorylase), plant protection against fungal and bacterial infections (siderophore production and synthesis of the antimicrobial compounds 4-hydroxybenzoate and 2-phenylethanol), and improved poplar growth and development through the production of the phytohormones indole acetic acid, acetoin, and 2,3-butanediol. Metabolite analysis confirmed by quantitative RT–PCR showed that, the production of acetoin and 2,3-butanediol is induced by the presence of sucrose in the growth medium. Interestingly, both the genetic determinants required for sucrose metabolism and the synthesis of acetoin and 2,3-butanediol are clustered on a genomic island. These findings point to a close interaction between Enterobacter sp. 638 and its poplar host, where the availability of sucrose, a major plant sugar, affects the synthesis of plant growth promoting phytohormones by the endophytic bacterium. The availability of the genome sequence, combined with metabolome and transcriptome analysis, will provide a better understanding of the synergistic interactions between poplar and its growth promoting endophyte Enterobacter sp. 638. This information can be further exploited to improve establishment and sustainable production of poplar as an energy feedstock on marginal, non-agricultural soils using endophytic bacteria as growth promoting agents.
Author Summary
Poplar is considered as the model tree species for the production of lignocellulosic biomass destined for biofuel production. The plant growth promoting endophytic bacterium Enterobacter sp. 638 can improve the growth of poplar on marginal soils by as much as 40%. This prompted us to sequence the genome of this strain and, via comparative genomics, identify functions essential for the successful colonization and endophytic association with its poplar host. Analysis of the genome sequence, combined with metabolite analysis and quantitative PCR, pointed to a remarkable interaction between Enterobacter sp. 638 and its poplar host with the endophyte responsible for the production of a phytohormone, and a precursor for another that poplar is unable to synthesize, and where the production of the plant growth promoting compounds depended on the presence of plant synthesized compounds, such as sucrose, in the growth medium. Our results provide the basis to better understanding the synergistic interactions between poplar and Enterobacter sp. 638. This information can be further exploited to improve establishment and sustainable production of poplar on marginal, non-agricultural soils using endophytic bacteria such as Enterobacter sp. 638 as growth promoting agents.
doi:10.1371/journal.pgen.1000943
PMCID: PMC2869309  PMID: 20485560
10.  A mass balance study of the phytoremediation of perchloroethylene-contaminated groundwater 
A mass balance study was performed under controlled field conditions to investigate the phytoremediation of perchloroethylene (PCE) by hybrid poplar trees. Water containing 7–14 mg L−1 PCE was added to the test bed. Perchloroethylene, trichloroethylene, and cis-dichloroethylene were detected in the effluent at an average of 0.12 mg L−1, 3.9 mg L−1, and 1.9 mg L−1, respectively. The total mass of chlorinated ethenes in the water was reduced by 99%. Over 95% of the recovered chlorine was as free chloride in the soil, indicating near-complete dehalogenation of the PCE. Transpiration, volatilization, and accumulation in the trees were all found to be minor loss mechanisms. In contrast, 98% of PCE applied to an unplanted soil chamber was recovered as PCE in the effluent water or volatilized into the air. These results suggest that phytoremediation can be an effective method for treating PCE-contaminated groundwater in field applications.
doi:10.1016/j.envpol.2009.02.033
PMCID: PMC2858582  PMID: 19345455
Phytoremediation; Perchloroethylene; Mass balance
11.  Genome Survey and Characterization of Endophytic Bacteria Exhibiting a Beneficial Effect on Growth and Development of Poplar Trees ▿ †  
The association of endophytic bacteria with their plant hosts has a beneficial effect for many different plant species. Our goal is to identify endophytic bacteria that improve the biomass production and the carbon sequestration potential of poplar trees (Populus spp.) when grown in marginal soil and to gain an insight in the mechanisms underlying plant growth promotion. Members of the Gammaproteobacteria dominated a collection of 78 bacterial endophytes isolated from poplar and willow trees. As representatives for the dominant genera of endophytic gammaproteobacteria, we selected Enterobacter sp. strain 638, Stenotrophomonas maltophilia R551-3, Pseudomonas putida W619, and Serratia proteamaculans 568 for genome sequencing and analysis of their plant growth-promoting effects, including root development. Derivatives of these endophytes, labeled with gfp, were also used to study the colonization of their poplar hosts. In greenhouse studies, poplar cuttings (Populus deltoides × Populus nigra DN-34) inoculated with Enterobacter sp. strain 638 repeatedly showed the highest increase in biomass production compared to cuttings of noninoculated control plants. Sequence data combined with the analysis of their metabolic properties resulted in the identification of many putative mechanisms, including carbon source utilization, that help these endophytes to thrive within a plant environment and to potentially affect the growth and development of their plant hosts. Understanding the interactions between endophytic bacteria and their host plants should ultimately result in the design of strategies for improved poplar biomass production on marginal soils as a feedstock for biofuels.
doi:10.1128/AEM.02239-08
PMCID: PMC2632133  PMID: 19060168
12.  Mycobacterial ESAT-6 and katG are Recognized by Sarcoidosis CD4+ T Cells When Presented by the American Sarcoidosis Susceptibility Allele, DRB1*1101 
Journal of Clinical Immunology  2009;30(1):157-166.
Introduction
Genetic associations of American sarcoidosis susceptibility implicate MHC class II allele, DRB1*1101. We previously reported immune recognition of Mycobacterium peptides from peripheral cells of 26 sarcoidosis subjects, 24 PPD− healthy volunteers, and eight with latent tuberculosis infection.
Materials and Methods
In order to further link these genetic and immunologic pillars of sarcoidosis pathogenesis, we performed flow cytometry on these same subjects to identify the cells responsible for immune responses to ESAT-6 and katG peptides, followed by HLA typing to determine allelic associations with recognition.
Discussion and Conclusion
Sarcoidosis CD4+ T cells were primarily responsible for the systemic responses. Recognition was inhibited by monoclonal antibody against HLA-DR and HLA-DQ, but not HLA-DP. Immune recognition of ESAT-6 peptide NNALQNLARTISEAG was associated with possession of DRB1*1101. ESAT-6 and katG presented by antigen-presenting cells expressing DRB1*1101-induced Th-1 responses from sarcoidosis T cells, thus providing a mechanistic insight for the association of HLA DRB1*1101 with sarcoidosis, and sarcoidosis T cell interaction with microbial antigens.
doi:10.1007/s10875-009-9311-y
PMCID: PMC2821522  PMID: 19536643
Sarcoidosis; MHC class II; Th-1 cytokines; CD4+ T cells
13.  Modulation of Lymphocyte Proliferation by Antioxidants in Chronic Beryllium Disease 
Rationale: Occupational exposure to beryllium (Be) can result in chronic granulomatous inflammation characterized by the presence of Be-specific CD4+ T cells. Studies show that oxidative stress plays a role in the pathogenesis of chronic inflammatory disorders.
Objectives: We hypothesized that Be-induced oxidative stress modulates the proliferation of Be-specific CD4+ T cells.
Methods: Thirty-three subjects with chronic beryllium disease (CBD), 15 subjects with beryllium sensitization, and 28 healthy normal control subjects were consecutively enrolled from the Occupational and Environmental Health Clinic of the National Jewish Medical and Research Center.
Measurements and Main Results: All studies were performed with Ficoll-Hypaque–isolated peripheral blood mononuclear cells from subsets of the study subjects. Decreased intracellular levels of the thiol antioxidants, glutathione and cysteine, were observed in peripheral blood mononuclear cells from subjects with beryllium sensitization and CBD, as compared with healthy control subjects. Beryllium stimulation decreased intracellular thiol antioxidants by more than 40%, accompanied by increased reactive oxygen species levels and the proliferation of Be-specific blood CD4+ T cells from subjects with CBD. Be-induced T-cell proliferation was inhibited by treatment with the thiol antioxidant N-acetylcysteine or the catalytic antioxidant manganese(III) 5,10,15,20-tetrakis(4-benzoic acid)porphyrin (MnTBAP). MnTBAP treatment also inhibited T-cell proliferation in response to the unrelated, MHC class II–restricted antigen tetanus toxoid. Treatment of CBD blood lymphocytes, but not antigen-presenting cells, with MnTBAP decreased Be-induced T-cell proliferation by more than 40%.
Conclusions: Beryllium can mediate a thiol imbalance leading to oxidative stress that may modulate the proliferation and clonal expansion of Be-specific blood CD4+ T cells. These data suggest that Be-induced oxidative stress plays a role in the pathogenesis of granulomatous inflammation in CBD.
doi:10.1164/rccm.200707-1021OC
PMCID: PMC2361422  PMID: 18218990
T cells; reactive oxygen species; glutathione; N-acetylcysteine; oxidative stress
14.  Immunotoxicology of beryllium lung disease 
Beryllium induces non-caseating granulomatous inflammation in humans exposed to the metal dust or fumes in both occupational and non-occupational settings. The resulting condition, chronic beryllium disease (CBD), affects principally the lungs, lymphatics, and skin and continues to plague modern industry. Beryllium exerts several important immunotoxic effects, including induction of a beryllium-antigen specific adaptive immune response and the triggering of inflammatory and innate immune responses. Genetic susceptibility plays a role in CBD adaptive immune responses, mainly mediated through single nucleotide polymorphisms in HLA-DP and, to a lesser extent, HLA-DR. The adaptive response is characterized by influx and proliferation of CD4+ central and effector memory T cells expressing Th1 cytokines. Insights into the immunopathogenesis of CBD have implications for the understanding of other immune-mediated granulomatous disorders and for metal antigen behavior.
doi:10.1007/BF02897985
PMCID: PMC2723296  PMID: 21432059
beryllium; berylliosis; Chronic Beryllium Disease; granuloma; metal immunotoxicity
15.  Gene-environment interactions in sarcoidosis 
Clinics in dermatology  2007;25(3):267-275.
Susceptibility to most human diseases is polygenic, with complex interactions between functional polymorphisms of single genes governing disease incidence, phenotype, or both. In this context, the contribution of any discrete gene is generally modest for a single individual, but may confer substantial attributable risk on a population level. Environmental exposure can modify the effects of a polymorphism, either by providing a necessary substrate for development of human disease or because the effects of a given exposure modulate the effects of the gene. In several diseases, genetic polymorphisms have been shown to be context-dependent, i.e. the effects of a genetic variant are realized only in the setting of a relevant exposure. Since sarcoidosis susceptibility is dependent on both genetic and environmental modifiers, the study of gene-environment interactions may yield important pathogenetic information and will likely be crucial for uncovering the range of genetic susceptibility loci. However, the complexity of these relationships implies that investigations of gene-environment interactions will require the study of large cohorts with carefully-defined exposures and similar clinical phenotypes. A general principle is that the study of gene-environment interactions requires a sample size at least several-fold greater than for either factor alone. To date, the presence of environmental modifiers has been demonstrated for one sarcoidosis susceptibility locus, HLA-DQB1, in African-American families. This article reviews general considerations obtaining for the study of gene-environment interactions in sarcoidosis. It also describes the limited current understanding of the role of environmental influences on sarcoidosis susceptibility genes.
doi:10.1016/j.clindermatol.2007.03.005
PMCID: PMC1920704  PMID: 17560304
16.  Beryllium-Induced TNF-α 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-α secretion. We tested the hypothesis that Be-induced, CBD bronchoalveolar lavage (BAL) T cell, transcription-dependent, TNF-α 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-α (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-α versus 55 pg/ml (range, 0–454) by unstimulated cells. Using real-time RT-PCR, Be-stimulated TNF-α production at 6 h was preceded by a 5-fold increase in TNF-α pre-mRNA copy number:β-actin copy number (Be median ratio 0.21; unstimulated median ratio 0.04). The median ratio of mature TNF-α mRNA:β-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-α 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-α mRNA levels 50% while 2AP decreased levels > 80%, relative to Be exposure alone. Beryllium exposure specifically upregulated transcription factors AP-1 and NF-κB. The data suggest that Be exposure induces transcription-dependent TNF-α production, potentially due to upregulation of specific transcription factors.
doi:10.1165/rcmb.2006-0021TR
PMCID: PMC2176111  PMID: 16980557
granuloma; T lymphocytes; cytokines; gene regulation; lung
17.  Cellular Recognition of Mycobacterium tuberculosis ESAT-6 and KatG Peptides in Systemic Sarcoidosis▿  
Infection and Immunity  2006;75(1):527-530.
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.
doi:10.1128/IAI.00732-06
PMCID: PMC1828402  PMID: 17088357
18.  Risk factors for symptom onset in PI*Z alpha-1 antitrypsin deficiency 
Background
In an early study of highly symptomatic patients with PI*Z alpha-1 antitrypsin deficiency (AAT), tobacco smoking was identified as a risk factor by comparing the age of symptom onset in smokers and nonsmokers. Age of symptom onset has not been well studied in relationship to other environmental exposures.
Methods
Environmental exposures were assessed in 313 PI*Z adults through retrospective self-administered questionnaire. Age of onset of symptoms with and without these exposures were analyzed through survival analysis.
Results
Personal smoking was the most important risk factor, associated with earlier onset of cough and wheeze, and showed a dose-dependent relationship with the onset of dyspnea. Childhood environmental tobacco smoke (ETS) exposure was independently associated with younger age of onset of cough. Earlier onset of wheeze was also associated with childhood respiratory infections and family history of emphysema. The report of childhood respiratory infections was associated with childhood ETS exposure, but no statistically significant interactions were noted.
Conclusions
We conclude that both personal and secondhand exposure to tobacco smoke in childhood are likely to accelerate the onset of symptoms in AAT deficient patients. Respiratory infections in childhood may also contribute to this risk.
PMCID: PMC2707814  PMID: 18044105
alpha-1 antitrypsin deficiency; tobacco smoke pollution; respiratory symptoms; lower respiratory illness
19.  Frequency of beryllium-specific, central memory CD4+ T cells in blood determines proliferative response 
Journal of Clinical Investigation  2005;115(10):2886-2893.
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+ TEM 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.
doi:10.1172/JCI24908
PMCID: PMC1199530  PMID: 16151531
20.  Environmental, occupational, and genetic risk factors for alpha-1 antitrypsin deficiency. 
Environmental Health Perspectives  2003;111(14):1749-1752.
Alpha-1 antitrypsin (AAT) deficiency is an inherited genetic disorder currently diagnosed in approximately 5,000 people in the United States. Although some individuals with AAT deficiency are asymptomatic, the condition often leads to deterioration of lung function in adults and is associated with emphysema, asthma, chronic obstructive pulmonary disease, and other respiratory diseases. In children, AAT deficiency can result in severe liver disease, including fatal cirrhosis in newborn infants. Although much is known about the clinical pathology of AAT deficiency, researchers are just beginning to characterize environmental, occupational, and genetic modifiers affecting the onset and progression of diseases related to AAT deficiency. On 19 August 2002, a group of basic scientists, clinicians, environmental health researchers, and public interest groups gathered at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, to discuss ongoing research on these topics. The goals of this workshop were to a) assess the present state of knowledge regarding environmental and occupational risk factors contributing to AAT deficiency morbidity and mortality, b) define future research needs in this area, and c) explore collaborative opportunities to advance understanding of risk factors affecting the progression of AAT deficiency-related disease. Participants agreed that new research initiatives in these areas represent an opportunity to benefit both basic science, through enhanced understanding of gene-environment interaction, and the AAT deficiency patient community, through innovative new approaches to disease management and treatment.
PMCID: PMC1241718  PMID: 14594626
21.  CD28 costimulation independence of target organ versus circulating memory antigen-specific CD4+ T cells 
Journal of Clinical Investigation  2003;112(5):776-784.
T cell receptor engagement with CD28 costimulation is generally required for naive T cell activation, whereas reactivation of memory cells is less dependent on CD28 costimulation. We studied this process in chronic beryllium disease, in which the frequency of antigen-specific CD4+ T cells in the lung is large and circulating antigen-specific cells are also detectable. In the lung, a large fraction of CD4+ T cells stopped expressing CD28 mRNA and protein, and this change in phenotype correlated with lung inflammation. In the presence of concentrations of CTLA-4Ig that inhibited the CD28-B7 interaction, beryllium-specific CD4+ T cells in lung were still able to proliferate and secrete IFN-γ in response to beryllium in culture. This functional independence of CD28 costimulation included lung CD28+ effector cells. Although lung CD4+CD28– cells retained the ability to secrete Th1-type cytokines in response to beryllium, they showed less proliferative capacity and were more susceptible to cell death compared with CD28+ T cells. In contrast to lung cells, inhibition of the CD28-B7 interaction markedly reduced responses of beryllium-specific T cells in blood. Taken together, these findings suggest transition within memory CD4+ T cells from CD28 dependence in central memory cells to functional independence and then loss of CD28 expression in effector cells.
doi:10.1172/JCI200318317
PMCID: PMC182206  PMID: 12952926
22.  Target organ localization of memory CD4+ T cells in patients with chronic beryllium disease 
The Journal of Clinical Investigation  2002;110(10):1473-1482.
Chronic beryllium disease (CBD) is caused by exposure to beryllium in the workplace, and it remains an important public health concern. Evidence suggests that CD4+ T cells play a critical role in the development of this disease. Using intracellular cytokine staining, we found that the frequency of beryllium-specific CD4+ T cells in the lungs (bronchoalveolar lavage) of 12 CBD patients ranged from 1.4% to 29% (mean 17.8%), and these T cells expressed a Th1-type phenotype in response to beryllium sulfate (BeSO4). Few, if any, beryllium-specific CD8+ T cells were identified. In contrast, the frequency of beryllium-responsive CD4+ T cells in the blood of these subjects ranged from undetectable to 1 in 500. No correlation was observed between the frequency of beryllium-responsive bronchoalveolar lavage (BAL) CD4+ T cells as detected by intracellular staining and lymphocyte proliferation in culture after BeSO4 exposure. Staining for surface marker expression showed that nearly all BAL T cells exhibit an effector memory cell phenotype. These results demonstrate a dramatically high frequency and compartmentalization of antigen-specific effector memory CD4+ cells in the lungs of CBD patients. These studies provide insight into the phenotypic and functional characteristics of antigen-specific T cells invading other inaccessible target organs in human disease.
doi:10.1172/JCI15846
PMCID: PMC151812  PMID: 12438445
23.  Implementation of a Worksite Wellness Program Targeting Small Businesses 
Objective:
To assess small business adoption and need for a worksite wellness program in a longitudinal study of health risks, productivity, workers' compensation rates, and claims costs.
Methods:
Health risk assessment data from 6507 employees in 260 companies were examined. Employer and employee data are reported as frequencies, with means and standard deviations reported when applicable.
Results:
Of the 260 companies enrolled in the health risk management program, 71% continued more than 1 year, with 97% reporting that worker wellness improves worker safety. Of 6507 participating employees, 34.3% were overweight and 25.6% obese. Approximately one in five participants reported depression. Potentially modifiable conditions affecting 15% or more of enrollees include chronic fatigue, sleeping problems, headaches, arthritis, hypercholesterolemia, and hypertension.
Conclusions:
Small businesses are a suitable target for the introduction of health promotion programs.
doi:10.1097/JOM.0000000000000279
PMCID: PMC4274320  PMID: 25563536

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