Diesel effects on human health: a question of stress?
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Air Pollutants↗
Biomedical subjects
D Diaz-Sanchez
Publications and source records attributed to D Diaz-Sanchez.
Secondhand smoke induces allergic sensitization in mice.
Epidemiological studies have suggested increased prevalence of atopy in children of maternal smokers. Although secondhand smoke or environmental tobacco smoke (ETS) has been shown to augment allergic responses, its role in atopic sensitization is still controversial. We studied whether ETS could initiate a Th2 response and thus induce primary allergic sensitization. Mice were exposed for 10 consecutive days to either 1% aerosolized OVA, ETS (5 cigarettes), or both ETS and OVA. C57BL/6 mice receiving both ETS and OVA developed OVA-specific IgE and IgG1, 12, 14, and 25 days after the initial exposure, whereas those receiving OVA alone did not. Thirty days after the initial challenge (20 days after its completion), mice were re-exposed to OVA. Bronchoalveolar lavage performed 24 h later revealed an influx of eosinophils in the group initially challenged with both ETS and OVA, but not in those exposed to ETS alone or OVA alone. Increases in IL-5, GM-CSF, and IL-2 were observed in bronchoalveolar lavage from this OVA/ETS-exposed group, whereas IFN-gamma levels were significantly inhibited. These results suggest that ETS can induce allergic sensitization to a normally harmless Ag, and they may explain why secondhand smoke is a major risk factor for the development of allergy in children.
Allergens↗
The role of particulate pollutants in pulmonary inflammation and asthma: evidence for the involvement of organic chemicals and oxidative stress.
We review the literature indicating that the adverse health effects of ambient particulate matter involve the generation of oxidative stress and inflammation, as well as immunomodulating effects by particle-associated chemicals. We discuss evidence that diesel exhaust particle organic extracts induce reactive oxygen species in macrophages and bronchial epithelial cells, two key cell types targeted by particulate matter in the lung. Reactive oxygen species activate the promoters of cytokines and chemokines involved in allergic inflammation through activator protein-1 and nuclear factor- kappaB signaling pathways, which may explain exacerbation of allergic inflammation. Organic diesel exhaust particle chemicals also induce apoptosis and necrosis in bronchial epithelial cells via a mitochondrial pathway. This may be responsible for epithelial shedding and bronchial hyperreactivity in asthma.
Asthma↗
Diesel exhaust as a model xenobiotic in allergic inflammation.
We investigated the effects of diesel exhaust particulates on the human allergic response using in vivo human nasal challenges. Diesel particles and phenanthrene, one of their constituent polyaromatic hydrocarbons, were shown to enhance total allergic antibody (IgE) production, enhance allergen-specific IgE in the presence of allergen, and induce sensitization to a neoantigen.
Animals↗
In vivo nasal challenge with diesel exhaust particles enhances expression of the CC chemokines rantes, MIP-1alpha, and MCP-3 in humans.
Diesel exhaust particles (DEP) enhance allergic inflammation by increasing in vivo IgE and cytokine production in the human upper respiratory mucosa. CC chemokines have been shown to play an important role in inflammation. We examined whether DEP could alter the production of CC chemokines by cells residing in the human nasal mucosa. At both 6 and 24 h following intranasal DEP challenge, the levels of nasal RANTES, MIP-1alpha, and MCP-3 were significantly elevated compared to baseline. In contrast, DEP did not enhance levels of Eotaxin at any time, demonstrating that the action of DEP was not simply a global effect on all CC chemokines. Challenge with saline resulted in no significant change in expression of any chemokine at any time. Challenge with DEP also resulted in an increase in total cell counts in nasal lavage fluids. Increases in lymphocyte, monocyte/macrophage, and neutrophil cells were observed but there was no change in eosinophil cell numbers. In contrast, there was a significant enhancement of ECP protein levels in washes performed 6 to 24 h after DEP challenge. Elevated specific nasal chemokine expression following exposure to DEP likely participates in the inflammation, cellular infiltration, and increase in IgE observed in the absence of allergen.
Adult↗
Pollution and the immune response: atopic diseases--are we too dirty or too clean?
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Bronchial Hyperreactivity↗
Diesel exhaust particles directly induce activated mast cells to degranulate and increase histamine levels and symptom severity.
BACKGROUND: The ability of combustion products, such as diesel exhaust particles (DEPs), to modulate the immune system has now been firmly established. DEPs can synergize with allergen at the human upper respiratory mucosa to enhance allergen-specific IgE production, initiate a T(H)2 cytokine environment, and even promote primary allergic sensitization. Experiments suggest that these effects result from the initial activation of mast cells to produce IL-4. OBJECTIVE: We sought to demonstrate that in vivo mast cell activation by DEPs plus allergen will also affect the release of classic mast cell mediators and consequently enhance the immediate-phase response. METHODS: Dust mite-sensitive subjects were challenged intranasally with allergen, and symptom scores and histamine levels in nasal wash samples were compared after prechallenge with 0.3 mg of DEPs. RESULTS: If the subjects were first sprayed with DEPs, mean symptom scores rose from 3.7 to 9.9; additionally, only one fifth of the amount of intranasal dust mite allergen was required to induce clinical symptoms. DEPs alone had no effect. The changes in symptoms correlated with histamine levels measured in nasal lavage specimens from these subjects. Although challenge with DEPs alone did not induce histamine release, challenge with both DEPs and allergen resulted in 3-fold higher histamine concentrations than those seen with allergen alone. In contrast, carbon black particles (elemental carbon devoid of chemicals) had no effect. The role of chemicals was confirmed because degranulation of a murine mast cell line by FcepsilonRI cross-linking was increased significantly (by 72%) by the soluble organic chemicals extracted from DEPs. CONCLUSIONS: Overall, these results suggest that exposure to DEPs can enhance the severity of clinical symptoms to allergen by enhancing mast cell degranulation.
Adult↗
Early IL-4 production driving Th2 differentiation in a human in vivo allergic model is mast cell derived.
IL-4 is central to the formation of IgE and the development of Th2 effector cells, both key features of an allergic response. We have examined IL-4 production early in the formation of an allergic response by using a previously established human in vivo model of allergic rhinitis where allergic subjects are challenged internasally with allergen and the particulate pollutant diesel exhaust particles (DEP). This model is characterized by enhanced IgE production and deviation to a Th2-type cytokine profile in nasal lavage fluid from these subjects. In this model, IL-4 protein and IL-4-positive cells could first be detected 4 h after challenge and maximal production was observed after 18 h. Two-color flow cytometric analysis for the detection of intracellular IL-4 and surface markers was performed on nasal cells recovered 4 h after challenge. At this time, CD117(+) (c-kit+) cells constituted between 65 and 100% of the IL-4(+) cells, while 0-12% of the IL-4(+) cells were CD3 positive. No IL-4(+) CD19/CD20(+) or IL-4(+) CD56(+) cells were detected at 4 h. As the allergic response progressed the primary source of IL-4 changed. At the peak of IL-4 production, 18 h after challenge, CD3(+) comprised the majority of cells staining for intracellular IL-4 (73 to 100%). Thus we show an initial role for cells of the mast cell/basophil lineage residing in the nasal mucosa in the initial production of IL-4, which frames the subsequent immune response by expanding the repertoire of TH2 cytokine-producing cells in the local microvicinity.
Adult↗
Effect of topical fluticasone propionate on the mucosal allergic response induced by ragweed allergen and diesel exhaust particle challenge.
Glucocorticoids block the local allergic response in a variety of ways. However, studies have also shown that glucocorticoids increase in vitro IgE synthesis and that treatment with corticosteroids may result in elevated serum IgE concentrations. The ability of topical glucocorticoids to modulate the mucosal IgE response has not been elucidated. We studied the effect of topical steroid (fluticasone propionate) treatment on the local allergic antibody response induced by challenge with either allergen or diesel exhaust particles (DEP). A parallel group study was performed with ragweed-allergic subjects, each subject serving as his/her own control. Nasal provocation challenges were performed on three groups. One group received ragweed allergen, another diesel exhaust particles, and the third saline. The study was repeated following 1 week of treatment with intranasal fluticasone propionate. Each group received the same challenge as before. The concentrations of total immunoglobulins (IgE, IgG, IgA, and IgM), anti-ragweed antibody, IgE- and IgA-secreting cells, epsilon (epsilon) mRNA, and cytokine mRNAs (IL-2, -4, -5, -6, TNF-alpha, INF-gamma) were measured in nasal lavages performed before and at various time points after challenge. Treatment with fluticasone propionate for 7 days caused a decrease in the concentrations of nasal IgE protein, IgE-producing cells, total epsilon mRNA, and all the cytokine mRNAs tested. Furthermore, treatment with fluticasone propionate inhibited the production of allergen-specific IgE and cytokine mRNAs following challenge with ragweed antigen. However, fluticasone treatment did not significantly inhibit the enhancement of mucosal IgE production or cytokine mRNAs observed following nasal challenge with DEP. These results indicate that 1-week treatment with topical fluticasone propionate was effective in blocking local effects of allergen exposure but was unable to inhibit the adjuvant-like effect of DEP.
Administration, Intranasal↗
Nasal challenge with diesel exhaust particles can induce sensitization to a neoallergen in the human mucosa.
BACKGROUND: Diesel exhaust particles (DEPs) increase in vivo IgE and cytokine production at the human upper respiratory mucosa, exacerbating allergic inflammation. OBJECTIVE: We examined the ability of DEP exposure to lead to primary sensitization of humans by driving a de novo mucosal IgE response to a neoantigen, keyhole limpet hemocyanin (KLH). METHODS: Ten atopic subjects were given an initial nasal immunization with 1 mg of KLH followed by 2 biweekly nasal challenges with 100 microg of KLH. Identical nasal KLH immunization was then performed on 15 different atopic subjects, but DEPs were administered 24 hours before each KLH exposure. RESULTS: Exposure to KLH alone led to the generation of an anti-KLH IgG and IgA humoral response, which was detected in nasal fluid samples. No anti-KLH IgE appeared in any subjects. In contrast, when challenged with KLH preceded by DEPs, 9 of the 15 subjects produced anti-KLH-specific IgE. KLH-specific IgG and IgA at levels similar to that seen with KLH alone could also be detected. Subjects who received DEPs and KLH had significantly increased IL-4, but not IFN-gamma, levels in nasal lavage fluid, whereas these levels were unchanged in subjects receiving KLH alone. CONCLUSION: These studies demonstrate that DEPs can act as mucosal adjuvants to a de novo IgE response and may increase allergic sensitization.
Adjuvants, Immunologic↗
Enhancement of allergic inflammation by the interaction between diesel exhaust particles and the immune system.
There is growing evidence that fossil fuel combustion products act as adjuvants in the immune system and may lead to enhancement of allergic inflammation. Through this mechanism, particulate air pollutants may be an important contributor to the increased prevalence and morbidity of asthma and allergic rhinitis. In this communication we focus on the role of diesel exhaust particles (DEPs) in skewing the immune response towards IgE production and induction of allergic inflammation. We review experimental studies in animals and humans showing that DEPs enhance IgE production by a variety of mechanisms, including effects on cytokine and chemokine production, as well as activation of macrophages and other mucosal cell types. We discuss metabolic and cellular activation pathways linked to chemicals such as polycyclic aromatic hydrocarbons contained in DEPs and demonstrate how these molecular events may impact cytokine, chemokine, and accessory molecule expression in the immune system.
Animals↗
Combined nasal challenge with diesel exhaust particles and allergen induces In vivo IgE isotype switching.
In this study we undertook to provide evidence for local in vivo isotype switching to IgE following nasal challenges. Detection of deleted switch circular DNA (switch circles) by a novel nested polymerase chain reaction-based approach was employed as definitive molecular evidence of Ig isotype switching. Nasal challenge in humans with diesel exhaust particles (DEP) plus ragweed antigen has been shown to enhance local IgE production, stimulate local cytokine production, and markedly increase mucosal IgE antibody to ragweed. Four days after combined intranasal DEP plus ragweed challenge, we detected and characterized clones of deleted switch circular DNA (Sepsilon /Smu) representing switching from mu to epsilon from nasal lavage cells. No switch circular DNA was detected in nasal lavage cells following challenge with DEP alone nor with ragweed allergen alone. These results indicate that the combination of mucosal stimulation with DEP and ragweed allergen is capable of driving in vivo isotype switching to IgE in humans with ragweed allergy. These results are the first direct demonstration of in vivo IgE isotype switching in humans.
Adult↗
Combined diesel exhaust particulate and ragweed allergen challenge markedly enhances human in vivo nasal ragweed-specific IgE and skews cytokine production to a T helper cell 2-type pattern.
We have previously shown that in vivo nasal challenge with diesel exhaust particles (DEP) induces both quantitative and qualitative changes in local IgE production and stimulates generalized local cytokine production. We have now investigated the combined effects of intranasal challenge with DEP plus ragweed allergen on local humoral immune responses. We collected nasal lavages from ragweed sensitized subjects at different times after nasal challenge. As compared with challenge with ragweed alone, challenge with both DEP and ragweed induced markedly higher ragweed-specific IgE but not total IgE levels or IgE-secreting cell numbers. Total and specific IgG4 levels also were enhanced, while total IgG levels were not. Synergy was also observed between the DEP and ragweed in altering the profile of epsilon mRNAs generated by alternative splicing, mRNAs that code for different expressed IgE proteins. Intranasal challenge with ragweed alone induced inconsistent and low levels of mucosal cytokine mRNAs. In contrast, challenge with both ragweed plus DEP resulted in decreased expression for Th1-type cytokines (IFN-gamma and IL-2) but elevated expression of mRNA for other cytokines (IL-4, -5, IL-6, IL-10, IL-13). This synergy between DEP and natural allergen exposure is suggested as a key feature in increasing allergen-induced respiratory allergic disease.
Adult↗
The organic component of diesel exhaust particles and phenanthrene, a major polyaromatic hydrocarbon constituent, enhances IgE production by IgE-secreting EBV-transformed human B cells in vitro.
Suspended airborne particulate matter such as diesel exhaust particles (DEP) have been implicated in the increased incidence of respiratory allergic diseases that has occurred over the past century. Studies in vitro and in vivo have shown that DEP may enhance allergic antibody (IgE) expression. DEP contain a wide spectrum of polycyclic aromatic hydrocarbons (PAH) that have been reported to have direct effects on the immune system, including the modulation of IgE production using various human and murine cell populations. We investigated the effects of the organic extract of DEP (PAH-DEP) and particularly, phenanthrene, a major component of DEP, in vitro on IgE production by 2C4/F3, a human Epstein-Barr virus transformed isotype switched, IgE producing B cell line. Phenanthrene consistently enhanced 2C4/F3 IgE production two- to threefold. This in vitro enhancement was associated with an increased expression of total IgE mRNA. Furthermore, the pattern of mRNA's coding for distinct isoforms of the epsilon chain was altered by both DEP-PAH and phenanthrene. While phenanthrene increased the level of productive epsilon transcripts, it did not increase epsilon germ line transcription. These effects were not due to an alteration of the cell cycle. Unstimulated 2C4/F3 cells contained detectable mRNA for IL6, IL10, TNF-alpha, and interestingly IL4; however, addition of PAH-DEP or phenanthrene did not significantly alter the level of these cytokines and thus did not appear to account for our findings. Thus, we have used our in vitro model to dissect the mechanism of DEP-PAH on IgE production in postswitch IgE producing cells and shown that phenanthrene, an important component in DEP and other pollutants, can act in a similar manner.
B-Lymphocytes↗
Regulation of the expression of distinct human secreted IgE proteins produced by alternative RNA splicing.
The use of splice sites for human epsilon mRNAs is tightly regulated, as the potential number of splice products far exceeds that actually produced. Our studies show that use of the epsilon alternative splices is regulated by a limited number of stimuli, and the relative production of the epsilon mRNA variants follows a developmental profile. In addition, we have found disease-related changes in the pattern of epsilon mRNA variants encoding distinctive IgE isoforms. Analysis of the biological activity of expressed recombinant IgE proteins and measurement of their levels in disease conditions will directly answer questions as to the biological relevance of the changes observed in epsilon mRNA splicing. This information will then be able to be used for rational therapeutic design interventions in IgE-mediated disorders.
Alternative Splicing↗
The role of diesel exhaust particles and their associated polyaromatic hydrocarbons in the induction of allergic airway disease.
The increase in allergic airway disease has paralleled the increase in the use of fossil fuels. Studies were undertaken to examine whether extracts of polyaromatic hydrocarbons (PAH) from diesel exhaust particles (DEP) (PAH-DEP) acted as mucosal adjuvants to help initiate or enhance immunoglobulin E (IgE) production in response to common inhaled allergens. In vitro studies demonstrated that PAH-DEP enhanced IgE production by tonsillar B-cells in the presence of interleukin-4 (IL-4) and CD40 monoclonal antibody, and altered the nature of the IgE produced, i.e. a decrease in the CH4'-CHe5 variant, a marker for differentiation of IgE-producing B-cells, and an increase in the M2' variant. In vivo nasal provocation studies using 0.30 mg DEP in saline also showed enhanced IgE production in the human upper respiratory mucosa, accompanied by a reduced CH4'-CHe5 mRNA splice variant. The effects of DEP were also isotype-specific, with no effect on IgG, IgA, IgM, or albumin, but it produced a small increase in the IgG4 subclass. The ability of DEP to act as an adjuvant to the ragweed allergen Amb a I was examined by nasal provocation in ragweed allergic subjects using 0.3 mg DEP, Amb a I, or both. Although allergen and DEP each enhanced ragweed-specific IgE, DEP plus allergen promoted a 16-times greater antigen-specific IgE production. Nasal challenge with DEP also influenced cytokine production. Ragweed challenge resulted in a weak response, DEP challenge caused a strong but non-specific response, while allergen plus DEP caused a significant increase in the expression of mRNA for TH0 and TH2-type cytokines (IL-4, IL-5, IL-6, IL-10, IL-13) with a pronounced inhibitory effect on IFN-gamma gene expression. These studies suggest that DEP can enhance B-cell differentiation, and by initiating and elevating IgE production, may play an important role in the increased incidence of allergic airway disease.
Animals↗
Enhanced nasal cytokine production in human beings after in vivo challenge with diesel exhaust particles.
BACKGROUND: Diesel exhaust particles (DEPs) have been implicated in the worldwide increased incidence of allergic airway disorders over the past century. They can enhance in vivo IgE production in the human upper respiratory mucosa. OBJECTIVES: The study was carried out to determine whether DEPs can alter the production of cytokines by cells residing in the nasal mucosa. METHODS: Eighteen hours after intranasal challenge with saline solution or DEPs, we studied the levels of messenger RNA for cytokines in nasal lavage cells and the number of subjects in whom cytokine mRNA could be detected. RESULTS: Before challenge, most subjects' nasal lavage cells had detectable levels of only interferon-gamma, Il-2, and IL-13 mRNA. After challenge, the cells produced readily detectable mRNA for IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, and interferon-gamma. In addition, the levels of all cytokine mRNA increased. Enhanced IL-4 protein was also present in the postchallenge lavage fluid. Although the cells in nasal lavage before and after challenge do not necessarily represent the same cells either in number or type, the broad increase in cytokine production was not simply the result of an increase in T cells recovered in the lavage fluid. CONCLUSION: An increase in nasal cytokine expression after exposure to DEPs can be predicted to contribute to enhanced local IgE production and thus play a role in the increased incidence of respiratory allergic disease.
Adult↗
The contrasting effects of CD8+ T cells on primary, established and Nippostrongylus brasiliensis-induced IgE responses.
Recent data have indicated that CD8+ T cells suppress rodent IgE responses. In this study we investigated the effect of CD8+ T cells on primary and established IgE responses in euthymic and athymic nude rats. Euthymic PVG rats were depleted of CD8+ T cells by intraperitoneal injection of a CD8-specific monoclonal antibody (OX8), which resulted in an apparent loss of 92% of splenic and 98% of peripheral blood CD8+ T cells. The CD8+ T-cell depleted animals failed to mount a significant IgE response compared with control animals given an irrelevant monoclonal antibody (OX21). Furthermore, PVG nude rats reconstituted with purified CD4+ thoracic duct lymphocytes (TDL) alone failed to mount a significant IgE response, while animals given unfractionated TDL (containing CD4+ and CD8+ T cells) did. Depletion of CD8+ T cells 7 days prior to immunization and subsequent reconstitution at the time of immunization restored the IgE response. In contrast, removal of CD8+ T cells 1 month after induction of IgE by immunization with ovalbumin (OVA) and ricin prolonged the IgE response. In all cases IgG antibody responses were unaffected by the presence or absence of CD8+ T cells. This study shows that some CD8+ T cells are required for IgE, but not IgG, production to soluble antigen in a primary immune response. However, later in the immune response CD8+ T cells were shown to inhibit IgE production. These effects were apparently restricted to the immune response to soluble antigen, as Hooded Lister rats infected with 9000 larvae of the nematode Nippostrongylus brasiliensis produced high sustained levels of circulating IgE, in excess of 10 micrograms/ml, regardless of whether CD8+ T cells were depleted before or 1 month after infection.
Animals↗