The Effect of Particles on Allergic Immune Responses

Berit Granum,1 and Martinus Løvik

Department of Environmental Medicine, National Institute of Public Health, P.O. Box 4404 Nydalen, N-0403 Oslo, Norway

Received February 26, 2001; accepted September 19, 2001


    INTRODUCTION
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 INTRODUCTION
 Particulate Air Pollution
 The Effect of Particles...
 The Effect of Particle...
 The Effect of the...
 Physical Characteristics of...
 Particles and...
 The Importance of the...
 Concluding Remarks
 REFERENCES
 
In recent decades, an increased prevalence of allergic conditions has been observed in developed countries (Howarth, 1998Go). The development of allergic diseases depends upon both genetic predisposition and the environment. Genetic alterations, however, are not sufficient to explain the observed increase in the prevalence of allergy and asthma since these changes have occurred rapidly, over only a few decades, in very large outbred populations (Hopkin, 1997Go). Thus, environmental factors appear to play an important role. Both epidemiological and laboratory studies have shown that airborne pollutants, such as particulate matter, sulfur dioxide, nitrogen dioxide, and ozone, may be capable of causing adverse effects on respiratory health (reviewed in Anderson, 1997Go; Devalia et al., 1994Go; Jörres et al., 1996Go: Molfino et al., 1991Go; Nicolai, 1997Go; Nightingale et al., 1999Go; Siegel et al., 1997Go: Studnicka et al., 1997Go; Timonen and Pekkanen, 1997Go). In this review, we will limit our discussion to particles. However, in the real-life situation, environmental gases and particles are found in a mixture, and there are studies demonstrating that there may be a close interaction between different pollutants. These interactions may modulate the effect from the single pollution component (Adamson et al., 1999Go; reviewed in Gerrity, 1995Go and Schlesinger, 1995Go).

Experimental studies investigating the effect of particles on allergy-related immune responses have used different types of material: (1) mixtures of different particle types (e.g., total suspended particulate matter; Li et al., 1997Go; Ormstad, 2000Go; Takafuji et al., 1989Go); (2) single particle suspensions (natural or model particles; Diaz-Sanchez et al., 1999Go; Fujieda et al., 1998Go; Gilmour et al., 2000Go; Granum et al., 2001aGo; Imrich et al., 2000Go; Løvik et al., 1997Go; van Zijverden et al., 2000Go); or (3) solutions containing chemical substances often found adsorbed onto environmental particles (extracts of a given particle type or chemical solutions containing one particular chemical; Bömmel et al., 2000Go; Dreher et al., 1997Go; Fahy et al., 2000Go; Gilmour et al., 2000Go; Lambert et al., 2000Go; Takenaka et al., 1995Go; Tsien et al., 1997Go).

The main purpose of this article is to review studies on the effect of the particle core per se (that is the particle by itself), physical particle properties (e.g., size, number, surface area, dose-weight), and particle-bound chemical substances and metals on allergy-related immune responses. Allergy-related immune responses are also called Th2 (T helper 2) dependent, in contrast to Th1 dependent responses. The effect of particles on sensitization and provocation phases will be discussed, and the influence of the genetic background for the effect of particles will be reviewed. Some possible mechanisms behind the effect of particles will be considered briefly. However, a detailed discussion on this subject is beyond the scope of this article.


    Particulate Air Pollution
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 INTRODUCTION
 Particulate Air Pollution
 The Effect of Particles...
 The Effect of Particle...
 The Effect of the...
 Physical Characteristics of...
 Particles and...
 The Importance of the...
 Concluding Remarks
 REFERENCES
 
Airborne particulate matter consists of both solid particles and liquid droplets of different sizes, compositions, and origins. They can range from small molecules less than 0.001 µm to pollens and spores ranging from 2 to 50 µm, and very large visible dust particles in the range of 1000 µm (reviewed in Salvaggio, 1994Go). Thus, particles may be defined as any small fragments of material or droplets, either organic or inorganic, viable or nonviable. Traditionally, the most frequently used definition of particulate matter (PM) is PM10 (particles with an aerodynamic diameter less than 10 µm). These particles are often referred to as inhalable particles. There are, however, an increasing number of studies indicating that the level of PM2.5 (< 2.5 µm in diameter) is more closely related to adverse health effects and mortality than PM10 or PM2.5–10 (2.5–10 µm in diameter; Peters et al., 1997Go; Schwartz et al., 1999Go; Schwartz and Neas, 2000Go), and today the use of measurements of the PM2.5 fraction is increasing. The PM0.1 fraction (< 0.1 µm in diameter; ultrafine particles) is rapidly getting more attention (reviewed in Oberdörster, 2000Go; Penttinen et al., 2001Go; Wichmann and Peters, 2000Go). However, the use of PM0.1 measurements is still in an early research stage.

Environmental PM is generated from a wide range of natural and man-made sources, and the composition of the particulate air pollution in one area may vary enormously from the composition in another area. In developed countries, however, the PM2.5 fraction is reported to consist mainly of carbon particles that are mostly generated from human activities such as combustion of wood and fossil fuels, and secondary particles generated by chemical reactions in the atmosphere (acid condensates, sulfates, nitrates; Ormstad et al., 1997Go; Seaton et al., 1995Go). The PM2.5–10 fraction predominantly consists of inorganic minerals, such as wind-blown dust from soil and sand (reviewed in Williams, 1999Go). Table 1Go shows the estimated contribution of the main sources of PM10, PM2.5, and PM0.1 emissions in Europe in 1993 (excluding the former Soviet Union; reviewed in Holman, 1999Go). Important sources of PM2.5 and PM0.1 are power generation plants, road traffic, and ships. Two particle types generated from these sources are residual oil fly ash (ROFA) and diesel exhaust particles (DEP). Both ROFA and DEP consist of a carbonaceous particle core. High proportions of water-soluble sulfate and metals, especially vanadium, nickel, and iron are adsorbed to the carbon core of ROFA (Dreher et al., 1997Go), whereas components most often found on the carbon core of DEP are elemental and organic carbon species (e.g., polyaromatic hydrocarbons; Løvik et al., 1997Go; reviewed in Nel et al., 1998Go). DEP will vary in composition depending on engine, engine load, and type of diesel fuel, and the different DEP may show variations in their biological effects (Sjögren et al., 1996Go; van Zijverden, 2001Go). We will, however, for the simplicity of the discussion regard DEP as one entity.


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TABLE 1 Estimated Contribution of the Main Sources of PM10, PM2.5, and PM0.1 Emissions in Europe in 1993
 
In addition to adsorbed chemical substances, environmental carbon particles are shown to carry common allergens on their surface (Knox et al., 1997Go; Ormstad, 2000Go). Furthermore, endotoxin is found to be associated with ambient air particles (Imrich et al., 2000Go).


    The Effect of Particles Per Se
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 INTRODUCTION
 Particulate Air Pollution
 The Effect of Particles...
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 Particles and...
 The Importance of the...
 Concluding Remarks
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There are few studies investigating the effect of particles per se, that is the physical particle core, on specific IgE production and allergic immune responses. Such studies require the use of synthetic model particles or natural particles free of adsorbed substances. One aim of the research in our laboratory lately has been to explore the effect of the particle core on the specific IgE antibody production (adjuvant effect) by using well-characterized model particles such as polystyrene (PSP), amorphous silica, tetrafluoroethylen (teflon), and titanium dioxide (TiO2) (Granum et al., 2001aGo,bGo). After two intraperitoneal (ip) injections with the model allergen chicken ovalbumin (OVA) plus particles into naïve NIH/Ola mice (i.e., mice not presensitized with OVA), we observed no qualitative differences in the adjuvant capacity of the different particles. All particle types resulted in mixed Th1/Th2-like responses (increased serum levels of OVA-specific Th2 dependent IgE antibodies and Th1 dependent IgG2a antibodies compared to mice given OVA alone; Granum et al., 2001aGo). Similar effects were found after intranasal or intratracheal instillation with OVA plus PSP or silica particles to naïve NIH/Ola mice (Granum et al., 2001aGo,bGo). In a study by Kurup et al. (1994), BALB/c mice were exposed intranasally with soluble Aspergillus antigen or Aspergillus antigen coupled to PSP. Mice exposed to the particulate antigens showed a stronger allergy-related Th2-like response than mice exposed to the soluble antigen, as evidenced by higher IgE levels in sera, more eosinophils in the blood, and higher levels of cytokine production from lung and spleen cells. By using synthetic particles, the studies cited above indicate that particles per se can exert an adjuvant effect on antibody responses independent of adsorbed chemical substances found on environmental particles.

There are, in addition, several studies that have investigated the effect of particles on responses other than the adjuvant effect on antibody responses, such as inflammatory responses (Driscoll et al., 1997aGo; Finkelstein et al., 1997Go; Granum et al., 2001bGo; Løvik et al., 1997Go; Oberdörster et al., 1992Go). PSP or carbon black (CB) particles given subcutaneously (sc) in the hind footpad to mice (NIH/Ola and BALB/cA, respectively) were found to cause increased weight, cell numbers, and proliferation indexes in the draining popliteal lymph node (Granum et al., 2001bGo; Løvik et al., 1997Go). These results support the notion that particles per se may elicit cellular responses. In lung models, alveolar macrophages have been found to ingest both opsonized (antibody coated) and unopsonized latex particles rapidly and indiscriminately (Kobzik et al., 1993Go). Kobzik et al. reported a marked induction of tumor necrosis factor (TNF) release after uptake of opsonized but not after uptake of unopsonized particles in vitro. This is to be expected since one of the main functions of alveolar macrophages is clearance of numerous inert and innocuous particles without triggering a substantial proinflammatory response, whereas uptake of opsonized particles indicates the presence of foreign organic material and creates a "danger" signal (Kobzik, 1995Go). However, in other studies, alveolar macrophages have been shown to produce inflammatory mediators after exposure to unopsonized model particles (reviewed in Driscoll et al., 1997bGo; Goldsmith et al., 1998Go). These studies show that after internalization of different types of particles, alveolar macrophages and epithelial cells are activated to produce cytokines that are important for the recruitment of lymphocytes and inflammatory cells (reviewed in Driscoll et al., 1997bGo; Finkelstein et al., 1997Go). Several model particles, including ultrafine CB, TiO2, and latex particles, have also been shown to induce inflammation and oxidative stress (Donaldson et al., 2000Go; reviewed in Driscoll et al., 1997bGo; Stone et al., 2000Go). Oxidative damage in the lung may contribute to increased epithelial permeability. In turn, an increased number of particles may enter the interstitium, which is hypothesized to be crucial for elicitation of inflammatory responses (reviewed in Driscoll et al., 1997bGo; Oberdörster et al., 1992Go).

Together, these studies give substantial evidence that particles per se, without release of chemical components, may induce inflammatory responses in the lung. The inflammatory response may be an important mechanism behind the adjuvant effect exerted on antibody production by particles, in that a large number of antigen-presenting and inflammatory cells will be present at the time and place of allergen entry.


    The Effect of Particle-Associated Chemical Substances
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 INTRODUCTION
 Particulate Air Pollution
 The Effect of Particles...
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 Particles and...
 The Importance of the...
 Concluding Remarks
 REFERENCES
 
There are several studies that support the notion that adsorbed chemical substances (including metals) often found on environmental particles can increase allergy-related immune responses. ROFA and DEP represent two important types of environmental pollutants, and the effect of metals found on ROFA and polyaromatic hydrocarbons (PAH) found on DEP have been studied by several investigators (Dreher et al., 1997Go; Fahy et al., 1999Go; Heo et al., 2001Go; Lambert et al., 2000Go; Takenaka et al., 1995Go; Tsien et al., 1997Go). In a study by Lambert et al. (2000), Brown Norway rats were given an intratracheal instillation with ROFA or equivalent concentrations of nickel, iron, or vanadium sulfates. Three days later the rats were sensitized by two intratracheal instillations, 24 h apart, with house dust mite allergen (Der f1). Two weeks after sensitization, an additional instillation with Der f1 was given. Lambert et al. reported that the various metal sulfates produced similar adjuvant effects to those seen with ROFA, although certain metals appeared to affect different endpoints, nickel strongly enhanced the production of Der f1-specific IgE antibodies, which were sufficient to cause significantly increased antigen-induced bronchoconstriction responses. Iron did not affect the antibody response, lymphocyte proliferation, or the immediate allergic response, but had an effect on the inflammatory component of allergic lung disease (increased eosinophil activation and levels of total protein). After challenge, vanadium gave increased lymphoproliferative responses and increased levels of Der f1-specific IgE antibodies. This study suggests that treatment with ROFA or its metal constituents prior to allergic sensitization may affect the sensitization stage such that following a subsequent allergen challenge, the secondary immune response and lung injury, because of the inflammation, may be significantly increased. The effect of environmental particles on allergic immune responses may dependent on interaction between the physical particle and particle-associated metals. It can, therefore, be argued that test solutions containing only soluble metal constituents will merely give indirect evidence of the effect of the particle-associated metals. However, in an in vitro study by Quay et al. (1998), the production of interleukin-6 (IL-6) from human airway epithelial cells (BEAS-2B) after exposure with ROFA, was inhibited by pretreatment of ROFA with the metal chelator deferoxamine. Similarly, IL-8 production from human lung epithelial cells (A549), stimulated in vitro with coal fly ash, was completely inhibited when the coal fly ash was pretreated with the metal chelator desferrioxamine B (Smith et al., 2000Go). These studies give further evidence for the effect of particle-associated metals.

PAH extracted from DEP and other PAH (e.g., pyrene, phenanthrene), often adsorbed to DEP, have been found to have several effects on allergic immune responses, including upregulation of IL-4 production (Bömmel et al., 2000Go), increased production of IgE (Suzuki et al., 1993Go; Takenaka et al., 1995Go; Tsien et al., 1997Go), and induction of inflammatory responses (Fahy et al., 1999Go; Terada et al., 1997Go).

Finally, it should be mentioned that endotoxin from Gram-negative bacteria is virtually ubiquitous, and can influence inflammatory and adjuvant activity caused by particles (Becker et al., 1996Go; Daniels et al., 2000Go; Monn and Becker, 1999Go; Ning et al., 2000Go). Ning et al. (2000) studied the effect of concentrated air particle suspensions containing trace amounts of endotoxin on inflammatory responses in murine alveolar macrophages. Both water-soluble and solid components of the sampled air particles showed biological activity (induction of TNF-{alpha} and macrophage inflammatory protein-2), although the majority of the biological activity and endotoxin content was associated with the solid particle components. They concluded that there is a synergistic interaction between the trace endotoxin and other proinflammatory components of the particles.


    The Effect of the Particle Core Per Se versus Adsorbed Chemical Substances
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 INTRODUCTION
 Particulate Air Pollution
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The effect from environmental particles on allergy-related immune responses are probably not due to only the particle core or only the adsorbed chemical substances, because both of these components as we have discussed above appear to contribute to the adjuvant effect. Most likely, there is a combined effect between these two factors. Løvik et al. (1997) investigated possible effects of the particle core and adsorbed chemical substances on allergy-related immune responses, by comparing the effect from DEP and CB particles on antibody responses to OVA. CB consists of carbon with only a low amount of adsorbed chemical substances compared to DEP. CB is, therefore, often used as a model particle for the carbon core of DEP. The two particle types used in this study were selected to be closely matched with regard to size and specific surface area. Both DEP and CB given sc together with OVA were reported to have an adjuvant effect on the production of specific IgE in naïve mice. The IgE adjuvant effect of CB was, however, slightly lower than the effect of DEP. Heo et al. (2001) made a similar observation after ip injections of OVA (with or without adjuvant) plus DEP extracts or insoluble DEP (the remaining part of DEP after extraction) to BDF1 mice. Although the DEP organic extract induced a significantly increased production of allergen-specific IgE and IgG1 compared to mice given OVA alone, the adjuvant effect was less than that elicited by the insoluble DEP core. Thus, these two studies indicate that the larger proportion of the adjuvant effect of DEP is associated with the particle core, with an additional contribution from adsorbed chemicals. In another study, naïve BALB/c mice were given a sc injection of TNP-OVA (2,4,6-trinitrophenyl coupled to OVA) plus DEP, CB (about 0.3 µm in diameter), or amorphous silica (1–5 µm in diameter) particles, combined with a challenge with TNP-OVA intranasally 28 days later (van Zijverden et al., 2000Go). In this study, the particles used gave distinctly different response patterns. DEP-treated animals showed a Th2-like response (increased serum levels of TNP-OVA specific IgG1 and IgE), CB-treated mice showed a mixed Th1/Th2-like response (increased serum levels of TNP-OVA specific IgG1, IgG2a, and IgE) and silica-treated mice showed a Th1-like response (increased levels of TNP-OVA specific IgG2a).

Results from the studies we have cited suggest that particles per se have an adjuvant activity in that particles with widely different chemical composition can enhance antibody responses. However, there is evidence that the basic effect from particles per se may be modified or increased by properties of the particle surface, such as adsorbed chemical substances. In this way, the particle per se may act as a general "motor" for antibody production, while chemical substances and possibly other factors (e.g., surface charge, structure, size) may steer the increased response towards a polarized Th1- or Th2-like response.


    Physical Characteristics of Particles
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 INTRODUCTION
 Particulate Air Pollution
 The Effect of Particles...
 The Effect of Particle...
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 Physical Characteristics of...
 Particles and...
 The Importance of the...
 Concluding Remarks
 REFERENCES
 
In a study by Granum et al. (2000a), the effect of different physical particle characteristics was investigated in a series of experiments in which the total dose-weight, particle size (diameter), total particle number, or total surface area of particles was kept constant. Naïve NIH/Ola mice were given two ip injections with OVA plus different doses of PSP. The serum levels of allergen-specific IgE increased with both an increasing number and increasing surface area of PSP, whereas there seemed to be no covariation between the dose-weight and the levels of allergen-specific IgE (Table 2Go). There were no clear associations between the levels of IgE and the size of PSP, but this may be due the relatively small size range of PSP that for technical reasons could be used in this study. The results from this study indicate that the total number and/or total surface area of PSP, rather than the dose-weight, are important parameters for the IgE adjuvant activity from PSP, and possibly for particles in general.


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TABLE 2 Effect of Physical Particle Characteristics of Polystyrene (PSP) on the Production of Allergen-Specific IgE in Mice
 
During inhalation, particle size will influence in what region of the airways the material will be deposited. This has been found to be of some importance in relation to airway allergen delivery (Pauluhn et al., 2000Go), and it is likely to be of importance also for the adjuvant effect of particles. In addition, small particles may be less efficiently transported out of the lungs by the mucociliary escalator, thus increasing their retention time in the lungs (reviewed in Gehr et al., 2000Go). Particle size has also been reported to be important for the translocation and internalization of particles in the lung, since ultrafine TiO2 particles (~ 20 nm in diameter) are shown to penetrate the epithelial barrier to a greater extent than fine TiO2 particles (~ 250 nm in diameter; Oberdörster et al., 1992Go). However, since the ultrafine and fine TiO2 particles, in the cited study, were given on an equal weight basis, it can be argued that the increased interstitial access of ultrafine particles was due to the increased number of particles (Churg et al., 1998Go).

The number of particles reaching the interstitial space of the lung has been reported to be directly proportional to the number of particles applied (Churg et al., 1998Go). A large surface area, on the other hand, may lead to a greater interaction with alveolar cells compared to a smaller surface area, thereby having the potential to elicit stronger cellular responses. The total surface area may also be important if the particles act as mediators of biochemical reactions (reviewed in Fubini, 1997Go). In addition, a large surface area may have a greater capacity to adsorb chemical substances, allergens, endotoxin, and other biological components than a small surface area. However, the relative contribution from different particle properties, such as the number and surface area of particles, is difficult to assess since they are closely related to each other.

Particle doses are usually expressed in terms of particle mass-weight per volume units of air (µg/m3, mg/m3). However, PM is a very heterogeneous mass consisting of particles varying in size, shape, and specific weight. In a study in Erfurt, Germany, the number and mass concentration of PM was sampled during the winter season, 1991–1992 (Table 3Go; data from Peters et al., 1997Go). The overall number of particles ranging from 0.01 to 2.5 µm was dominated by the number of ultrafine particles (< 0.1 µm in diameter), whereas most of the particle mass was found to consist of particles between 0.1 and 0.5 µm. In the cited study, adverse respiratory effects were associated with the number of the ultrafine particles. Similar findings were made in a study in Helsinki, Finland, in that the daily mean number concentration of particles was dominated by the ultrafine particles. The daily mean number concentration of particles, but not particle mass (PM10, PM2.5–10, PM2.5, and PM1, < 1 µm in diameter), was associated with daily deviations in peak expiratory flow. Particle number concentrations of ultrafine particles had the strongest effect (Penttinen et al., 2001Go). These studies illustrate the fact that there can be a large number of small particles in ambient air that hardly contribute to the total mass and still have important biological effects. Weight measurements alone, therefore, leave out possibly important physical characteristics of PM, such as the number concentration, size distribution, and the total surface area. When particles have a smooth surface and a simple shape, their approximate geometric surface area can be calculated, but the estimation of the true surface area becomes more complicated when the particles have a complex shape (reviewed in Fubini, 1997Go). Measurements of the total surface area in an automated way are, therefore, virtually impossible to perform, and other measures of particles must be sought (Ayres, 1998Go). Since both the size distribution and number concentration of particles can be measured in an automated way (e.g., by using a photon correlation spectrometer), this procedure may be an appropriate alternative to the measurement of the total surface area. Therefore, in relation to allergy, relevant measurements of airborne PM would be weight measurements supplemented by the number of sized particles per volume unit of air.


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TABLE 3 The Number and Mass Concentration of Ambient Particulate Matter Collected during the Winter Season, 1991–1992, in Erfurt, Germany
 

    Particles and Allergy—Sensitization and Provocation
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 INTRODUCTION
 Particulate Air Pollution
 The Effect of Particles...
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An allergic reaction falls into two phases. In the sensitization or induction phase, an allergic immune response is triggered by contact with allergen. Specific IgE antibodies are produced and will bind to Fc{varepsilon}-receptors on mast cells. When sufficient levels of allergen-specific IgE have been reached, renewed encounter with the allergen will trigger the allergic inflammatory response that includes mast cells and eosinophils (Fig. 1Go). The sensitization phase can be subdivided into the primary response that is the very first response to the allergen, and secondary or booster responses when preexisting allergic immunity is increased by renewed exposure to allergen.



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FIG. 1. Simplified illustration of the allergic reaction and the effect of DEP on the sensitization and provocation phase of the allergic reaction, and on nonspecific inflammatory responses. In the sensitization phase, allergens are taken up by APC (macrophages, dendritic cells, or mature B cells), processed, and peptide fragments are presented on the surface. The peptide is recognized by pTh cells, which start to proliferate and differentiate into Th2 cells. Subsequently, Th2 cells start to secrete cytokines that are important for the differentiation and isotype switching of B cells to become IgE secreting plasma cells. The IgE antibodies bind to the Fc{varepsilon}-receptors on mast cells, which are then said to be sensitized. The provocation phase can take place several weeks or years later, when the allergen is internalized again. The allergen cross-links the membrane-bound IgE antibodies on sensitized mast cells, which immediately release their mediators to the surroundings. This immediate reaction can be followed by a more sustained inflammatory response, which involves cells such as eosinophils. These cells contribute significantly to the immunopathology of an allergic response. Results from experimental human and animal studies give evidence that DEP can affect several of the different stages in the allergic immune response (see text for details). APC, antigen-presenting cells; DEP, diesel exhaust particles; Eos, eosinophils; IL, interleukin; GM-CSF, granulocyte-macrophage colony-stimulating factor; Mc, mast cells; M{phi}, macrophages; pTh, precursor T helper cells; RANTES, regulated on activation normal and T cell expressed and secreted, Th, T helper cells; TNF, tumor necrosis factor.

 
With regard to allergic sensitization, there is increasing experimental evidence from both mouse and human studies that particles augment the allergic immune response (Diaz-Sanchez et al., 1999Go; Granum et al., 2000bGo, 2001bGo; Heo et al., 2001Go; Lambert et al., 1999Go, 2000Go; Løvik et al., 1997Go; Takafuji et al., 1989Go). Results from experimental human and animal studies on DEP show that these particles may interfere with the sensitization phase of the allergic reaction (left section in Fig. 1Go). In an experimental human study, Diaz-Sanchez et al. (1999) investigated if DEP could induce a de novo mucosal IgE response to the neoantigen keyhole limpet hemocyanin (KLH) under conditions in which the neoantigen alone could not induce any IgE response. Individuals with other allergies than to KLH were given intranasal administration with DEP and KLH. Exposure to allergen alone led to production of specific IgG and IgA, whereas there was no detectable levels of specific IgE. When the KLH challenge was preceded by DEP, on the other hand, the majority of the subjects produced detectable levels of specific IgE. In addition, subjects given both DEP and KLH had increased levels of IL-4, but not interferon-{gamma}. This study demonstrated that DEP has a capacity to increase allergic sensitization. However, only allergy-prone subjects were included in the cited study. These persons may have an increased probability of responding with allergic responses when exposed to a neoantigen. One can argue that DEP did not alter the immune response by polarizing the response to KLH toward an allergic reaction, but merely increased the "natural" immune response in these individuals. There is, however, evidence from experimental animal models that particles may enhance allergic sensitization also in strains of mice not particularly prone to develop IgE responses (Granum et al., 2000bGo).

It has been found that particles will increase the primary response when present either before the first exposure to allergen (Granum et al., 2001bGo; Lambert et al., 2000Go; van Zijverden, 2001Go) or when particles are coadministered with the first dose of allergen (Granum et al., 2001bGo; Heo et al., 2001Go; Løvik et al., 1997Go; Takafuji et al., 1989Go). However, the strongest adjuvant effect from particles was observed when particles were given simultaneously with all allergen doses (Granum et al., 2001bGo; van Zijverden, 2001Go). It should be noted that in experimental systems, particles may also have some adjuvant effect on the immune response when the particles are administered a short time after allergen exposure (Granum et al., 2001bGo).

There is evidence that mast cells may be affected by particles resulting in an increased booster response in the sensitization phase. After intranasal administration of allergen and DEP to allergic humans, there was an increased production of IL-4 (Wang et al., 1999Go). During the local mucosal allergic response, cells of the mast cell/basophil lineages were reported to contribute considerably to the production of IL-4 in the initial reaction after the exposure. This IL-4 production was believed to polarize the immune response towards a Th2 response, and expand the number and type of cells producing IL-4. Subsequently, other cells (predominantly Th cells) became the major source of IL-4 as the polarized Th2 response was established (left and middle section in Fig. 1Go).

There are both epidemiological and human experimental studies that give evidence for an involvement of particulate air pollution in the provocation phase of the allergic response (Diaz-Sanchez et al., 1997Go, 2000Go; Fujieda et al., 1998Go; Norris et al., 1999Go; Schwartz and Neas, 2000Go; Timonen and Pekkanen, 1997Go; van der Zee et al., 1999Go). In a study by Diaz-Sanchez et al. (2000), histamine levels and symptom scores (severity of nasal itching, nasal congestion and rhinorrhea, and number of sneezes) were measured after intranasal administration of DEP and allergen (house dust mite) to sensitized human subjects. Compared to subjects given allergen alone, subjects given DEP and allergen had higher symptom scores and a 3-fold increased release of histamine. DEP alone had no effect. This study indicates that DEP in combination with an allergen can aggravate allergic immune responses in sensitized subjects by increasing the release of histamine from mast cells and thus contribute the induction of the provocation phase (middle and right section in Fig. 1Go). Another important mechanism for the effect of particles on the provocation phase may be particle-mediated induction of nonspecific inflammatory responses (that is allergen-independent responses; see right section in Fig. 1Go). Since airway epithelial cells and alveolar macrophages are the initial target cells for interaction with particles, these cells are most likely to be affected by particles (reviewed in Salvi and Holgate, 1999Go). After the particle-induced activation of epithelial cells, these cells produce cytokines such as IL-1, IL-6, IL-8, TNF-{alpha}, GM-CSF, and RANTES, whereas macrophages are shown to produce cytokines such as TNF-{alpha} and IL-8 (reviewed in Boland et al., 2000Go; Driscoll et al., 1997bGo; Nel et al., 1998Go; Salvi and Holgate, 1999Go). The nonspecific inflammatory effects of particles may add to the allergic inflammation.


    The Importance of the Genetic Background
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 INTRODUCTION
 Particulate Air Pollution
 The Effect of Particles...
 The Effect of Particle...
 The Effect of the...
 Physical Characteristics of...
 Particles and...
 The Importance of the...
 Concluding Remarks
 REFERENCES
 
There are studies reporting an interstrain variation in murine susceptibility to both environmental particles and gases (Ichinose et al., 1997Go; Kleeberger, 1995Go; Kleeberger et al., 2000Go; Miyabara et al., 1998Go; Ohtsuka et al., 2000aGo). Significant interstrain differences in the magnitude of infiltration of polymorphonuclear leukocytes and lung permeability after exposure to ozone has been reported (reviewed in Kleeberger, 1995Go). By performing a genome screen using recombinant inbred strains of mice derived from ozone-susceptible C57BL/6J and ozone-resistant C3H/HeJ progenitors, chromosomal locations of susceptibility genes were identified (Kleeberger et al., 2000Go). The results from this study indicate that a significant quantitative trait locus on chromosome 4 may explain a significant portion of the genetic variance in ozone-induced hyperpermeability in the lungs, and these results support a role for Tlr4 as a strong candidate susceptibility gene. This gene encodes the Toll-like receptor 4 (Tlr4), which functions as the transmembrane component of the lipopolysaccharide (LPS) receptor complex (Beutler, 2000Go).

With regard to particles, Ichinose et al. (1997) found interstrain differences for eosinophilic airway inflammation, goblet cell proliferation, and production of allergen-specific IgG1 after intratracheal instillations of DEP plus OVA to naïve mice. In a study by Granum et al. (2000b), the importance of genetic background concerning the adjuvant effect of PSP was explored. After ip injections with PSP plus OVA to naïve mice, there was a statistically significant adjuvant effect on the production of allergen-specific antibodies in NIH/Ola mice but not in C3H/HeJ mice. In BALB/c mice, on the other hand, PSP gave a weak, but not significant, antibody adjuvant activity. The C3H/HeJ mouse has a Lpsd mutation in the Tlr4 gene (Beutler, 2000Go; Hoshino et al., 1999Go; Poltorak et al., 1998Go). The most significant cell type that is affected by this mutation is the macrophage. The uptake of unopsonized particles (e.g., TiO2 and latex) has been shown to be mediated by scavenger receptors of types AI, AII, and MARCO (Palecanda et al., 1999Go), and thus occur independently of Tlr4. However, mutant macrophages do not secrete inflammatory cytokines (e.g., IL-1, IL-6, TNF-{alpha}) on exposure to LPS, fail to phagocytize opsonized particles, and fail to produce reactive oxygen species or nitric oxide in response to LPS (Anderson, 2000Go). The lack of an adjuvant effect of PSP in the C3H/HeJ mouse could, hypothetically, be due to reduced inflammatory response because of the defect in the Tlr4 gene.

Additional candidate susceptibility genes in mice that may be important for the adjuvant activity of particles have been identified. Ohtsuka et al. (2000b) identified susceptibility loci for alveolar macrophage immune dysfunction induced by inhalation of sulfate-associated carbon particles in C57BL/6J and C3H/HeJ mice. These two mouse strains display two easily distinguishable alveolar macrophage function phenotypes after challenge with particles, in which C57BL/6J is termed responsive (susceptible) and C3H/HeJ is termed resistant. A genome-wide linkage analysis of an intercross (F2) cohort identified significant and suggestive quantitative trait loci on chromosomes 17 and 11. A number of the candidate genes identified on chromosome 17 may be important for the particle-induced effect on allergy-related immune responses. Among these are the gene coding for TNF-{alpha} and genes coding for mast cell proteases 6 and 7.

These findings in mice indicate that genetic variation in the response to both gaseous and particle pollutants may exist also in human individuals. In several studies, candidate susceptibility genes that may be important for the expression of asthma and allergic diseases have been identified (reviewed in Barnes and Marsh, 1998Go; Feijen et al., 2000Go; Howard et al., 2000Go). There are, on the other hand, a scarcity of studies identifying candidate genes that may be important for the effect of air pollution. However, it has been demonstrated in experimental studies that inflammatory and/or lung function responses to ozone and sulfur dioxide differ between asthmatic individuals (Holz et al., 1999Go; Winterton et al., 2001Go). Further, as mentioned earlier, there may be a synergistic interaction between particle-bound endotoxin and other proinflammatory components of particles (Ning et al., 2000Go). CD14 is a high-affinity receptor for LPS expressed on macrophages and monocytes and to a lesser extent on polymorphonuclear neutrophils. CD14 lacks a transmembrane and cytoplasmic domain and is therefore believed not to be directly responsible for transmitting a signal across the plasma membrane. There is increasing evidence that CD14 act cooperatively with Tlr4 in the response to LPS. Thus, CD14 focuses LPS on the cell surface, whereas Tlr4 act as the signal transducer into the cell (reviewed in Beutler, 2000Go; Ingalls et al., 1999Go). This LPS-mediated activation induces the secretion of several proinflammatory cytokines such as IL-1, IL-6, and TNF-{alpha} (Daniels et al., 2000Go). Results from human studies indicate that polymorphisms in CD14 and Tlr4 can affect the expression of allergic responses. Koppelman et al. (2001) studied the association of a polymorphism in the CD14 gene with phenotypes of atopy (e.g., total serum IgE levels, intracutaneous skin test, allergic rhinitis) and asthma (e.g., bronchial hyperresponsiveness, physician's diagnosis) in an adult Dutch population. They observed that a –159 C-to-T promoter polymorphism in the CD14 gene may result in expression of a more severe allergic phenotype. This is similar to the findings in reports on human CD14-polymorphism from the Martinez group (Baldini et al., 1999Go; Vercelli et al., 2001Go). A study by Arbour et al. has provided evidence that mutations in the Tlr4 gene are associated with differences in the LPS responsiveness in humans. However, not all subjects who were hyporesponsive to LPS had mutations in the Tlr4 gene, and not everyone with the Tlr4 mutations was hyporesponsive to inhaled LPS (Arbour et al., 2000Go). Arbour et al. therefore suggested that mutations in the Tlr4 gene can act in concert with other genetic changes or acquired factors to influence the complex physiological response to inhaled LPS.

It can be hypothesized that the influence of particulate air pollution on both allergic sensitization, provocation and inflammatory responses, is a result of complex gene-gene interactions and gene-environment interactions, and that polymorphism in the different candidate susceptibility genes for both allergy and environmental components may determine the severity of the allergic phenotype (Fig. 2Go).



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FIG. 2. Theoretical scheme showing gene-environment and gene-gene interactions that may be important for individual differences with regard to the effect of particulate air pollution on allergic immune responses. It can be hypothesized that polymorphisms in candidate susceptibility genes important for the response to particles (particle core as well as adsorbed chemical substances), allergen, and other environmental agents such as LPS may determine the severity of the allergic phenotype. Furthermore, combinations of different gene-gene interactions may influence the adjuvant effect and the expression of the allergic phenotype.

 

    Concluding Remarks
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 INTRODUCTION
 Particulate Air Pollution
 The Effect of Particles...
 The Effect of Particle...
 The Effect of the...
 Physical Characteristics of...
 Particles and...
 The Importance of the...
 Concluding Remarks
 REFERENCES
 
Environmental factors appear to play a dominant role in the increased prevalence of allergic conditions. Particulate air pollution may influence both the sensitization and provocation phases of allergy. Particles may increase allergic sensitization through their adjuvant effect on IgE synthesis, whereas the provocation phase may be influenced by particle-induced oxidative and inflammatory reactions in the respiratory mucosa. Although there is an abundance of epidemiological evidence for the aggravation of allergic airway disorders by particulate air pollution (Norris et al., 1999Go; reviewed in Pope, 2000Go; Timonen and Pekkanen, 1997Go; van der Zee et al., 1999Go), the notion that particulate air pollution increases the induction of allergic immune responses rest mainly on evidence from experimental laboratory studies. There is a rather striking scarcity of epidemiological evidence for the importance of PM in the sensitization stage and thereby the increased prevalence. However, there are some studies on the association between air pollution and increased sensitization (Heinrich et al., 1999Go; Wyler et al., 2000Go). Wyler et al. (2000) reported an association between motor vehicle traffic and allergic sensitization. However, in the cited studies, pollutants other than particles may cause the observed effects. The lack of epidemiological evidence on an association between particulate air pollution and allergic sensitization could be caused by a true absence of an effect from particles on allergic sensitization in the real-life situation, or it could be caused by an inability of epidemiological methods to detect this particle effect. Epidemiological methods require clear exposure gradients to be an effective tool. We, along with others, have demonstrated that particle exposure do not have to be concomitantly with exposure to allergens to exert an adjuvant effect. In addition, the adjuvant effect from particle exposure may last for several days (Granum et al., 2001bGo). This will tend to erase relevant exposure gradients. Furthermore, fine and ultrafine particles appear to be the most effective adjuvants. Fine particles will, in contrast to coarse particles (2.5–10 µm in diameter), be carried over large distances, which will also erase and obscure exposure gradients. Ultrafine particles have only to a very limited extent been measured at all in the context of epidemiology of allergic diseases.

The effect of particles on allergic immune responses may differ between individuals, that is particles may have a strong effect only in certain individuals that are genetically susceptible to the influence from particles. The genes in question may determine, for example, the cytokine response to irritative stimuli in general, or may act more specifically on the cellular response to particles or particle-associated components. Thus, gene-environment interactions in the development and manifestations of allergy may include not only gene-allergen interactions, but also gene-particle interactions.

There is considerable evidence that both the physical particle core and adsorbed chemical substances may enhance allergy-related immune responses. The particle core may function as a general "motor," in that particles with widely different chemical compositions have been shown to increase both inflammatory responses and antibody production. Particle-associated components (e.g., chemical substances, allergens, endotoxin) and possible other factors may increase and/or modify the effect from the particle core and steer the response towards a polarized Th1- or Th2-like response.


    NOTES
 
1 To whom correspondence should be addressed. Fax: +47 22 04 26 86. E-mail: berit.granum{at}folkehelsa.no. Back


    REFERENCES
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 INTRODUCTION
 Particulate Air Pollution
 The Effect of Particles...
 The Effect of Particle...
 The Effect of the...
 Physical Characteristics of...
 Particles and...
 The Importance of the...
 Concluding Remarks
 REFERENCES
 
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