Enhancement of allergic inflammation by the interaction between diesel exhaust particles and the immune system☆,☆☆,★,★★
Section snippets
CELLULAR AND CYTOKINE ELEMENTS INVOLVED IN IgE PRODUCTION
IgE plays a major role in the pathogenesis of allergic inflammation in humans, both in the early and late phase of the mucosal response to allergens.19 Stratification of total IgE serum levels in a population acts as a good predictor for the prevalence of asthma in the identified subgroup populations.20 Before discussing the effects of DEPs on IgE synthesis, it is appropriate to briefly review some basic processes in IgE production.21 Although IgE production entails B-cell Ig isotype switching
ANIMAL STUDIES INDICATING THAT THE DEP IS AN ADJUVANT FOR IgE PRODUCTION
Animal studies have provided definitive data that DEPs, or extracts made from DEPs, affect IgE production (Table II).26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39
Effect or response References Increased total IgE production 27 Allergen-specific IgE enhancement after intra-peritoneal, intranasal, intratracheal, inhalational, or foot pad challenge with particles mixed with allergen 28-32 Intraperitoneal pyrene, extracted from DEP,
HUMAN STUDIES INDICATING THAT THE DEP IS AN ADJUVANT FOR IgE PRODUCTION
Human studies have extended the findings obtained in animal models (Table III).
Effects References Effects of aerosolized DEPs on nasal allergic response • Increased local production of IgE and IgE-secreting cells 40 • Qualitatively different IgE isoforms produced through alternative splicing of ϵ mRNA 40, 42 • Augmented production of allergen-induced antigen-specific IgE 44 • Nonspecific stimulation of a broad cytokine profile in the
DEP EFFECTS ON CELLULAR IMMUNE ELEMENTS INVOLVED IN ALLERGIC INFLAMMATION
Fig 2 outlines some of the cells involved in IgE production, including B lymphocytes, T lymphocytes, and APCs and also demonstrates how DEPs may interact with these elements. We have previously discussed the finding that intranasal challenge with DEPs selectively enhances the number of IgE-secreting B lymphocytes in the nasal mucosa.40 Additionally, DEP extracts have been shown to enhance IgE production in normal human tonsillar and peripheral blood B lymphocytes,43 as well as in a human
FUNCTIONAL CONSEQUENCES OF DEP-INDUCED MACROPHAGE MODULATION AND ITS RELEVANCE TO ALLERGIC INFLAMMATION
One potential mechanism for the adjuvant effect of DEPs on allergic inflammation is the enhancement of the role of macrophages as APCs. Because APCs interact with T cells, a perturbation of those cellular interactions may effect cytokine production in T cells (Fig 2). In this regard, PAHs have been demonstrated to enhance major histocompatibility type-II gene expression in murine macrophages, but this work needs to be confirmed.63 In our own studies we have focused on CD80 protein and message
DEP EFFECTS ON OTHER MUCOSAL CELL TYPES
In addition to the effects on cells of the immune system, DEPs also influence other mucosal cell types that play a role in allergic inflammation. Terada et al73 found that DEP extracts enhance human eosinophil adhesion to nasal epithelial cells, as well as causing eosinophil degranulation. Because eosinophil degranulation is associated with the release of mediators that promote allergic inflammation, this suggests that DEPs can promote eosinophil-mediated hypersensitivity. In earlier work the
METABOLIC PATHWAYS USED BY PAH TO ACTIVATE MACROPHAGES AND POSSIBLY OTHER CELL TYPES IN THE MUCOSAL IMMUNE SYSTEM
Although metabolic pathways for PAHs are well described in hepatocytes, comparatively little is known about these pathways in the cells of the immune system (Fig 6).76, 77 The best
METABOLIC CONVERSION OF PAH AND QUINONES INDUCE ROS, LEADING TO ACTIVATION OF INTRACELLULAR SIGNALING PATHWAYS AND INDUCTION OF GENE TRANSCRIPTION
The CYP1A1 catalytic cycle involves substrate binding followed by binding and activation of molecular oxygen to reactive intermediate species, which hydroxylate the substrate.104 The formation of hydrogen peroxide (H2 O2 ) and water as end products of the catalytic process is postulated to result from autoxidation of the cytochrome P450 complex.104 The initial reactive oxygen species that are generated are superoxide anions; spontaneous dismutation of superoxide anion yields H2 O2 . One
CONCLUSION
The industrial revolution began about 2 centuries ago, and the diesel engine went into production a little less than a century ago. Particulates generated by related human activities have now reached a level where they may reflect enough sunlight to lower global temperatures. Studies reviewed in this article show our new and increasing understanding of such materials, particularly DEPs and the chemicals contained therein. These data indicate that DEPs can act as mucosal adjuvants at the
Acknowledgements
We thank Peggy Shih for skillful preparation of the manuscript and Lynne Olson for designing and drawing the front cover illustration.
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From the Division of Clinical Immunology/Allergy, Department of Medicine, UCLA School of Medicine, University of California, Los Angeles.
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Supported by a United States Public Health service grant, AI-34567 (UCLA Asthma, Allergy, and Immunologic Disease Center) to Andre E. Nel and Andrew Saxon and funded by the National Institute of Allergy and Infectious Disease and the National Institutes of Environmental Health Sciences.
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Reprint requests: Andre Nel, MD, Division of Clinical Immunology/Allergy, Department of Medicine, UCLA Medical School, 10833 Le Conte Ave, Los Angeles, CA 90095-1680.
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