Asthma Induced by Isocyanates: a Model of
IgE-independent Asthma
Cristina E. Mapp, Piera Boschetto, Deborah Miotto, Edoardo De Rosa
Department of Clinical and Experimental Medicine, Section of Hygiene and Occupational Medicine, University of Ferrara
Abstract. Developments in the understanding of causes and natural history of asthma induced by isocyanates
may allow improved preventive strategies for occupational asthma (OA), and may also lead to improved un-
derstanding of mechanisms involved in IgE-independent nonoccupational asthma. Studies of genetic mark-
ers in OA induced by isocyanates suggest that HLA class II genes, glutathione S-transferase and NAT1
genotypes may predispose to development of this type of OA. Specific IgE antibodies against isocyanates are
not always found in subjects with OA caused by isocyanates, leading most researchers to consider this type
of OA, as a model of IgE-independent asthma. Evidence for cell-mediated immunity in OA induced by iso-
cyanates has been provided by bronchoalveolar lavage, bronchial biopsy and induced sputum studies. The
pathology of this type of asthma is similar to that of nonoccupational asthma, with cells such as eosinophils
and T lymphocytes that exhibit signs of activation, and with thickening of the reticular layer of the basement
membrane. Animal studies have shown that isocyanate asthma is driven primarily by CD4+ T cells and is
dependent upon the expression of Th2 cytokines. However, animal models are not always reflective of hu-
man responses. OA induced by isocyanates similarly to nonoccupational asthma, is a multifactorial condi-
tion, and it is likely that complex gene-environment interactions play a role. Better understanding of these
interactions is important for affected workers, and also has potential relevance for nonoccupational asthma.
Keywords: isocyanates, asthma, genetics, environment, exposure
agents, such as isocyanates, the presence of specificIgE antibodies has been documented in only a small OA has been suggested as a model of adult-onset subset of affected workers (5). The absence of demon- asthma (1, 2). The wide interest is justified because strable specific IgE antibodies in subjects with OA in- OA is estimated to account for approximately 15% of duced by LMW agents has led to speculation about the adult asthmatic population (3). In spite of the rec- IgE-independent immunological or even nonim- ognized harmful health effects of isocyanates, they are munological mechanisms (6). An area of current in- widely used in several industrialized countries and are terest in isocyanate asthma is the possibility that this the leading cause of OA. Thus, isocyanate-induced type of OA may be driven by T-cell recognition of iso- asthma is one of the most studied models of OA (4).
cyanates or isocyanate derivatives (7). To date, several The mechanisms by which these chemicals can induce lines of evidence indicate that cell-mediated immuni- host sensitization and asthma development remain ty (8, 9) and airway epithelium (4) are involved in the unclear. Available information indicates that a classi- pathogenesis of OA induced by exposure to iso- cal IgE-dependent hypersensitivity mechanism occurs for OA induced by high-molecular-weight (HMW) A number of recent publications have provided agents, while for most low-molecular-weight (LMW) further understanding of OA induced by exposure to C.E. Mapp, P. Boschetto, D. Miotto, E. De Rosa isocyanates and findings will be grouped under the following headings: animal studies of sensitization DQB1*0503 confers susceptibility to asthma induced and asthma, genetic studies, airway inflammation and by toluene diisocyanate (TDI), whereas DQB1*0501 offers protection (26). However, one study did notfind associations between isocyanate asthma andHLA-DR or HLA-DQ alleles, but in this study, ac- Animal studies of sensitization and asthma
curate phenotypes of the subjects included in thestudy were not provided (27). By contrast, HLA class Experimental animal models of isocyanate asth- I antigens and tumor necrosis factor α-308G are not ma have been described in review articles (10, 11) and associated with either susceptibility or protection to in several original studies (12-20). A common finding the development of TDI-induced asthma (28).
of these models is the demonstration of an immuno- A feature of isocyanate asthma is the develop- logical basis for the disease, including the involvement ment of persistent airway inflammation (29). Oxida- of T-helper type 1/2 responses as well as CD4 and tive stress is a key component of this inflammation CD8 T cells (21). Sensitized animals develop a specif- (30). The superfamily of glutathione-S transferase ic IgG and IgE antibody response, airway hyper-re- (GST) is critical for protecting cells from oxidative sponsiveness and inflammation accompanied by in- stress products. Individuals may differ in their ability creased expression of cytokines, similar to human dis- to deal with an oxidant burden, and such differences ease (22, 23). Moreover, dermal or respiratory expo- are in part genetically determined (31).
sure may be important in the workplace for the devel- Evidence of the involvement of GST has been opment of sensitization, and pulmonary pathology as- provided for workers exposed to TDI for 10 years or sociated with isocyanates can vary depending upon more. The frequency of the GSTP1 Val/Val genotype the exposure (i.e. low-level subchronic or high-dose was lower in asthmatic and hyperresponsive subjects, acute inhalation) (23). Another important finding is and the protective effect of homozygosity for the that sensitization can occur through subchronic in- GSTP1*Val allele increases in proportion to the dura- halation of vapor-phase diisocyanate at levels as low as tion of exposure to TDI (32). Therefore, subjects lack- 20 ppb. Even if animal models are not always reflec- ing this genotype may develop ongoing airway in- tive of human responses, they provide increased un- flammation and consequent airway remodeling, lead- derstanding of sensitization to LMW agents, such as Recently, it has also been shown that the N- acetyltransferase (NAT1) slow acetylator genotypeposed an increased risk of isocyanate asthma (33, 34).
Genetic studies
Any association between a genetic marker and risk ofdisease is relevant if findings of the study have been The study of gene-environment interactions is replicated. Asthma is a complex disease, and genetic facilitated in OA because it is possible to give precise susceptibility is one of the factors involved in this con- occupational case definitions, to estimate exposure to occupational sensitizers, and comparisons can bemade between affected workers and healthy workerswith similar exposures (24).
Airway inflammation and remodeling
Data obtained in studies on isocyanate asthma indicate that major histocompatibility complex class II The airway inflammation process is similar in proteins are important factors for the specificity of the IgE-dependent and IgE-independent asthma (36). In response to isocyanates (25). HLA class II molecules the airways, inflammatory cells are increased in num- are highly polymorphic and therefore plausible candi- ber and activated, resulting in the secretion of proin- date genes that influence the development of a specif- flammatory mediators and proteins (37, 38) with harmful effects on epithelial cells. Along with these nent disability, even after cessation of exposure (47).
findings, the thickening of the reticular basement Improvement does continue over long time, although membrane has been described (7). In isocyanate asth- at a slower rate than in the first two years after cessa- ma, the majority of T cells obtained from bronchial tion of exposure. Important determinants of improve- biopsy specimens of TDI asthmatics showed the CD8 ment are the total duration of exposure, the duration phenotype and produced interferon-γ (IFN-γ) and in- of symptoms, the severity of asthma, baseline lung volumes and the degree of airway hyper-responsive- A reasonable index of airway inflammation is ness at the time of diagnosis. Most subjects with OA eosinophilia, and eosinophil counts in sputum are use- retain specific bronchial reactivity to the sensitizing ful in OA induced by isocyanates (40). However, it is agent (HMW agent) even two or more years after ces- still unclear whether changes in sputum eosinophil sation of exposure (48). Similarly, in OA induced by count relate to airway hyper-responsiveness . Other isocyanates, after removal from exposure, specific studies have described an increase in neutrophils in bronchial reactivity has been described (49, 50). One sputum of subjects with isocyanate asthma (41, 42), of the hypotheses for the persistence of OA after the but their role should be further delineated. Non-inva- end of exposure is the presence of airway inflamma- sive methods of assessing airway inflammation includ- tion that can be documented even years after cessation ing analysis of induced sputum have been recently re- of exposure (51, 52). A recent study that involved in- viewed (43). The conclusions are that this non-inva- duced sputum has shown an increase of eosinophils, sive method is a valid and reproducible tool for study- neutrophils, and their product myeloperoxidase, and the neutrophil chemoattractant, IL-8, in subjects with It is almost universally accepted that airway in- persistent airway hyper-responsiveness many years af- flammation is present in both OA and non-occupa- ter the last exposure to both HMW and LMW agents tional asthma, whereas the role of airway remodelling (53). Authors concluded that airway inflammation is in the disease remains controversial. It provides an ex- the cause of persisting airway hyper-responsiveness planation for many conditions observed in asthmatics and asthmatic symptoms. Because sputum was not ex- (44). However, for some investigators, the thickening amined before cessation of exposure, the starting de- of the airway wall protects against airway narrowing gree of airway inflammation is lacking. The persis- and attenuates airway reactivity in subjects with asth- tence of airway inflammation in the absence of re-ex- ma (45). It is also unclear whether, in adult asthma, posure to the offending agent appears self-sustained.
airway inflammation occurs first and remodelling lat- Recent data indicate that, in isocyanate asthma, expo- er. In isocyanate asthma, 6 to 21 months after cessa- sure to TDI can augment cytocheratin-19 expression tion of exposure, the thickening of reticular layer of from the bronchial epithelial cell, which may involve the basement membrane, even if reduced, is still pre- immune responses as an autoantigen to induce airway sent, and it is therefore a marker of long-lasting struc- inflammation in this common type of OA (54).
tural changes of the airway wall (46).
Available data indicate that both airway inflam- mation and airway remodelling are present in OA in- Conclusions
duced by isocyanates, but further research is needed toestablish their role in causing obstruction, airway hy- per-responsiveness and chronic asthma.
agents remains controversial. Several lines of evidenceindicate that isocyanate-induced asthma is a multifac-torial disease involving genetic susceptibility, the im- mune system, and airway epithelium. To elucidate themechanisms of OA induced by isocyanates, further re- Numerous follow-up studies have shown that search is needed on the molecular interactions be- subjects with isocyanate asthma are left with perma- tween these chemicals and human airway proteins.
C.E. Mapp, P. Boschetto, D. Miotto, E. De Rosa Acknowledgements
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