Adam V. Wisnewski

Recent developments in diisocyanate asthma.

Despite recent advances in our understanding of diisocyanate-induced asthma, this disease remains a perplexing phenomenon. Studies reported in the past year have focused on: (i) diisocyanate antigens; (ii) the role of airway and skin epithelium; (iii) human immune responses to exposure; (iv) neurogenic pathways; and (v) genetic factors that may confer susceptibility. These studies support the hypothesis that diisocyanate asthma results from the host immune response to these chemicals, and may represent a mixed T helper type 1/2 response. A better understanding of the pathogenesis of diisocyanate asthma should facilitate the development of better diagnostic tests and strategies for disease surveillance and intervention.

Recent developments in diisocyanate asthma

OBJECTIVE To summarize the latest experimental findings on diisocyanate asthma and discuss the impact of these data on our understanding of disease pathogenesis and diagnosis. DATA SOURCES The literature reviewed includes articles from PubMed (National Library of Medicine) published within the last 3 years (1999-2001). In addition, pertinent older references are discussed to provide a historical perspective and background. STUDY SELECTION The data discussed were chosen to highlight key concepts relevant to diisocyanate asthma pathogenesis and are grouped accordingly. RESULTS In many ways, diisocyanate-induced asthma mirrors allergic asthma caused by other stimuli; however, the immune-mediated pathways believed to be central to the disease have been difficult to define. Recent studies on the human immune response to diisocyanates provide additional evidence supportive of an immune basis for pathogenesis but also highlight well-recognized differences between diisocyanate asthma and common atopic asthma. Studies on the antigenic form of diisocyanates and their interaction with epithelial tissues provide new insights that may help explain these apparent immunologic differences. Genetic factors that influence disease have begun to be identified but remain poorly characterized. Associations of particular major histocompatibility complex class II alleles with diisocyanate asthma further fuel the hypothesis that immune-dependent mechanisms underlie pathogenesis, whereas associations of glutathione S-transferase polymorphisms (in conjunction with recent studies defining the effects of diisocyanates on thiol-redox homeostasis) may implicate additional antigen-independent mechanisms. Long-term follow-up studies of diisocyanate asthma patients have confirmed the prognostic value of early removal of symptomatic patients from exposure and highlight the need for effective diagnostic tests of sensitivity and susceptibility. CONCLUSIONS Diisocyanate-induced asthma appears to be a multifactorial disease involving the immune system, airway epithelium, and genetic factors. The potential long-term adverse effects of diisocyanate exposure in sensitized patients underscore the need for further studies to elucidate the pathogenesis of this disease and identify biomarkers for sensitization and susceptibility.

Isocyanate-conjugated human lung epithelial cell proteins: A link between exposure and asthma?

BACKGROUND Isocyanates are a group of highly reactive cross-linking chemicals that cause airway inflammation and asthma in exposed individuals. Isocyanates have been detected along the airway epithelia of exposed workers and animals, prompting the hypothesis that isocyanates can directly bind to epithelial cell proteins. OBJECTIVE We tested the hypothesis that hexamethylene diisocyanate (HDI) binds directly to lung epithelial cell proteins and initiated studies to evaluate the immunostimulatory potential of HDI-conjugated lung epithelial cell proteins. METHODS Human lung epithelial cell lines were exposed to vapor- and liquid-phase HDI, and the cellular proteins were analyzed for HDI conjugation by Western blotting and tested for the ability to induce lymphocyte proliferation in vitro. RESULTS A number of epithelial cell polypeptides, ranging from 25 to 110 kd in apparent molecular weight, were conjugated with HDI after exposure of the human lung epithelial cell lines (A549 and NCI-H292) to HDI concentrations greater than 0.005% (vol/vol) in the liquid phase. Vapor-phase HDI exposure resulted in a more restricted HDI conjugation pattern, with major HDI-conjugated polypeptides migrating at 47, 71, and 91 kd. HDI-conjugated epithelial cell proteins specifically stimulated proliferation of PBMCs from subjects with isocyanate-induced asthma but not HDI-exposed nonasthmatic individuals or atopic subjects with nonisocyanate-related asthma. CONCLUSIONS The data demonstrate that epithelial cell proteins readily react with HDI and that HDI-conjugated epithelial cell proteins can stimulate lymphocyte proliferation. Further characterization and evaluation of HDI-conjugated epithelial cell proteins will elucidate their potential role in the pathogenesis of isocyanate-induced asthma.

Developments in laboratory diagnostics for isocyanate asthma

Purpose of review Isocyanates, reactive chemicals used to generate polyurethane, are a leading cause of occupational asthma worldwide. Workplace exposure is the best-recognized risk factor for disease development, but is challenging to monitor. Clinical diagnosis and differentiation of isocyanates as the cause of asthma can be difficult. The gold-standard test, specific inhalation challenge, is technically and economically demanding, and is thus only available in a few specialized centers in the world. With the increasing use of isocyanates, efficient laboratory tests for isocyanate asthma and exposure are urgently needed. Recent findings The review focuses on literature published in 2005 and 2006. Over 150 articles, identified by searching PubMed using keywords ‘diphenylmethane’, ‘toluene’ or ‘hexamethylene diisocyanate’, were screened for relevance to isocyanate asthma diagnostics. New advances in understanding isocyanate asthma pathogenesis are described, which help improve conventional radioallergosorbent and enzyme-linked immunosorbent assay approaches for measuring isocyanate-specific IgE and IgG. Newer immunoassays, based on cellular responses and discovery science readouts are also in development. Summary Contemporary laboratory tests that measure isocyanate-specific human IgE and IgG are of utility in diagnosing a subset of workers with isocyanate asthma, and may serve as a biomarker of exposure in a larger proportion of occupationally exposed workers.

Glutathione protects human airway proteins and epithelial cells from isocyanates

Background Glutathione (GSH), one of the major anti‐oxidants of the lung, has been linked to the human response to isocyanate exposure. However, the ability of GSH to modulate key chemical reactions, thought to be central to the development of human isocyanate allergy, has not been directly analyzed under biologic exposure conditions.

Human innate immune responses to hexamethylene diisocyanate (HDI) and HDI–albumin conjugates

Background Isocyanates, a leading cause of occupational asthma, are known to induce adaptive immune responses; however, innate immune responses, which generally precede and regulate adaptive immunity, remain largely uncharacterized.

Diisocyanate conjugate and immunoassay characteristics influence detection of specific antibodies in HDI-exposed workers.

Background The structural characteristics of diisocyanate chemical protein antigens vary depending upon the methods of production, and may influence diisocyanate antigen immunoassays. The impact of different antigen preparation methods on immunoassay sensitivity, specificity, and predictive value for identifying workers with diisocyanate asthma (DA) has not been systematically evaluated.

Pro/Con debate: Is occupational asthma induced by isocyanates an immunoglobulin E-mediated disease?

Isocyanates, low‐molecular weight chemicals essential to polyurethane production, are one of the most common causes of occupational asthma, yet the mechanisms by which exposure leads to disease remain unclear. While isocyanate asthma closely mirrors other Type I Immune Hypersensitivity (Allergic) disorders, one important characteristic of hypersensitivity (‘allergen’‐specific IgE) is reportedly absent in a large portion of affected individuals. This variation from common environmental asthma (which typically is induced by high‐molecular weight allergens) is important for two reasons. (1) Allergen‐specific IgE is an important mediator of many of the symptoms of bronchial hyper‐reactivity in ‘allergic asthma’. Lack of allergen‐specific IgE in isocyanate hypersensitive individuals suggests differences in pathogenic mechanisms, with potentially unique targets for prevention and therapy. (2) Allergen‐specific IgE forms the basis of the most commonly used diagnostic tests for hypersensitivity (skin prick and RAST). Without allergen‐specific IgE, isocyanates may go unrecognized as the cause of asthma. In hypersensitive individuals, chronic exposure can lead to bronchial hyperreactivity that persists years after exposure ceases. Thus, the question of whether or not isocyanate asthma is an IgE‐mediated disease, has important implications for disease screening/surveillance, diagnosis, treatment and prevention. The present Pro/Con Debate, addresses contemporary, controversial issues regarding IgE in isocyanate asthma.

Human antibody variable region gene usage in HIV-1 infection

Human antibody variable region gene usage during human immunodeficiency virus type 1 (HIV-1) infection is examined in the following review, and several hypotheses are presented to account for the distinct patterns of antibody gene expression associated with infection. Evidence supporting qualitatively biased antibody gene expression has been derived from analysis of the human humoral immune response by isoelectric focusing (IEF) and serological and molecular studies of immunoglobulin (Ig) from different lymphoid compartments of HIV-1-infected patients. Preferential usage of heavy-chain variable region (VH) gene families 1 and 4 is supported by serological studies of serum Ig and molecular characterization of anti-HIV-1 human monoclonal antibodies derived from infected patients. Negative biases against VH3 family gene usage are detected by polymerase chain reaction (PCR) studies of peripheral blood lymphocytes from AIDS patients but not by combinatorial phage display library techniques. Biased antibody gene usage and expression during HIV-1 infection may be related to HIV-1 pathogenesis by limiting the available HIV-1 neutralizing repertoire. Further molecular characterization of anti-HIV-1 antibodies and in vivo expression of V-region genes during HIV-1 infection should provide important information regarding antibody gene expression and its relationship to HIV-1 pathogenesis.

Pathogenesis and Disease Mechanisms of Occupational Asthma

Occupational asthma (OA) is one of the most common forms of work-related lung disease in all industrialized nations. The clinical management of patients with OA depends on an understanding of the multifactorial pathogenetic mechanisms that can contribute to this disease. This article discusses the various immunologic and nonimmunologic mechanisms and genetic susceptibility factors that drive the inflammatory processes of OA.