Immune sensitization to methylene diphenyl diisocyanate (MDI) resulting from skin exposure: albumin as a carrier protein connecting skin exposure to subsequent respiratory responses

Abstract

BackgroundMethylene diphenyl diisocyanate (MDI), a reactive chemical used for commercial polyurethane production, is a well-recognized cause of occupational asthma. The major focus of disease prevention efforts to date has been respiratory tract exposure; however, skin exposure may also be an important route for inducing immune sensitization, which may promote subsequent airway inflammatory responses. We developed a murine model to investigate pathogenic mechanisms by which MDI skin exposure might promote subsequent immune responses, including respiratory tract inflammation.MethodsMice exposed via the skin to varying doses (0.1-10% w/v) of MDI diluted in acetone/olive oil were subsequently evaluated for MDI immune sensitization. Serum levels of MDI-specific IgG and IgE were measured by enzyme-linked immunosorbant assay (ELISA), while respiratory tract inflammation, induced by intranasal delivery of MDI-mouse albumin conjugates, was evaluated based on bronchoalveolar lavage (BAL). Autologous serum IgG from "skin only" exposed mice was used to detect and guide the purification/identification of skin proteins antigenically modified by MDI exposure in vivo.ResultsSkin exposure to MDI resulted in specific antibody production and promoted subsequent respiratory tract inflammation in animals challenged intranasally with MDI-mouse albumin conjugates. The degree of (secondary) respiratory tract inflammation and eosinophilia depended upon the (primary) skin exposure dose, and was maximal in mice exposed to 1% MDI, but paradoxically limited in mice receiving 10-fold higher doses (e.g. 10% MDI). The major antigenically-modified protein at the local MDI skin exposure site was identified as albumin, and demonstrated biophysical changes consistent with MDI conjugation.ConclusionsMDI skin exposure can induce MDI-specific immune sensitivity and promote subsequent respiratory tract inflammatory responses and thus, may play an important role in MDI asthma pathogenesis. MDI conjugation and antigenic modification of albumin at local (skin/respiratory tract) exposure sites may represent the common antigenic link connecting skin exposure to subsequent respiratory tract inflammation.

Mass spectrometric identification of isocyanate-induced modifications of keratins in human skin

“…It has been hypothesized [6][7][8] that skin exposure to isocyanates can lead to systemic immune sensitization, eventually causing the typical isocyanate-induced asthma-like inflammatory responses. Indeed, the skin is a highly immunogenic organ, able to elicit serious systemic immune responses such as contact allergy, inter alia caused by skin protein modification [9,10].…”

Occupational exposure to selected isocyanates in Polish industry

“…For lacquer painters employed in automobile repair workshops, the authors established strong and statistically significant relationships between skin changes and pulmonary symptoms. Results of other studies also indicate the possibility of a relationship between allergic changes and the development of pathological symptoms (including occupational asthma) in lungs and airways [26][27][28]. This means that even in the case of proven low levels of isocyanates in work environments, one cannot exclude the possibility of the development of pulmonary diseases.…”

Oxidative Activity of Ammonium Persulfate Salt on Mast Cells and Basophils: Implication in Hairdressers’ Asthma

“…For other low-molecular-weight agents the generation of an adduct with HA, acting as a trigger for the immune response, has been reported [20,21]. These authors demonstrated that hexamethylene diisocyanate (HDI) conjugates to HA inducing an IgG response to this modified protein in HDI-exposed subjects [20,22].…”