T-cell receptor Vβ gene segment expression in diisocyanate-induced occupational asthma,☆☆,,★★

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Abstract

Background: Diisocyanates are the most common cause of occupational asthma induced by low-molecular-weight chemicals. The disease appears to be immunologically mediated but is independent of IgE antibody synthesis. An underlying genetic susceptibility is suggested by the fact that the disease only develops in approximately 5% to 10% of exposed workers. Objective: The study was designed to determine whether disease susceptibility is influenced by HLA and T-cell receptor Vβ gene segment usage. Methods: T-cell receptor Vβ gene repertoires were quantitated by using primer pairs specific for Vβ gene segments in conjunction with a common Cβ region primer. One group of workers with diisocyanate-induced occupational asthma produced diisocyanate-specific IgG and IgE antibodies, whereas the other group did not produce specific antibodies. Occupational asthma was previously confirmed by either workplace challenge or laboratory specific diisocyanate bronchoprovocation. Control groups consisted of diisocyanate-exposed workers who were free of symptoms, patients with nonoccupational asthma, and unexposed subjects who were free of symptoms. Results: Lymphocytes from workers with diisocyanate-induced occupational asthma had significantly decreased Vβ1 and Vβ5 gene segment expression before in vitro exposure to diisocyanates, compared with control groups. Percent Vβ1 and Vβ5 gene segment expression was selectively increased when peripheral blood mononuclear cells were stimulated in vitro with diisocyanate-conjugated proteins. Low-resolution HLA class II phenotyping revealed no significant differences in the distribution of HLA-DR or HLA-DQ alleles between diisocyanate-induced occupational asthma and control groups. Conclusions: These findings are consistent with a hypothesis that antigen-specific T-cell subpopulations may be sequestered in the lungs of workers with diisocyanate-induced occupational asthma and clonally expand after further exposure to diisocyanates. (J Allergy Clin Immunol 1997;99:245-50.)

Section snippets

Subject population

The diagnosis of DOA was based on history of diisocyanate exposure in the workplace, clinical symptoms that decreased away from work, and peak flow variability at work compared with away from work. The diagnosis of DOA was confirmed by either a workplace or laboratory challenge with diisocyanates. Workers with DOA were further characterized by whether they produced diisocyanate-specific IgE and/or IgG antibodies by using a standardized ELISA method described by Sarlo et al.11 An increased level

PBMC proliferation

The mean proliferative response ranged between 100 and 300 cpm for the HSA control and 50,000 and 100,000 cpm for mitogen (PHA). The maximal proliferative response was observed on day 4 for mitogen and on day 7 for antigen (HDI-HSA, TDI-HSA, or MDI-HSA). The mean proliferative response of PBMCs obtained from workers with DOA (n = 8) stimulated with HDI-HSA and MDI-HSA was significantly greater than the mean proliferative response of PBMCs obtained from diisocyanate-exposed and unexposed control

Discussion

Previous investigations of DOA have attempted to identify specific biomarkers that could be used to detect workers at risk for developing occupational asthma. Diisocyanate-specific IgG antibodies have been previously reported to represent a marker of exposure to diisocyanates, but neither IgG nor IgE antibodies have correlated well with disease activity.26 Similarly, use of PBMC proliferation as a biomarker for identifying workers at risk for DOA appears to be nonspecific for disease activity.2

Acknowledgements

We thank Shervin Yermian and Lynn Whitacre for their contributions to this project.

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    From the Divisions of aImmunology, bNephrology, and cPulmonary and Critical Care Medicine; ethe Department of Internal Medicine, Hoxworth Blood Center; and fthe Departments of Environmental Health and Molecular and Cellular Physiology, University of Cincinnati College of Medicine.

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    Supported by National Institutes of Health grants NIEHS-ES06096, NIEHS-ES06562, and NIEHS-ES06677 and by the Center for Indoor Air Research (93-08).

    Reprint requests: Jonathan A. Bernstein, MD, College of Medicine, University of Cincinnati, P.O. Box 670563, Cincinnati, OH 45267-0563.

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