Cell and molecular biology of chemical allergy
Meryl H. Karol, PhD; Orest T. Macina, PhD; and Albert Cunningham, PhD
Objective: The objective of this review is to provide current approaches to gain
increased understanding of the molecular basis of chemical allergenicity. Chemical
allergy refers to an allergic reaction to a low molecular weight agent (ie, Ͻ1 kD).
The symptoms and pathology of chemical asthma resemble those of allergy to larger
sized agents, such as pollens, weeds, and danders. The differences relate to mech-
anisms of disease. To stimulate an immune response, low molecular weight chem-
icals function as haptens and bind to carrier macromolecules. This article focuses on
the chemical reactions and physicochemical characteristics of chemical allergens.
Data Sources: Data were obtained from published clinical reports and from the
Documentation of Threshold Limit Values (1998) published by the American
Congress of Governmental Industrial Hygienists.
Results: In vitro studies indicate the stoichiometric reaction of some chemical
allergens with glutathione and the subsequent transfer of the allergen from gluta-
thione to other nucleophiles. Computer-generated structure-activity relationship
models have been developed for chemicals that induce respiratory allergy. The
models, based on physicochemical properties of the agents, have high sensitivity
and specificity.
Conclusions: The structure-activity relationship model suggests that chemical
binding is the essential feature of chemical allergens. Their in vivo reactions with
thiols may result in glutathione deficiency with consequent alteration in cellular
reduction-oxidation (redox) status, release of cytokines, and promotion of the T
helper cell 2 phenotype. Prevention of permanent disease is dependent on periodic
medical surveillance of affected workers. When detected early, the disease can
frequently be reversed.
molecular mechanism(s) of allerge-
nicity of LMW chemicals.
Chemical Sensitizers Are Haptens
LMW sensitizers are typically electro-
philes or proelectrophiles capable of
reaction with hydroxyl, amino, and
thiol functionalities on proteins. For
many, the identity of the macromolec-
ular target(s) to which binding results
in sensitization is unknown. Studies
with two diisocyanate allergens, tolu-
ene diisocyanate and hexamethylene
diisocyanate (HDI), have indicated a
rapid reaction of each under physio-
logic conditions with glutathione.4
Further, in the presence of certain pep-
tides, the adducts are transferred from
glutathione to nucleophilic sites on the
peptides, suggesting the possibility of
regeneration of the reactive chemicals
and binding to targets distant from the
initial site of reaction.4
Another consequence of chemical
binding to thiols may be development
of glutathione deficiency. Alteration of
cellular redox potential is known to
affect numerous physiologic and
pathophysiologic processes, including
activation of MAP kinase, induction of
cytokine expression,5 and promotion
of the T helper cell 2 phenotype.6 In
human bronchial epithelial cells, sen-
sitivity to tumor necrosis factor ␣ is
inversely correlated with cellular redox
state.5
Ann Allergy Asthma Immunol 2001;87(Suppl):28–32.
INTRODUCTION
The symptoms and pathology of
chemical asthma resemble those of
allergy to larger sized natural agents,
such as pollens, weeds, and danders.
Differences between chemical al-
lergy and allergy to environmental
agents relate to mechanisms of dis-
ease. Immunologic factors seem to
be important in the pathogenesis of
chemical asthma. In contrast to al-
lergy because of high molecular
weight agents, atopy is not a risk
factor for developing chemical al-
lergy. Immunoglobulin (Ig)E is infre-
quently detected in chemical asth-
ma.3 LMW allergens are either
inherently chemically reactive or are
metabolized in vivo into chemically
reactive species. They function as
haptens and bind to carrier macro-
molecules to initiate immunologic
stimulation. The chemistry of hapte-
nation may provide insight into the
A number of low molecular weight
(LMW) chemicals (ie, Ͻ1,000 D) are
known to cause respiratory sensitiza-
tion. Contact with these chemicals fre-
quently occurs in the workplace.
Symptoms include wheezing, tightness
in the chest, coughing, and shortness of
breath.1 Inflammation of the airways,
if present, is characterized by activated
lymphocytes and eosinophils in the
bronchial mucosa.2 Airway hyperreac-
tivity to nonspecific agents further
characterizes the disease.
The identity and immunologic activ-
ity of chemically adducted proteins has
received recent interest. Epithelial pro-
teins, adducted after contact with HDI,
were found to stimulate proliferation
of lymphocytes from HDI-asthmatic
patients, but not those from HDI-ex-
posed nonasthmatics nor from atopics
with non-HDI–induced asthma.7 Tolu-
ene diisocyanate was found to associ-
ate with ciliary tubulin of human air-
Department of Environmental and Occupational
Health, Graduate School of Public Health, Uni-
versity of Pittsburgh, Pittsburgh, Pennsylvania.
This study was supported by grant ES05651
from the National Institute of Environmental
Health Sciences.
Received for publication April 16, 2001.
Accepted for publication in revised form Sep-
tember 25, 2001.
way epithelial cells.8 Tubulin,
a
subunit protein of microtubules, pos-
sesses numerous sulfhydryl moieties
28
ANNALS OF ALLERGY, ASTHMA, & IMMUNOLOGY