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372 | MAY 2002 | VOLUME 2 www.nature.com/reviews/immunol

P E R S P E C T I V E S
and the development of atopy and asthma
during childhood
2325
. Although the effects of
passive smoking on adult human health are
equivocal, apprehension about the health
effects of smoking has made an important
contribution to the reduction in smoking rates
among young adults
16
.
However, it has been suspected for some
time that tobacco smoking, for all of its over-
whelming harmful effects, might protect
smokers from some diseases. Epidemiological
data indicate that smoking might decrease the
incidence and/or severity of several diseases,
including ulcerative colitis, sarcoidosis,
endometriosis, uterine fibroids, endometrial
cancer, farmers lung, pigeon breeders disease,
Parkinsons disease, Sjgrens syndrome and,
perhaps, Alzheimers disease
2628
. Interestingly,
many of these diseases are inflammatory dis-
eases or have an inflammatory component.
Smoking and the immune system
Chronic inhalation of cigarette smoke alters a
wide range of immunological functions,
including innate and adaptive immune
responses. It has been speculated that many of
the health consequences of chronic inhalation
of cigarette smoke might be due to its adverse
effects on the immune system
29
. The possibil-
ity that the increased prevalence of diseases
that are associated with cigarette smoke might,
in part, be due to tobacco-smoke-induced
changes in the immune and inflammatory
processes was recognized first in the 1960s
(reviewed in REF. 29). In this article, I review the
Although the health risks of tobacco
smoking are well documented, there is
increasing evidence that smokers have a
lower incidence of some inflammatory and
neurodegenerative diseases. Many of the
adverse and beneficial effects of smoking
might result from the ability of cigarette
smoke to suppress the immune system.
Nicotine, which is one of the main
constituents of cigarette smoke, suppresses
the immune system but might have
therapeutic potential as a neuroprotective
and anti-inflammatory agent.
Health consequences of smoking
Cigarette smoking is a worldwide epidemic,
and it is one of the main preventable causes of
death and disability. In the United States alone,
smoking results in approximately 431,000
deaths each year, which amounts to a financial
loss that exceeds US $100 billion in healthcare
and indirect costs (such as lost wages and
losses in productivity)
1
. Cigarette smoking sig-
nificantly increases the risk of heart disease,
lung cancer and microbial infections (such as
respiratory infections, periodontitis and bacte-
rial meningitis)
27
. Tobacco use is also associ-
ated with delayed recovery from injuries and a
higher incidence of atherosclerosis, chronic
obstructive pulmonary disease (COPD),
Crohns disease, rheumatoid arthritis and can-
cers of the lung, mouth, larynx, oesophagus
and bladder
3,4,810
. In addition, female smokers
have a greater propensity for miscarriages,
low-birthweight babies, adverse menstrual
symptoms, osteoporosis and transmission of
HIV-1 from mother to child
1114
. Although the
prevalence of smoking is similar among
AfricanAmerican and white American men,
the death rate from cerebrovascular diseases
and lung cancer is markedly different. The
age-adjusted death rate of AfricanAmerican
men from these diseases is nearly twice that of
white American men
15
. So, racial background
might have a role in smoking-associated mor-
bidity and mortality.
For nearly four decades, health depart-
ments worldwide have alerted individuals to
the health hazards of cigarette smoking and,
in the United States, the results have been
impressive; the overall rate of smoking among
adults has dropped from 42.4% in 1965 to
24.7% in 1995 (REFS 1,16). However, there was
an alarming increase in the frequency of ciga-
rette smoking by high-school students from
1993 to 1997 in the United States (FIG. 1).
Moreover, tobacco use has increased markedly
worldwide since the 1980s
16
. Therefore,
tobacco use is an important public-health
issue, both in the United States and globally
17
.
Since the early 1980s, there has been grow-
ing concern that the inhalation of environ-
mental tobacco smoke (ETS) also known as
secondhand or passive smoke
18
(BOX 1),
might adversely affect the health of non-smok-
ers
19,20
. ETS might be responsible for some res-
piratory diseases and the aggravation of aller-
gic responses; however, it is debatable whether
ETS actually increases the incidence of lung
cancer
21,22
. Children might be particularly sen-
sitive to ETS, and there is increasing evidence
that ETS, primarily through parental cigarette
smoking, is associated with an increased risk
of respiratory infections, bacterial meningitis,
Effects of cigarette smoke on the
immune system
Mohan Sopori
SCI E NCE AND SOCI ETY
25
20
15
10
5
0
25
20
15
10
5
0
Females Males
Year Year
12th
11th
10th
9th
12th
11th
10th
9th
1993 1995 1997 1993 1995 1997
P
e
r
c
e
n
t
a
g
e

s
m
o
k
i
n
g

f
r
e
q
u
e
n
t
l
y
P
e
r
c
e
n
t
a
g
e

s
m
o
k
i
n
g

f
r
e
q
u
e
n
t
l
y
Figure 1 | Rates of cigarette smoking among high-school students according to grade and sex
during 1993, 1995 and 1997. Two distinct patterns emerge from the graphs: the frequency of cigarette
smoking among eleventh and twelfth grade students (ages 17 and 18 years) of both sexes increased from
1993 to 1995, but decreased from 1995 to 1997; and there is an alarming increase in the frequency of
smoking among ninth and tenth grade boys and girls (ages 15 and 16 years) from 1993 to 1997.
Reproduced, with permission, from Primary Care (REF. 16) (1999) W. B. Saunders Company.
2002 Nature Publishing Group
P E R S P E C T I V E S
NATURE REVIEWS | I MMUNOLOGY VOLUME 2 | MAY 2002 | 373
tumour cells was significantly lower in
smoke-exposed mice
29
. Moreover, chronic
exposure to cigarette smoke increases the fre-
quency of spontaneous lung tumours in
rats
40
. These studies indicate that the elevated
risk of cancers in smokers might result par-
tially from the effects of cigarette smoke on
the immune system.
Cigarette smoke and adaptive immunity.
Adaptive immunity involves specific immune
responses that are elicited by antigens of vari-
ous origins (for example, pathogens or vac-
cines) and that are executed primarily by
T cells and B cells. A well-documented effect
of cigarette smoking in humans is leukocyto-
sis (an increased number of blood leukocytes);
however, the function of these cells is greatly
reduced (reviewed in REFS 26,29). Smoking is
an important confounding cause of morbid-
ity during an influenza epidemic
41,42
. This
might result, in part, from lower titres and a
decreased half-life of influenza-specific anti-
bodies in cigarette smokers. Several investiga-
tors have shown that long-term smoking
significantly reduces serum levels of
immunoglobulins in humans
39
. In general,
animal studies have supported these findings;
the antibody response to various antigens was
reduced significantly as a consequence of
chronic exposure to cigarette smoke
(reviewed in REFS 26,30). Moreover, mice that
were chronically exposed to cigarette smoke
were more susceptible to influenza and
murine sarcoma viruses. However, in spite of
reduced immunoglobulin levels, smokers
have increased levels of autoantibodies,
notably anti-nuclear rheumatoid factors
43,44
.
Also, experiments in animal models show
that chronic exposure to cigarette smoke
inhibits the clearance of Pseudomonas aerugi-
nosa from the lung, and these animals
develop COPD-like lesions in the lung
38
. So,
smoking produces various morphological,
physiological, biochemical and enzymatic
changes in AMs that might impair antibacte-
rial defences, cellular regulatory activity and
inflammatory responses in the lung, leading
to lung pathogenesis.
Because cigarette smoking is associated
with an increased risk of various cancers, sev-
eral investigators have evaluated the effects of
cigarette smoking on the function of natural
killer (NK) cells a lymphoid cell type that
is recognized for its role in the surveillance of
tumour growth. NK-cell activity against cul-
tured melanomas and other cancer cells was
reduced significantly in smokers compared
with non-smokers
39
. These data were con-
firmed and extended in animal models, in
which resistance to the growth of implanted
immunological consequences of cigarette
smoking in humans and experimental ani-
mals, and the components of cigarette smoke
(BOX 1) that might be responsible for these
effects. Where appropriate, the relevance of
these findings to human diseases is discussed.
A large body of literature now exists on the
consequences of cigarette-smoke inhalation
on the human immune system
26,2931
. The
qualitative and quantitative effects of cigarette
smoke on the immune system might depend
on the duration of smoking, as well as the sex
and ethnicity of the subjects that are studied.
Although cigarette smoking in humans has
been linked to increased susceptibility to
numerous infections, and changes in
humoral and cellular immune responses, the
extent of these changes varies significantly
between studies.
Cigarette smoke and innate immunity. The
lungs are an important route of exposure to
environmental pathogens and antigens; non-
specific and specific defence mechanisms are
involved in clearing these foreign substances
from the lungs. In the respiratory tract of
mammals, the mucociliary escalator of the
large airways removes most inhaled foreign
matter. Protection against the foreign material
reaching the lung alveoli involves innate
and adaptive immune responses. Alveolar
macrophages (AMs) and other monocytes are
the most important part of the innate immune
response in the lungs. Cigarette smoking is a
significant risk factor for acute respiratory-
tract illnesses and COPD, and AMs in the
bronchoalveolar lavage might have a crucial
role in these diseases. Cigarette smoking
increases the number of AMs by several fold,
and these cells express increased levels of lyso-
somal enzymes and secrete elastase
26,32
. These
enzymes might damage connective tissue and
parenchymal cells of the lung, which could
contribute to the pathogenesis of COPD (for
example, chronic bronchitis and emphysema)
(FIG. 2). In addition, AMs from smokers pro-
duce significantly higher levels of oxygen radi-
cals and have higher myeloperoxidase activity;
these are important mediators of the killing of
intracellular pathogens. However, in spite of
the increases in oxygen-radical production
and myeloperoxidase activity, AMs from
smokers have a reduced ability to phagocytose
and/or kill bacteria, such as Staphylococcus
aureus and Listeria monocytogenes
33,34
.
Moreover, several reports indicate that AMs
from smokers are functionally impaired and
secrete significantly lower levels of pro-
inflammatory cytokines
35
. These cytokines are
crucial for early responses to pathogens and
the upregulation of local host defences
36,37
.
Box 1 | Composition of cigarette smoke
Tobacco contains more than 4,500 compounds in the particulate and vapour phases. These
compounds comprise five known human carcinogens and many toxic agents, including carbon
monoxide, ammonia, acrolein, acetone, nicotine, benzopyrenes, hydroquinone and nitrogen
oxides. The particulate and vapour phases are described operationally as fractions of cigarette
smoke that are retained or passed through a Cambridge filter, respectively.
Mainstream smoke is tobacco smoke that is generated during puff-drawing in the burning
cone of a tobacco product, which is inhaled directly by the smoker before it is released into the
surrounding air. Sidestream smoke includes the smoke components that are emitted into the air
during the burning of a tobacco product during and between puffs, and the smoke components
that diffuse through the cigarette paper.
Environmental tobacco smoke (ETS) is composed of sidestream smoke and exhaled
mainstream smoke. Exposure to ETS is defined as the exposure of a person to tobacco-
combustion products from smoking by others. Passive smoking and involuntary smoking are
synonymous terms. Exposure to ETS is also used to describe the exposure of a fetus to tobacco-
combustion products and/or their metabolites from an actively or passively smoking mother.
Because a cigarette burns at a much higher temperature during inhalation, the concentration
of many carcinogenic and toxic compounds is higher in sidestream smoke than mainstream
smoke. Moreover, although a cigarette filter reduces the concentration of many of these
compounds in mainstream smoke, it has no significant effect on the composition of sidestream
smoke. See REF. 18 for further details.
it has been suspected
for some time that tobacco
smoking, for all of its
overwhelming harmful
effects, might protect
smokers from some
diseases.
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374 | MAY 2002 | VOLUME 2 www.nature.com/reviews/immunol
P E R S P E C T I V E S
Many constituents of cigarette smoke have
been shown to modulate the function of
immune cells after in vitro and/or in vivo
administration. For example, acrolein, a
toxic unsaturated aldehyde, affects neutrophil
function
48
and decreases the resistance of the
lungs to infections
49
. Chronic exposure to
benzo[a]pyrene induces dose-related decreases
in the mass and cellularity of lymphoid tissues,
and maternal exposure to benzo[a]pyrene
alters the development of T cells and immune
responses in the offspring
50
. Hydroquinone
one of the main metabolites of benzene
which is present in large quantities in cigarette
tar, has been shown to inhibit the progression
of T lymphoblasts into the cell cycle
51
.
Nicotine, the addictive substance in cigarette
smoke, has multiple effects on the immune
system, which are summarized below.
Nicotine is immunosuppressive
Cigarette smoke that contains high levels of tar
and nicotine induces immunological changes
faster than cigarette smoke that contains lower
So, although smoking decreases the level of
specific antibodies, it increases autoantibody
levels. This could explain, at least in part, the
higher susceptibility of smokers to both
microbial infections and certain autoimmune
diseases (for example, rheumatoid arthritis).
In addition to helping B cells to produce
antibodies, T cells have an important role in
antimicrobial defence. Smoking increases the
number of peripheral-blood CD4
+
T cells in
Caucasians; however, in AfricanAmericans,
smoking causes a dose-dependent decrease in
the number of these T cells
45
. Investigators
have observed that T cells from smokers and
animals that were exposed to cigarette smoke
have a decreased ability to proliferate in
response to T-cell mitogens, which indicates a
deficient cell-mediated immune response
(reviewed in REFS 26,30). Animal experiments
have shown also that cigarette smoke that con-
tains higher levels of tar and nicotine induces
changes in T-cell responsiveness more rapidly
than smoke that contains lower levels of these
compounds (reviewed in REFS 26,29).
Secondhand smoke and the immune system.
Epidemiological studies strongly indicate that
exposure of children under the age of three
years to ETS increases their risk of developing
respiratory-tract illnesses
2325
. This suscepti-
bility might be due to the adverse effects of
cigarette smoke on the immune system. There
is no evidence to indicate that significant
immunological changes are associated with
the exposure of humans or animals to ETS.
However, experiments using secondhand-
smoke (sidestream cigarette smoke) conden-
sates on cell cultures indicated that it might
affect allergic responses and macrophage
function
46,47
. Therefore, at present, the immun-
ological effects of ETS are largely unknown;
but, there are indications that secondhand
smoke might affect some parameters of the
immune system.
Immunomodulatory effects
Tobacco smoke is a complex mixture of more
than 4,500 chemicals, many of which have
toxic and/or carcinogenic activity (BOX 1).
Smooth muscle
Goblet cell
Epithelial cell
Mucus
Smoke
Goblet-cell
hyperplasia
Increased
mucus
production
Chronic
bronchitis
Breakdown of
elastin/collagen
ECM proteins
Destruction of
alveolar septi
Emphysema
Chemokines/
cytokines
Elastase
Collagenase
Neutrophil Macrophage
Figure 2 | Simplified schematic of the mechanism by which cigarette smoke might cause COPD. Neutrophils and macrophages accumulate in
the lungs of smokers, leading to inflammation and the release of cellular products, such as enzymes that break down collagen and elastin in the lung and/or
stimulate mucus production, resulting in emphysema and/or chronic bronchitis, respectively. COPD, chronic obstructive pulmonary disease; ECM,
extracellular matrix.
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NATURE REVIEWS | I MMUNOLOGY VOLUME 2 | MAY 2002 | 375
T cells from smokers and cigarette-smoke-
exposed animals
55,56
. Moreover, enhanced
replication of influenza virus and Legionella
pneumophila (a causative agent of pneumonia)
was observed in the lungs of nicotine-treated
animals and AM cell lines, respectively
57,58
.
These results indicate that nicotine is an
important immunosuppressive constituent of
cigarette smoke.
Neuroimmune effects of nicotine. In addition
to the potential direct effects of nicotine on
leukocyte responses
58,59
, nicotine might influ-
ence the immune system through the central
nervous system (CNS). An intimate relation-
ship exists between the neuroendocrine and
immune systems, and a large body of evidence
indicates that there is a bidirectional commu-
nication between the CNS and the immune
system
60
. The brain modulates the immune
system through two known pathways: the pro-
duction of glucocorticoids through activation
of the hypothalamuspituitaryadrenal
(HPA) axis and the activation of the auto-
nomic nervous system (FIG. 3). Nicotine is a
potent neuroactive compound, and our results
show that the in vivo immunosuppressive
effects of nicotine might be mediated through
the CNS, as well as in the periphery
31,59
.
Studies with adrenalectomized animals
61
and
inhibitors of the autonomic nervous system
indicate that the CNS-mediated immunosup-
pressive effects of nicotine are transmitted to
the immune system primarily through the
autonomic nervous system and are indepen-
dent of the HPA axis. So, drugs that modulate
communication between the brain and the
immune system might regulate some of the
effects of nicotine or cigarette smoke on
immune responses.
Therapeutic use of nicotine. Inflammation is a
double-edged sword; although excessive
inflammation can be life-threatening, ade-
quate inflammation is required for the devel-
opment of immune responses, clearance of
pathogens and recovery from tissue injuries.
As discussed above, cigarette smokers have a
lower incidence of several inflammatory dis-
eases and, compared with non-smokers,
smokers have slower and less satisfactory
healing of wounds that result from trauma,
disease or surgical procedures
10
. An early indi-
cator of inflammation is a rise in body tem-
perature, and results from our laboratory
indicate that, compared with control animals,
nicotine-treated animals have significantly
lower-temperature fevers in response to a
sterile abscess that is produced by the injec-
tion of turpentine
62
. Moreover, morbidity and
mortality due to severe lung inflammation in
Moreover, immunosuppression was observed
in nicotine-treated animals for several weeks
after nicotine administration
53
. Similarly,
patients with ulcerative colitis did not relapse
until several months after nicotine treat-
ment
54
. These observations indicate that nico-
tine suppresses the immune system in a man-
ner similar to cigarette smoke, and that the
effects might remain for sometime after treat-
ment. Studies to delineate the mechanisms by
which nicotine suppresses the immune sys-
tem indicate that after binding an antigen,
T cells from nicotine-treated animals cannot
normally transmit the antigen-receptor-
mediated signals that would allow them to
enter into the cell cycle and proliferate.
Recent studies indicate that a similar defect in
antigen-mediated signalling is also seen in
levels of these components
26
. So, tar and/or
nicotine might be the immunosuppressive
components of cigarette smoke. On the basis
of particle size, cigarette smoke is composed of
two phases the vapour phase and the par-
ticulate phase each of which contains thou-
sands of different chemicals. Unlike whole cig-
arette smoke, chronic exposure to the vapour
phase does not suppress the immune system,
which indicates that one or more components
in the particulate phase is immunosuppressive
(reviewed in REF. 52). In cigarette smoke, most
of the nicotine is associated with the particu-
late phase, and animals that are treated chroni-
cally with nicotine have a significant loss of
antibody responses and T-cell proliferation,
which is reminiscent of animals that are
chronically exposed to cigarette smoke
52
.
CRH
Nicotinic
receptors
Autonomic
nervous system
Adrenal gland
CORT
T cells
Sympathetic Parasympathetic
Hypothalamus
Pituitary gland
ACTH b a
Figure 3 | A simplified schematic of possible communication between the CNS and the immune
system through nicotinic acetylcholine receptors. Nicotine from cigarette smoke enters the brain
and interacts with nicotinic receptors in the brain. Activation of nicotinic receptors could modulate the
immune response by either of two pathways: a | activation of the hypothalamuspituitaryadrenal axis,
whereby corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the release of
adrenocorticotropic hormone (ACTH) from the pituitary gland, which, in turn, stimulates the production of
glucocorticoids (CORT) by the adrenal gland increased levels of CORT suppress the immune system;
and b | activation of the autonomic nervous system, which connects the brain directly to the visceral target
tissues, including lymphoid tissues, through sympathetic and parasympathetic innervations
72
.
Noradrenaline from the sympathetic nerve terminals might modulate T-cell function through adrenoceptors
that are present on T cells
62
. The role of the parasympathetic nervous system in the regulation of T-cell
function is not clear.
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376 | MAY 2002 | VOLUME 2 www.nature.com/reviews/immunol
P E R S P E C T I V E S
5. Obeid, P. & Bercy, P. Effects of cigarette smoking on
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response to influenza infection were reduced
significantly in nicotine-treated mice
62
. So,
nicotine is an anti-inflammatory agent and it
might moderate the severity of some inflam-
matory diseases
54,63
. However, smoking does
not reduce the severity of all inflammatory
diseases, and some inflammatory responses
might even worsen. For example, of the two
inflammatory bowel diseases, ulcerative colitis
is rare among smokers, but Crohns disease is
35 times more prevalent
64
.
Nicotine has been used increasingly as a
treatment for symptoms of nicotine with-
drawal during smoking cessation, with
promising results. Animal experiments indi-
cate that nicotine might prevent neuronal
loss
65
, and evidence is growing that nicotine
given orally as a pill or gum, or by transder-
mal patch to humans might prevent or ame-
liorate cutaneous inflammation, Tourettes
syndrome, Parkinsons disease and other
neurodegenerative diseases. Although nico-
tine improves some cognitive responses in
Alzheimers patients
66
, epidemiological
studies do not unequivocally support the
beneficial effects of cigarette smoking in
Alzheimers disease
27
. Nicotine might benefit
patients with ulcerative colitis, endometriosis
and sarcoidosis. Although some of the bene-
ficial effects of nicotine might result from its
anti-inflammatory properties, other explana-
tions have been proposed for its cognitive and
neuroprotective effects
67,68
. For example, nico-
tine might stimulate the basal forebrain
cholinergic system and/or increase dopamine
production and decrease glutamate toxicity.
There is a great deal of concern within the sci-
entific community about the long-term
effects of nicotine-containing products as
therapeutics. In addition to its effects on the
immune system, nicotine might have bipolar
effects in some inflammatory diseases. This is
shown clearly by the differential responses of
the two inflammatory bowel diseases
ulcerative colitis and Crohns disease to
cigarette smoke in humans and to nicotine in
experimental models of these diseases
69
.
Therefore, nicotine might even be contraindi-
catory for some inflammatory conditions.
However, in many cases, the benefits of nico-
tine therapy might outweigh its potential
adverse effects on the immune system.
Moreover, preliminary data from our labora-
tory indicate that chronic nicotine exposure
might affect immunological memory to only
a moderate degree. Given that immunological
memory to common pathogens is established
generally at an age before the widespread use
of cigarettes or other nicotine-containing
products, the use of therapeutic doses of nico-
tine in later life might not severely affect
immunity against common infections.
Another concern is the possibility that nico-
tine might aggravate cardiovascular disease;
however, recent analysis indicates that nico-
tine therapy, at least in the short term (36
months), might be quite safe
70
. Agonists of
nicotinic acetylcholine receptors are potential
painkillers that have significantly fewer side
effects than opiates
71
. Nonetheless, nicotine is
a drug, and its long-term effects on human
health are largely unknown.
Conclusions
Tobacco smoking continues to be an impor-
tant preventable cause of morbidity and mor-
tality worldwide. In addition to its adverse
effects in cardiovascular disease, lung cancer
and COPD, cigarette smoke suppresses the
immune system. Many components of ciga-
rette smoke, including nicotine, might have
immunomodulatory effects. Nicotine is the
main immunosuppressive constituent of ciga-
rette smoke, which inhibits both the innate
and adaptive immune responses. Unlike ciga-
rette smoke, nicotine is not yet considered to
be a carcinogen. However, because of its
addictive property, acute cardiovascular effects
and effects on the immune system, there are
apprehensions about its use as a therapeutic
agent. Although more research is required to
evaluate the biological effects of long-term
nicotine use in humans, results from animal
experiments and limited human trials indicate
that nicotine or its agonists/analogues might
aid in smoking cessation, the treatment of
some types of inflammatory and neurodegen-
erative conditions, and the development of
new pain-relieving drugs.
Mohan Sopori is at the Immunology Program,
Lovelace Respiratory Research Institute,
2425 Ridgecrest Drive, SE Albuquerque,
New Mexico 87108, USA.
e-mail: msopori@lrri.org
doi:10.1038/nri803
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Acknowledgements
I would like to acknowledge the National Institutes of Health, the
Lovelace Medical Foundation and the United States Army Medical
Research for supporting my studies.
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