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Females
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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.
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PERSPECTIVES
immunological consequences of cigarette
smoking in humans and experimental animals, 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 system26,2931. 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; nonspecific 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 respiratorytract 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 lysosomal enzymes and secrete elastase26,32. 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 produce significantly higher levels of oxygen radicals 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 proinflammatory cytokines35. These cytokines are
crucial for early responses to pathogens and
the upregulation of local host defences36,37.
PERSPECTIVES
Goblet cell
Epithelial cell
Smooth muscle
Smoke
Chronic
bronchitis
Increased
mucus
production
Goblet-cell
hyperplasia
Mucus
Chemokines/
cytokines
Elastase
Breakdown of
elastin/collagen
ECM proteins
Collagenase
Neutrophil
Macrophage
Destruction of
alveolar septi
Emphysema
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.
374
Immunomodulatory effects
Nicotine is immunosuppressive
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PERSPECTIVES
T cells from smokers and cigarette-smokeexposed animals55,56. 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, respectively57,58.
These results indicate that nicotine is an
important immunosuppressive constituent of
cigarette smoke.
Nicotinic
receptors
CRH
Hypothalamus
Pituitary gland
ACTH
Adrenal gland
Autonomic
nervous system
Sympathetic
Parasympathetic
CORT
T cells
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 innervations72.
Noradrenaline from the sympathetic nerve terminals might modulate T-cell function through adrenoceptors
that are present on T cells62. The role of the parasympathetic nervous system in the regulation of T-cell
function is not clear.
PERSPECTIVES
response to influenza infection were reduced
significantly in nicotine-treated mice62. So,
nicotine is an anti-inflammatory agent and it
might moderate the severity of some inflammatory diseases54,63. 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 prevalent64.
Nicotine has been used increasingly as a
treatment for symptoms of nicotine withdrawal during smoking cessation, with
promising results. Animal experiments indicate that nicotine might prevent neuronal
loss65, and evidence is growing that nicotine
given orally as a pill or gum, or by transdermal patch to humans might prevent or ameliorate cutaneous inflammation, Tourettes
syndrome, Parkinsons disease and other
neurodegenerative diseases. Although nicotine improves some cognitive responses in
Alzheimers patients66, epidemiological
studies do not unequivocally support the
beneficial effects of cigarette smoking in
Alzheimers disease27. Nicotine might benefit
patients with ulcerative colitis, endometriosis
and sarcoidosis. Although some of the beneficial effects of nicotine might result from its
anti-inflammatory properties, other explanations have been proposed for its cognitive and
neuroprotective effects67,68. For example, nicotine 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 scientific 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 diseases69.
Therefore, nicotine might even be contraindicatory for some inflammatory conditions.
However, in many cases, the benefits of nicotine therapy might outweigh its potential
adverse effects on the immune system.
Moreover, preliminary data from our laboratory 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 nicotine in later life might not severely affect
376
5.
6.
7.
8.
9.
Tobacco smoking continues to be an important preventable cause of morbidity and mortality worldwide. In addition to its adverse
effects in cardiovascular disease, lung cancer
and COPD, cigarette smoke suppresses the
immune system. Many components of cigarette smoke, including nicotine, might have
immunomodulatory effects. Nicotine is the
main immunosuppressive constituent of cigarette smoke, which inhibits both the innate
and adaptive immune responses. Unlike cigarette 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 neurodegenerative 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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27.
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29.
30.
31.
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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.
Online links
DATABASES
The following terms in this article are linked online to:
CancerNet: http://www.cancer.gov/search/
bladder cancer | endometrial cancer | lung cancer
Entrez: http://www.ncbi.nlm.nih.gov/entrez/
HIV-1
LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/
elastase | myeloperoxidase
OMIM: http://www.ncbi.nlm.nih.gov/Omim/
Alzheimers disease | asthma | atherosclerosis | Crohns
disease | endometriosis | osteoporosis | Parkinsons disease |
rheumatoid arthritis | sarcoidosis | Sjgrens syndrome |
Tourettes syndrome | ulcerative colitis
Access to this interactive links box is free online.
ERRATUM
The human CD69 gene maps to the natural-killer gene complex on chromosome 12p, not chromosome 19 as stated incorrectly in
this Review. For further details, see Lpez-Cabrera et al. Molecular cloning, expression and chromosomal localization of the human
earliest lymphocyte activation antigen AIM/CD69, a new member of the C-type animal lectin superfamily of signal-transmitting
receptors. J. Exp. Med. 178, 537547 (1993).
Also, reference 26 in this article should have been Arce, I. et al. Molecular and genomic characterization of human DLEC, a novel
member of the C-type lectin receptor gene family preferentially expressed on monocyte-derived dendritic cells. Eur. J. Immunol. 31,
27332740 (2001).
A. Dzionek et al. (REF. 3 in the original Review) have published the molecular characterization of the BDCA-2 antigen and have
shown that it is encoded by the same gene as DLEC (HGMV-approved symbol CLECSF11). Therefore, DLEC and BDCA-2 are the
same protein.