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SCIENCE AND SOCIETY

Effects of cigarette smoke on the


immune system
Mohan Sopori

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 significantly increases the risk of heart disease,
lung cancer and microbial infections (such as
respiratory infections, periodontitis and bacterial meningitis)27. Tobacco use is also associated with delayed recovery from injuries and a
higher incidence of atherosclerosis, chronic
obstructive pulmonary disease (COPD),
Crohns disease, rheumatoid arthritis and cancers of the lung, mouth, larynx, oesophagus
and bladder3,4,810. 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 child1114. 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 men15. So, racial background
might have a role in smoking-associated morbidity and mortality.
For nearly four decades, health departments worldwide have alerted individuals to
the health hazards of cigarette smoking and,
in the United States, the results have been

372

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 system29. The possibility 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

25

25
Females

20

15

Males

20

12th
11th

12th

10th

11th

9th

10th

10

15

10

9th

Percentage smoking frequently

Health consequences of smoking

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 cigarette smoking by high-school students from
1993 to 1997 in the United States (FIG. 1).
Moreover, tobacco use has increased markedly
worldwide since the 1980s16. Therefore,
tobacco use is an important public-health
issue, both in the United States and globally17.
Since the early 1980s, there has been growing concern that the inhalation of environmental tobacco smoke (ETS) also known as
secondhand or passive smoke18 (BOX 1),
might adversely affect the health of non-smokers19,20. ETS might be responsible for some respiratory diseases and the aggravation of allergic responses; however, it is debatable whether
ETS actually increases the incidence of lung
cancer21,22. Children might be particularly sensitive 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,

Percentage smoking frequently

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.

and the development of atopy and asthma


during childhood2325. 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 adults16.
However, it has been suspected for some
time that tobacco smoking, for all of its overwhelming 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 disease2628. Interestingly,
many of these diseases are inflammatory diseases or have an inflammatory component.

0
1993

1995

1997

Year

1993

1995

1997

Year

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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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.

Also, experiments in animal models show


that chronic exposure to cigarette smoke
inhibits the clearance of Pseudomonas aeruginosa from the lung, and these animals
develop COPD-like lesions in the lung38. So,
smoking produces various morphological,
physiological, biochemical and enzymatic
changes in AMs that might impair antibacterial defences, cellular regulatory activity and
inflammatory responses in the lung, leading
to lung pathogenesis.

it has been suspected


for some time that tobacco
smoking, for all of its
overwhelming harmful
effects, might protect
smokers from some
diseases.
Because cigarette smoking is associated
with an increased risk of various cancers, several 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 cultured melanomas and other cancer cells was
reduced significantly in smokers compared
with non-smokers39. These data were confirmed and extended in animal models, in
which resistance to the growth of implanted

tumour cells was significantly lower in


smoke-exposed mice29. Moreover, chronic
exposure to cigarette smoke increases the frequency of spontaneous lung tumours in
rats40. These studies indicate that the elevated
risk of cancers in smokers might result partially 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 various origins (for example, pathogens or vaccines) and that are executed primarily by
T cells and B cells. A well-documented effect
of cigarette smoking in humans is leukocytosis (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 morbidity during an influenza epidemic41,42. This
might result, in part, from lower titres and a
decreased half-life of influenza-specific antibodies in cigarette smokers. Several investigators have shown that long-term smoking
significantly reduces serum levels of
immunoglobulins in humans39. 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 factors43,44.

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 tobaccocombustion 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 tobaccocombustion 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.

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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.

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 cells45. 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 contains 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).

374

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 illnesses2325. This susceptibility 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 secondhandsmoke (sidestream cigarette smoke) condensates on cell cultures indicated that it might
affect allergic responses and macrophage
function46,47. Therefore, at present, the immunological effects of ETS are largely unknown;
but, there are indications that secondhand
smoke might affect some parameters of the
immune system.

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
function48 and decreases the resistance of the
lungs to infections49. 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 offspring50. 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 cycle51.
Nicotine, the addictive substance in cigarette
smoke, has multiple effects on the immune
system, which are summarized below.

Immunomodulatory effects

Nicotine is immunosuppressive

Tobacco smoke is a complex mixture of more


than 4,500 chemicals, many of which have
toxic and/or carcinogenic activity (BOX 1).

Cigarette smoke that contains high levels of tar


and nicotine induces immunological changes
faster than cigarette smoke that contains lower

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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.

levels of these components26. 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 particulate phase each of which contains thousands of different chemicals. Unlike whole cigarette 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 particulate phase, and animals that are treated chronically with nicotine have a significant loss of
antibody responses and T-cell proliferation,
which is reminiscent of animals that are
chronically exposed to cigarette smoke52.

Moreover, immunosuppression was observed


in nicotine-treated animals for several weeks
after nicotine administration53. Similarly,
patients with ulcerative colitis did not relapse
until several months after nicotine treatment54. These observations indicate that nicotine suppresses the immune system in a manner similar to cigarette smoke, and that the
effects might remain for sometime after treatment. Studies to delineate the mechanisms by
which nicotine suppresses the immune system indicate that after binding an antigen,
T cells from nicotine-treated animals cannot
normally transmit the antigen-receptormediated 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

NATURE REVIEWS | IMMUNOLOGY

Neuroimmune effects of nicotine. In addition


to the potential direct effects of nicotine on
leukocyte responses58,59, nicotine might influence the immune system through the central
nervous system (CNS). An intimate relationship exists between the neuroendocrine and
immune systems, and a large body of evidence
indicates that there is a bidirectional communication between the CNS and the immune
system60. The brain modulates the immune
system through two known pathways: the production of glucocorticoids through activation
of the hypothalamuspituitaryadrenal
(HPA) axis and the activation of the autonomic 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 periphery31,59.
Studies with adrenalectomized animals61 and
inhibitors of the autonomic nervous system
indicate that the CNS-mediated immunosuppressive effects of nicotine are transmitted to
the immune system primarily through the
autonomic nervous system and are independent 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, adequate inflammation is required for the development of immune responses, clearance of
pathogens and recovery from tissue injuries.
As discussed above, cigarette smokers have a
lower incidence of several inflammatory diseases and, compared with non-smokers,
smokers have slower and less satisfactory
healing of wounds that result from trauma,
disease or surgical procedures10. An early indicator of inflammation is a rise in body temperature, 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 injection of turpentine62. Moreover, morbidity and
mortality due to severe lung inflammation in

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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.

nicotine is a drug, and


its long-term effects on
human health are largely
unknown.

6.

7.
8.
9.

immunity against common infections.


Another concern is the possibility that nicotine might aggravate cardiovascular disease;
however, recent analysis indicates that nicotine therapy, at least in the short term (36
months), might be quite safe70. Agonists of
nicotinic acetylcholine receptors are potential
painkillers that have significantly fewer side
effects than opiates71. Nonetheless, nicotine is
a drug, and its long-term effects on human
health are largely unknown.

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

2.

3.

4.

11.

12.

13.
14.

15.

Conclusions

1.

10.

Centers for Disease Control and Prevention (CDC).


Achievements in public health, 19001999. Tobacco use
United States, 19001999. Morb. Mortal. Wkly Rep.
48, 986993 (1999).
Reducing the Health Consequences of Smoking: 25
Years of Progress. A Report of the Surgeon General CDC
Publication No. 89-8411 (US Department of Health and
Human Services, Washington DC, 1989).
The Health Consequences of Smoking: Cancer. A Report
of the Surgeon General (US Department of Health and
Human Services, Washington DC, 1982).
Doll, R. & Peto, R. Mortality in relation to smoking: 20
years observations on male British doctors. BMJ
2, 15251536 (1976).

| MAY 2002 | VOLUME 2

16.

17.
18.

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.
31.

Obeid, P. & Bercy, P. Effects of cigarette smoking on


periodontal health: a review. Adv. Ther. 17, 230237
(2000).
Nuorti, J. P. et al. Cigarette smoking and invasive
pneumococcal disease. Active bacterial core surveillance
team. N. Engl. J. Med. 342, 681689 (2000).
Gold, R. Epidemiology of bacterial meningitis. Infect. Dis.
Clin. North Am. 13, 515525 (1999).
Saag, K. G. et al. Cigarette smoking and rheumatoid
arthritis severity. Ann. Rheum. Dis. 56, 463469 (1997).
Nagai, S., Hoshino, Y., Hayashi, M. & Ito, I. Smokingrelated interstitial lung diseases. Curr. Opin. Pulm. Med.
6, 415419 (2000).
Silverstein, P. Smoking and wound healing. Am. J. Med.
93, S22S24 (1992).
Kirk, J. K., Spangler, J. G. & Celestino, F. S. Prevalence of
osteoporosis risk factors and treatment among women
aged 50 years and older. Pharmacotherapy 20, 405409
(2000).
Mishra, G. D., Dobson, A. J. & Schofield, M. J. Cigarette
smoking, menstrual symptoms and miscarriage among
young women. Aust. N. Z. J. Public Health 24, 413420
(2000).
Seltzer, V. Smoking and womens health. Int. J. Gynaecol.
Obstet. 70, 159163 (2000).
Burns, D. N. et al. Cigarette smoking, premature rupture
of membranes and vertical transmission of HIV-1 among
women with low CD4+ levels. J. AIDS 7, 718726 (1994).
Tobacco Use Among US Racial/Ethnic Minority Groups
African Americans, American Indians and Alaska
Natives, Asian Americans and Pacific Islanders, and
Hispanics. Report of the Surgeon General (US
Department of Health and Human Services, Washington
DC, 1998).
Smith, S. S. & Fiore, M. C. The epidemiology of tobacco
use, dependence and cessation in the United States.
Prim. Care 26, 433461 (1999).
Bartecchi, C. E., MacKenzie, T. D. & Schrier, R. W. The
global tobacco epidemic. Sci. Am. 272, 4451 (1995).
Jaakkola, M. S. & Jaakkola, J. J. K. Assessment of
exposure to environmental tobacco smoke. Eur. Respir. J.
10, 23842397 (1997).
Respiratory Health Effects of Passive Smoking: Lung
Cancer and Other Disorders Monograph No. 4,
Publication No. 93-3605 (US Environmental Protection
Agency, Washington DC, 1993).
Witschi, H., Load, J. P. & Pinkerton, K. E. The toxicology
of environmental tobacco smoke. Annu. Rev. Pharmacol.
Toxicol. 37, 2952 (1997).
Mantel, N. Dubious evidence of heart and cancer deaths
due to passive smoking. J. Clin. Epidemiol. 45, 809813
(1992).
Adlkofer, F. Lung cancer due to passive smoking a
review. Int. Arch. Occup. Environ. Health. 74, 231241
(2001).
Tashkin, D. P. et al. The UCLA population studies of
chronic obstructive respiratory disease. VII. Relationship
between parental smoking and childrens lung function.
Am. Rev. Respir. Dis. 129, 891897 (1984).
Holberg, C. J. et al. Child day care, smoking by
caregivers and lower respiratory tract illness in the first
3 years of life. Pediatrics 91, 885892 (1993).
Sherrill, D. L. et al. Longitudinal effects of passive
smoking on pulmonary function in New Zealand children.
Am. Rev. Respir. Dis. 145, 11361141 (1992).
Sopori, M. L., Goud, N. S., & Kaplan, A. M. in
Immunotoxicology and Immunopharmacology (eds
Dean, J. H. et al.) 413433 (Raven, New York, 1994).
Fratiglioni, L. & Wang, H. X. Smoking and Parkinsons
and Alzheimers disease: review of the epidemiological
studies. Behav. Brain Res. 113, 117120 (2000).
Manthorpe, R. et al. Lower frequency of focal lip
sialadenitis (focus score) in smoking patients. Can
tobacco diminish the salivary gland involvement as
judged by histological examination and anti-SSA/Ro and
anti-SSB/La antibodies in Sjogrens syndrome? Ann.
Rheum. Dis. 59, 5460 (2000).
Holt, P. G. & Keast, D. Environmentally induced changes
in immunological function: acute and chronic effects of
inhalation of tobacco smoke and other atmospheric
contaminants in man and experimental animals.
Bacteriol. Rev. 41, 205216 (1977).
Holt, P. G. Immune and inflammatory function in cigarette
smokers. Thorax 42, 241249 (1987).
Sopori, M. L. & Kozak, W. Mechanisms and effects of
immunomodulation by cigarette smoke.
J. Neuroimmunol. 81, 138146 (1998)

www.nature.com/reviews/immunol

2002 Nature Publishing Group

PERSPECTIVES
32. Reynolds, H. Y. Bronchoalveolar lavage. Am. Rev. Respir.
Dis. 135, 250263 (1987).
33. Martin, R. R. & Warr, G. A. Cigarette smoking and
pulmonary macrophages. Hosp. Prac. 12, 97104 (1977).
34. King, T. E. Jr, Savici, D. & Campbell, P. A. Phagocytosis
and killing of Listeria monocytogenes by alveolar
macrophages: smokers versus nonsmokers. J. Infect.
Dis. 158, 13091316 (1988).
35. McCrea, K. A. et al. Altered cytokine regulation in the
lungs of cigarette smokers. Am. J. Respir. Crit. Care
Med. 150, 696703 (1994).
36. Kishimoto, T. The biology of interleukin-6. Blood 74, 110
(1989).
37. Beutler, B. The complex regulation and biology of TNF
(cachectin). Oncogenesis 2, 918 (1990).
38. Thomas, W. R., Holt, P. G. & Keast, D. Cigarette smoke
and phagocyte function: effect of chronic exposure
in vivo and acute exposure in vitro. Infect. Immunol. 20,
468475 (1978).
39 Ferson, M., Edwards, A., Lind, A., Milton, G. W. & Hersey, P.
Low natural-killer-cell activity and immunoglobulin levels
associated with smoking in human subjects. Int. J.
Cancer 23, 603609 (1979).
40. Dalbey, W. E., Nettesheim, P., Griesemer, R., Caton, J. E.
& Guerin, M. R. Chronic inhalation of cigarette smoke by
F344 rats. J. Natl Cancer Inst. 64, 383390 (1980).
41. Finklea, J. F., Sandifer, S. H. & Smith, D. D. Cigarette
smoking and epidemic influenza. Am. J. Epidemiol. 90,
390399 (1969).
42. Kark, J. D., Lebiush, M. & Rannon, L. Cigarette smoking
as a risk factor for epidemic A(H1N1) influenza in young
men. N. Engl. J. Med. 307, 10421046 (1982).
43. Mathews, J. D., Whittingham, S., Hooper, B. M., Mackay,
I. R. & Stenhouse, N. S. Association of autoantibodies
with smoking, cardiovascular morbidity and death in the
Busselton population. Lancet 2, 754758 (1973).
44. Masdottir, B. et al. Smoking, rheumatoid factor isotypes
and severity of rheumatoid arthritis. Rheumatology 39,
12021205 (2000).
45. Tollerud, D. J. et al. T-cell subsets in healthy black
smokers and non-smokers: evidence for ethnic group as
an important response modifier. Am. J. Respir. Dis. 144,
612616 (1991).
46. Seymour, B. W. P., Pinkerton, K. E., Friebertshauser, K. E.,
Coffman, R. L. & Gershwin, L. J. Second-hand smoke is
an adjuvant for T-helper-2 responses in a murine model of
allergy. J. Immunol. 159, 61696175 (1997).
47. Edwards, K., Braun, K. M., Evans, G., Sureka, A. O. &
Fan, S. Mainstream and sidestream cigarette smoke
condensates suppress macrophage responsiveness to
interferon-. Hum. Exp. Toxicol. 18, 233240 (1999).
48. Finkelstein, E. I., Nardini, M. & van der Vliet, A. Inhibition
of neutrophil apoptosis by acrolein: a mechanism of
tobacco-related lung disease? Am. J. Physiol. Lung Cell.
Mol. Physiol. 281, L732L739 (2001).

49. Holian, A. & Li, L. Acrolein: a respiratory toxin that


suppresses pulmonary host defense. Rev. Environ.
Health 13, 99108 (1998).
50. Rodriguez, J. W. et al. Maternal exposure to
benzo[a]pyrene alters development of T lymphocytes in
offspring. Immunopharmacol. Immunotoxicol. 21,
379396 (1999).
51. Li, Q. et al. Inhibition of human T-lymphoblast proliferation
by hydroquinone. Toxicol. Appl. Pharmacol. 139,
317323 (1996).
52. Sopori, M. L. in Neuronal Nicotinic Receptors:
Pharmacology and Therapeutic Opportunities (eds
Aneric, S. P. & Brioni, J. D.) 197209 (WileyLiss, New
York, 1998).
53. Geng, Y., Savage, S. M., Razani-Boroujerdi, S. &
Sopori, M. L. Effects of nicotine on the immune response.
II. Chronic nicotine treatment induces T-cell anergy.
J. Immunol. 156, 23842390 (1996).
54. Guslandi, M. Long-term effects of a single course of
nicotine treatment in acute ulcerative colitis: remission
maintenance in a 12-month follow-up study. Int. J.
Colorectal Dis. 14, 261262 (1999).
55. Suzuki, N., Wakisaka, S., Takeba, Y., Mihara, S. &
Sakane, T. Effects of cigarette smoking on Fas/Fas-ligand
expression of human lymphocytes. Cell. Immunol. 192,
4853 (1999).
56. Kalra, R., Singh, S. P., Savage, S. M., Finch, G. L. &
Sopori, M. L. Effects of cigarette smoke on the immune
response: chronic exposure to cigarette smoke impairs
antigen-mediated signaling in T cells and depletes IP3sensitive calcium stores. J. Pharmacol. Exp. Ther. 293,
166171 (2000).
57. Sopori, M. L., Kozak, W., Savage, S. M., Geng, Y. &
Kluger, M. J. Nicotine-induced modulation of T-cell
function: implications for inflammation and infection. Adv.
Exp. Med. Biol. 402, 279289 (1998).
58. Matsunaga, K., Klein, T. W., Friedman, H. & Yamamoto, Y.
Involvement of nicotinic acetylcholine receptors in
suppression of antimicrobial activity and cytokine
responses of alveolar macrophages to Legionella
pneumophila infection by nicotine. J. Immunol. 167,
65186524 (2001).
59. Sopori, M. L. et al. Effect of nicotine on the immune
system: possible regulation of immune responses by
central and peripheral mechanisms.
Psychoneuroendocrinology 23, 189204 (1998).
60. Blalock, J. E. The immune system: our sixth sense.
Immunologist 2, 815 (1994).
61. Singh, S. P. et al. Acute and chronic nicotine exposures
modulate the immune system through different
pathways. Toxicol. Appl. Pharmacol. 164, 6572
(2000).
62. Bortik, M. M., Brooks, W. H. & Roszman, T. L. Modulation
of T-cell proliferation by stimulation of the -adrenergic
receptor. Cell. Immunol. 148, 408421 (1993).

63. Mills, C. M., Hill, S. A. & Marka, R. Transdermal nicotine


suppresses cutaneous inflammation. Arch. Dermatol.
133, 823825 (1997).
64. Matri, S., Karoui, S. & Filali, A. Tobacco and inflammatory
bowel disease. Tunis. Med. 78, 693698 (2000).
65. Socci, D. J. & Arendash, G. W. Chronic nicotine
treatment prevents neuronal loss in neocortex resulting
from nucleus basalis lesions in young adult and aged
rats. Mol. Chem. Neuropathol. 27, 285305 (1996).
66. White, H. K. & Levin, E. D. Four-week nicotine skin-patch
treatment effects on cognitive performance in Alzheimers
disease. Psychopharmacology 143, 158165 (1999).
67. McGehee, D. S., Heath, M. J. S., Gelber, S., Devay, P. &
Role, L. W. Nicotine enhancement of fast excitatory
synaptic transmission in CNS by presynaptic receptors.
Science 269, 16921696 (1995).
68. Levin, E. D. & Simon, B. B. Nicotinic acetylcholine
involvement in cognitive function in animals.
Psychopharmacology 138, 217230 (1998).
69. Eliakim, R. et al. Dual effects of chronic nicotine
administration: augmentation of jejunitis and amelioration
of colitis induced by iodoacetamide in rats. Int. J.
Colorectal Dis. 16, 1421 (2001).
70. Benowitz, N. L. in Nicotine Safety and Toxicity (ed.
Benowitz, N. L.) 185194 (Oxford University Press, 1998).
71. Decker, M. W. & Meyer, M. D. Therapeutic potential of
neuronal nicotinic acetylcholine receptor agonists as novel
analgesics. Biochem. Pharmacol. 58, 917923 (1999).
72 Felton, D. L., Felton, S. Y., Bellinger, D. L., Carson, S. L. &
Ackerman, K. D. Noradrenergic sympathetic neuronal
interactions with the immune system: structure and
function. Immunol. Rev. 100, 225260 (1987).

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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ERRATUM

C-TYPE LECTIN RECEPTORS ON DENDRITIC CELLS AND


LANGERHANS CELLS
Carl G. Figdor, Yvette van Kooyk and Gosse J. Adema
Nature Reviews Immunology 2, 7784

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.

NATURE REVIEWS | IMMUNOLOGY

VOLUME 2 | MAY 2002 | 3 7 7

2002 Nature Publishing Group

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