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Impacts of cigarette smoking on immune responsiveness: Up and down or upside down?

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Cigarette smoking is associated with numerous diseases and poses a serious challenge to the current healthcare system worldwide. Smoking impacts both innate and adaptive immunity and plays dual roles in regulating immunity by either exacerbation of pathogenic immune responses or attenuation of defensive immunity. Adaptive immune cells affected by smoking mainly include T helper cells (Th1/Th2/Th17), CD4+CD25+ regulatory T cells, CD8+ T cells, B cells and memory T/B lymphocytes while innate immune cells impacted by smoking are mostly DCs, macrophages and NK cells. Complex roles of cigarette smoke have resulted in numerous diseases, including cardiovascular, respiratory and autoimmune diseases, allergies, cancers and transplant rejection etc. Although previous reviews have described the effects of smoking on various diseases and regional immunity associated with specific diseases, a comprehensive and updated review is rarely seen to demonstrate impacts of smoking on general immunity and, especially on major components of immune cells. Here, we aim to systematically and objectively review the influence of smoking on major components of both innate and adaptive immune cells, and summarize cellular and molecular mechanisms underlying effects of cigarette smoking on the immune system. The molecular pathways impacted by cigarette smoking involve NFκB, MAP kinases and histone modification. Further investigations are warranted to understand the exact mechanisms responsible for smoking-mediated immunopathology and to answer lingering questions over why cigarette smoking is always harmful rather than beneficial even though it exerts dual effects on immune responses.
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Oncotarget1
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www.impactjournals.com/oncotarget/ Oncotarget, Advance Publications 2016
Impacts of cigarette smoking on immune responsiveness: Up
and down or upside down?
Feifei Qiu1, Chun-Ling Liang1, Huazhen Liu1, Yu-Qun Zeng2, Shaozhen Hou3, Song
Huang3, Xiaoping Lai3, Zhenhua Dai1
1Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences and Guangdong Provincial Hospital of
Chinese Medicine, Guangzhou, Guangdong, China
2Department of Nephrology, The Second Afliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou,
Guangdong, China
3School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
Correspondence to: Zhenhua Dai, email: zdai2009@outlook.com
Keywords: cigarette smoking, immunoregulation, adaptive immunity, and innate immunity
Received: September 16, 2016 Accepted: November 12, 2016 Published: November 25, 2016
ABSTRACT
Cigarette smoking is associated with numerous diseases and poses a serious
challenge to the current healthcare system worldwide. Smoking impacts both
innate and adaptive immunity and plays dual roles in regulating immunity by
either exacerbation of pathogenic immune responses or attenuation of defensive
immunity. Adaptive immune cells affected by smoking mainly include T helper cells
(Th1/Th2/Th17), CD4+CD25+ regulatory T cells, CD8+ T cells, B cells and memory
T/B lymphocytes while innate immune cells impacted by smoking are mostly DCs,
macrophages and NK cells. Complex roles of cigarette smoke have resulted in numerous
diseases, including cardiovascular, respiratory and autoimmune diseases, allergies,
cancers and transplant rejection etc. Although previous reviews have described the
effects of smoking on various diseases and regional immunity associated with specic
diseases, a comprehensive and updated review is rarely seen to demonstrate impacts
of smoking on general immunity and, especially on major components of immune cells.
Here, we aim to systematically and objectively review the inuence of smoking on
major components of both innate and adaptive immune cells, and summarize cellular
and molecular mechanisms underlying effects of cigarette smoking on the immune
system. The molecular pathways impacted by cigarette smoking involve NFκB, MAP
kinases and histone modication. Further investigations are warranted to understand
the exact mechanisms responsible for smoking-mediated immunopathology and to
answer lingering questions over why cigarette smoking is always harmful rather than
benecial even though it exerts dual effects on immune responses.
INTRODUCTION
Cigarette smoking is prevalent worldwide and it has
been reported that approximately 1/3 of the adult population
smokes tobacco [1]. Smoke from tobacco combustion
contains numerous harmful chemicals, including, but not
limited to, carbon monoxide, nicotine, nitrogen oxides
and cadmium [2, 3]. Exposure of tobacco smoke has been
considered as an important cause of preventable death
worldwide [4, 5] and related to the development of brain,
respiratory, cardiovascular diseases, infections and cancers
[6–9] (Table 1). Meanwhile, smoking has been implicated
in the production of many immune or inammatory
mediators, including both pro-inammatory and anti-
inammatory cytokines [10–14]. Recently, many studies
have demonstrated that cigarette smoking has far-reaching
effects on chronic inammation and autoimmunity at a
systemic level [2, 10, 15, 16], including rheumatoid arthritis
(RA), psoriasis, chronic obstructive pulmonary disease
(COPD) and systemic lupus erythematosus (SLE). Although
reviews have been previously conducted to describe effects
of cigarette smoking on various diseases and local immunity
associated with a specic disease, a comprehensive review
demonstrating impacts of cigarette smoking on major
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Table 1: Major diseases caused by cigarette smoking
Disease Disease Disease
Cancers Lung cancer Autoimmune
diseases
Rheumatoid arthritis Graft rejection Cardiovascular
graft
Renal carcinoma Chronic obstructive
pulmonary disease Renal graft
Bladder cancer Systemic lupus
erythematosus
Lung
transplantaion
Pancreatic carcinoma Inammatory bowel
disease
Cardiac
transplantation
Breast cancer Crohn's disease Hepatic
transplantation
Hepatocellular cancer Ulcerative colitis Lower extremity
bypass
Esophageal squamous
cell carcinoma Psoriatic arthritis Infrainguinal
bypass
Oral cavity cancer Ankylosing
spondylitis Skin graft
Pharynx cancer Systemic sclerosis
Hematopoietic
stem cell
transplantation
Nasopharynx carcinoma Diabetes mellitus
Oral and
respiratory
diseases
Acute eosinophilic
pneumonia
Stomach cancer Macular degeneration Asthma
Uterine cervix cancer Graves'
hyperthyroidism
Chronic
obstructive
pulmonary disease
Myeloid leukaemia Goodpasture's
syndrome
Hypersensitivity
pneumonitis
Pregnancy Preterm birth Thromboangiitis
obliterans
Rhinitis
Fetal growth restriction Primary biliary
cirrhosis Periodontitis
Placental abrubtion Neurological
diseases Alzheimer's Disease Gingivitis
Placenta previa Stroke Recurrent
wheezing
Low birthweight Small vessel ischemic
disease
Cardiovascular
diseases
Myocardial
infarction
Sudden infant death
syndrome Cerebral aneurysms Cardiac
arrhythmia
Silent cerebral
infarction Atherothrombosis
Parkinson's disease Thromboangiitis
obliterans
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components of immune cells is lacking. We have previously
found that smoking hinders long-term allograft survival
induced by costimulatory blockade [17]. Here, we aim to
systematically review dual inuences of smoking on main
components of immune cells of both innate and adaptive
immunity, and summarize the molecular and cellular
mechanisms underlying the effects of cigarette smoking on
the immune cells.
EFFECTS OF CIGARETTE SMOKING
ON ADAPTIVE IMMUNITY
T lymphocytes
T lymphocytes (T cells) are a major subset of
immune cells mediating adaptive immunity. In general,
activation and differentiation of naive T cells upon antigen
recognition generate effector T cells and, at a small
frequency, memory and regulatory T cells [18–24]. These
cells exert their functions in response to specic antigens
through their helper, effector, cytotoxic or regulatory
capacities. Previous studies have shown the profound
impacts of cigarette smoking on T cells and their release
of proinammatory mediators (Figure 1).
T helper cells
Epidemiological studies have suggested that either
rsthand or secondhand tobacco smoking is an important
contributor in the development of many diseases. It’s
been known that cigarette smoking is a major cause of
COPD characterized by chronic airow obstruction [25].
Forsslund et al [26] analyzed T cells in bronchoalveolar
lavage (BAL) uid and peripheral blood from 40 non-
smokers, 40 smokers with normal pulmonary function
and 38 COPD patients. They found that the percentage
of CD8+ BAL cells of smoking groups was higher than
that of non-smoking groups while the frequency of CD4
+
T cells in both BAL and blood of smokers was lower
than that of non-smokers. Zhang et el. [27] found that the
homeostasis of circulating T helper cells was disrupted
in chronic COPD patients compared with healthy non-
smokers. Second-hand smoke (SHS) also affected T
cell components. Analyses of blood cotinine, a nicotine
metabolite, and T-cell subpopulations from non-smokers
demonstrated that passive smoking was positively
correlated with the prevalence of naive CD3+ T cells [28].
Taken together, active smoking increases the percentage
of CD8+ T cells but lowers CD4+ T cells in humans while
passive smoking generally augments human CD3+ T cells.
Further studies demonstrated that the percentage
of Th17 cells in circulating T cell subsets from COPD
patients was higher than that of current smokers without
COPD and healthy subjects while the percentage of Th1
cells was also increased in COPD patients and current
smokers without COPD [29]. Mice with COPD induced
by chronic tobacco smoke also exhibited a rise in Th17
subset accompanying with upregulation of Th17-series
of cytokines (IL-6, IL-17A and IL-23) in the lung tissue
Figure 1: Effects of cigarette smoking on the development and function of both innate and adaptive immune cells.
Cigarette smoking alters the development, cytokine production, and effector function of both innate immune cells, including DCs,
macrophages and NK cells, and adaptive immune cells, such as cytotoxic CD8+ T cells, CD4+ Th cells, regulatory T cells and B cells,
leading to pro-inammatory responses and/or dysfunction of immune cells. (“Altered” denotes contradictory results with both upregulation
and downregulation)
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and peripheral blood [30]. A study on BAL from mice,
which were exposed to tobacco smoke for at least six
months, showed that the number of Th1 and Th17 cells
was signicantly elevated [31]. Mice with emphysema
had an increased expression of Th1-type cytokine IFN-γ
and Th17-type IL-17A [32, 33] and/or augmented
numbers of Th17/Tc17 and Tc1 cells [33, 34]. Therefore,
both murine experiments and human studies suggest that
increases in Th1 and Th17 cell subsets are associated
with pulmonary inammation as a result of cigarette
smoke exposure (CSE).
Crohn’s disease (CD) is a chronic inammatory
bowel disease that leads to obvious morbidity [35], and is
epidemiologically correlated with cigarette smoking [36,
37]. Many studies have revealed that immune responses
mediated by Th1 and Th17 cells play an important role
in CD [38–40], and that nicotine, a major component of
tobacco smoke, can worsen the trinitrobenzene sulfonic
acid (TNBS)-induced colitis in mice with an increased
percentage of Th17 cells [41]. In contrast, CSE was found
to have a different effect on Th17 cells in ulcerative colitis.
Nicotine relieved oxazolone-induced colitis and reduced
the number of Th17 cells in mice [41]. Montbarbon et
al pretreated C57BL/6 mice with cigarette smoke for 14
days and then induced their colitis by dextran sodium
sulfate (DSS). They observed that smoke exposure
improved colonic inammation with an obviously reduced
production of colonic Th1/Th17 cytokines, including
TNFα, IFN-γ and IL-17 [42]. The contradictory effects
of smoke/nicotine on two types of experimental colitis
in mice resulted from different pathologic changes. It
has been known that TNBS-induced colitis was Th1 cell-
mediated whereas oxazolone-induced colitis was Th2
cell-oriented [43, 44]. Galitovskiy et al. [41] showed that
Th1 cytokine IL-12 signicantly decreased the protein
expression of α7 nicotinic acetylcholine receptors (α7
nAChR), which was expressed on murine CD4+ T cells
and relayed anti-inammatory signals, while Th2 cytokine
IL-4 enhanced α7 nAChR expression. Therefore, nicotine
exhibited dual effects on colitis of differential animal
models due to the opposite expression prole of anti-
inammatory α7 nAChR. CSE also inuenced other
autoimmune diseases by regulating Th17 responses.
Torii et al. evaluated the percentage of circulating Th17
among CD3+ cells in peripheral blood mononuclear cells
(PBMCs) of psoriatic patients and found that smokers
had higher levels of Th17+ T cells than non-smokers and
that tobacco smoke extract enhanced Th17 generation in
vitro [45]. Moreover, smoking was suggested to induce
rheumatoid arthritis by promoting Th17 responses through
Aryl hydrocarbon receptor on human T cells [46, 47].
Th2 cells are mainly primed by IL-4 and secrete
effector cytokines against extracellular parasites. It
was reported that CSE exacerbated the Th2-mediated
airway inammation in mice treated with OVA [48], and
enhanced mRNA and protein expression of thymic stromal
lymphopoietin [49], which was important for Th2-specic
allergic inammation. It was also observed that prenatal
secondhand smoke signicantly elevated the secretion of
Th2 cytokines, including IL-4 and IL-13, and promoted
activation and polarization of Th2 cells and pulmonary
inammation in BALB/C mice [50, 51]. Mishra et al. [52]
revealed that nicotine treatments to Brown Norway rats,
which were sensitized with allergens, apparently reduced
the expression level of pulmonary Th2-related chemokines
and cytokines, and inhibited eosinophil migration. These
animal studies indicate that cigarette smoking mostly
promotes Th2 immune responses as well as Th2-related
pulmonary inammation and asthma, although nicotine
may attenuate allergy via reducing Th2 responses.
In summary, data from both human and animal
studies indicate that Th17 cell is actively involved
in worsening smoking-associated inammation and
autoimmune diseases, including COPD, CD, colitis,
RA and psoriasis, although nicotine can mitigate colitis
in mice via suppression of IL-17 expression. Moreover,
cigarette smoking may promote autoimmune diseases by
enhancing Th1 polarization. Smoking also promotes Th2-
mediated pulmonary inammation and allergy in animal
studies. Further investigations, especially in humans, are
needed to provide mechanistic insight into the effects of
cigarette smoke on Th1/Th2/Th17 responses and allergy
or autoimmune diseases mediated by these T helper cells.
CD8+ T cells
CD8+ T cells are also known as cytotoxic T
lymphocytes (CTLs), which play an important role in
host immune defense via killing infected or damaged
cells. It was reported that chronic CSE could not induce
inammation or immune responses and emphysema in
CD8 knockout mice [53]. Further studies demonstrated
that IP-10 from CD8
+
T cells facilitated the production of
macrophage elastase, contributing to elastin fragmentation
and pulmonary injury [53]. These results indicated that
CD8
+
T cells serve as a key mediator of COPD. Nadigel et
al. [54] found that human CD8+ T cells, either from lung
tissue of COPD patients or exposed to cigarette smoke
condensate, expressed more TLR4 and TLR9 proteins
as compared with controls, while CSE also induced the
activation of circulating CD8+ T cell with an increase
in cytokine expression. Moreover, analysis of clinical
specimens from 9 smokers with COPD and 7 healthy
smokers for lung resection showed that CD8+ T cells
were also increased in the peripheral airways of COPD
patients compared with healthy smokers [55], and their
proliferation was induced by CSE [56, 57]. Another
study on emphysema mice demonstrated that cigarette
smoke not only increased the percentage of IL-21
+
Th17
and IL-21R+ CD8+ T cells in peripheral blood, but also
enhanced their expressions of IL-17 and IL-21, which
in turn upregulated perforin and granzyme B in CD8+ T
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cells, indicating that cytotoxic function of CD8 + T cells
can be regulated by Th17 cells in emphysema [58]. On
the contrary, early investigation had revealed that smokers
with COPD (n=12) had less circulating CD8
+
T cells and
more chemokine receptor CXCR3 on CD8+ T cells than
smokers without COPD (n=14) and nonsmokers (n=13),
while smokers with and without COPD had more activated
and cytotoxic (CD27-CD45RA+) CD8+ T cells in the
peripheral blood than normal nonsmokers [59].
In conclusion, overwhelming majority of studies in
humans have shown that smoking increases the number
of CD8+ T cells and their activation and function. The
contradictory data from initial studies showing a reduction
in human CD8+ T cell numbers under the smoking
condition could be attributed to gender and genetic
background or racial difference. However, studies in both
humans and animals indicate that cigarette smoke not just
alters the total number of CD8+ T cells, but also induces
or enhances their functional responses. Meanwhile, these
ndings suggest that the inuences of cigarette smoking
on CD8+ T cells may vary, depending on the differential
tissue microenvironment and pathological conditions.
Regulatory T cell (Treg)
Tregs play an essential role in maintaining
immunologic homeostasis and tolerance through
its immunosuppressive capacity. Epidemiologic
investigations have revealed that smoke exposure is
associated with the imbalance of Tregs in COPD patients
or smokers. Barceló et al. [60] reported a signicant
downregulation of CD4+ CD25+ Treg cells in BAL uid
of patients with COPD compared with healthy smokers.
Subsequent analyses by other groups demonstrated a
similar tendency in circulating CD4
+
and CD8
+
Tregs of
COPD patients [61, 62]. Furthermore, smoking or passive
cigarette smoke exposure during gestation contributed to
reduced Treg numbers in cord blood [63], resulting in a
higher risk of neonatal atopic dermatitis and food allergy.
On the other hand, mounting evidence demonstrated that
COPD patients had a prominent increase in Treg cells.
The analysis of BLA uid from smokers and COPD
patients showed that the percentage of CD4
+
CD25
+
Tregs
was augmented compared with healthy non-smokers
[64–66]. Moreover, the prevalence of CD4+FoxP3+
Treg cells was also elevated in the pulmonary tissue
and peripheral blood of COPD patients compared with
non-smokers [29, 67]. Although an increased frequency
of CD4+CD25+ T cells was observed in smokers with
normal pulmonary function, the alteration of FoxP3+
and CD127+ expression was not seen when compared
to non-smokers [66]. Three subpopulations of human
Tregs were reported. The suppressive subpopulations
contained both resting CD25++CD45RA+ Tregs (rTregs)
and activated CD25
+++
CD45RA
-
Tregs (aTregs) while the
pro-inammatory subpopulations were cytokine-secreting
CD25++CD45RA- (FrIII) cells [68]. Hou et al [69] found
that COPD patients had a lower percentage of suppressive
Tregs (rTregs and aTregs) but higher percentage of
FrIII cells compared with healthy smokers, although the
frequencies of three subsets of Tregs were all increased
in smokers compared to non-smokers, suggesting that
Treg imbalance (aTreg+rTreg vs. Fr III) has an impact on
pathogenesis of COPD.
Taken together, impacts of cigarette smoking on
human Treg numbers remain contradictory. We propose
that cigarette smoking impairs immunosuppressive
function of Tregs by reducing the number of suppressive
Tregs or increasing the prevalence of non-suppressive
Tregs, leading to an enhanced autoimmune component in
COPD pathogenesis, while increased Treg numbers may
occur in some smokers under circumstances, leading to
worsened respiratory infections. More in-depth studies
are required to clearly dene net impacts of cigarette
smoking on Treg generation and function in smokers with
or without a specic medical condition.
B cells
Recent investigations have focused on the
mechanisms underlying smoking-induced changes in
distribution and function of B cells. Epidemiologic
studies showed that cigarette smoking resulted in higher
prevalence of (class-switched) memory B cells in
peripheral blood and memory IgG+ B cells in the lung
[70, 71]. Smokers also exhibited an elevated level of
circulating IgE, leading to the potential development of
atopic diseases and asthma [72]. It has been reported that
nicotinic receptors, including alpha4 and alpha7 subunits,
are present and play important roles in B cell lines [73,
74]. Chronic nicotine exposure increased the expression
of alpha4 and alpha7 subunits and induced proliferation of
hybridoma B cells [73]. A retrospective study on prostate
inammation showed that the risk of acute inammation
of current smokers was higher than that of former smokers
(OR, 1.35; P, 0.001) and never-smokers (OR, 1.36; P,
0.001), and the risk of chronic inammation in the baseline
biopsy was related with current smoking, indicating that
cigarette smoking was correlated with acute and chronic
prostatic inammation [75]. Cigarette smoking also caused
inammation in prostate cancer and a B cell signature in
prostate tumors in current smokers, contributing to an
increase in the expression of immunoglobulin by B cells
inltrating the tumor [76]. On the other hand, smokers
with Helicobacter pylori (H. pylori) infection had a lower
number and impaired function of regulatory B cells than
non-smokers with also H. pylori infection [77]. Moreover,
analyses of immunoglobulins demonstrated a decreased
production of IgA, IgG and IgM in smokers [78–80]
while a study on the avidity of IgG using modied VLP
ELISAs revealed that the higher risk of having the low
avidity of HPV16/18 IgG in B cells was also associated
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with cigarette smoking [81]. Recent investigations have
focused on the mechanisms underlying smoking-induced
distribution and development of B cells. They developed
from bone marrow-derived hematopoietic stem cells that
rst differentiated into precursor and progenitor B cells
and then immature B cells [82]. It was found that tobacco
smoke exposure led to obvious downregulation of murine
marrow B220+CD34- pre-B cells and/or B220+CD34+
pro-B cells without signicant changes in cell apoptosis
and cell cycle [83, 84].
In summary, studies on humans again have
generated contradictory data showing that cigarette
smoking increases frequency of memory B cells and
IgE production, lowers regulatory B cell numbers, but
decreases production of IgA, IgG and IgM in smokers
while smoke exposure downregulates murine marrow
pre-B cells or pro-B cells. Meanwhile, smoking raises
the risk of inammation in prostate cancer and B cell
signature in the tumors.
Memory lymphocytes
Memory T cells are a subset of T lymphocytes that
have been previously challenged by foreign pathogens
or antigens and can respond rapidly and vigorously
upon reencounter with the same antigen [85]. Similarly,
memory B cells can quickly and effectively generate
antibodies upon encounter with a previously-met antigen
[86]. Thus, both memory lymphocytes play important
roles in human immune defenses. Early studies showed
that tobacco smoking apparently elevated memory T cells
(CD3+CD45RO+, CD4+CD45RO+) and class-switched
memory B cells in human peripheral blood [70, 87–89].
Active smoking in COPD patients also induced high levels
of class-switched memory B cells in blood and IgG+
memory B cells in the lung [71]. However, subsequent
ndings indicated an opposite effect of tobacco smoking
on human memory T cells. Vardavas et al [28] found a
signicant correlation of secondhand smoke with reduced
frequencies of CD3+CD45RO+ and CD4+CD45RO+
memory T cells in the blood of children, accompanying
with augmented percentages of CD3
+
and CD4
+
CD45RA
+
naive T cells. We speculate that the contradictory roles of
cigarette smoke in the circulating memory T cells of adults
and children are possibly due to immature immune system
in children, which is different from that of adult immune
system. Cigarette smoking seemed to attenuate rather than
strengthening the response of children memory T cells via
suppressing their generation.
Secondhand smoke exposure reduced effector and
memory T cells in the lungs and spleens of mice infected
with Mycobacterium tuberculosis [90], demonstrating
suppressive effects of cigarette smoke on immune
responses to infection. Further investigations showed
that in vitro pretreatments with 4-(Methylnitrosamino)-
1-(3-pyridyl)-1-butanone (NNK), a major carcinogen
component of tobacco, impaired the expansion of
cytotoxic T lymphocytes (CTLs) following their transfer
into mice but elevated the frequency of precursor memory
CLTs, resulting in a nal moderate decline in memory
CLTs [91]. Moreover, acute nicotine exposure attenuated
the expansion of murine CTLs in vivo after transfer as well
as their later differentiation into memory CTLs [92].
In summary, smoking enhances T cell memory in
adult while reducing it in children. In mice, smoking also
reduces memory T cells, especially CTLs. These results
indicate that cigarette smoking exerts duel inuences on
the generation of memory T cells, perhaps depending on
an individual’s genetic background and environment.
EFFECTS OF CIGARETTE SMOKING
ON INNATE IMMUNITY
Growing evidence has indicated the positive
association of cigarette smoking with abnormality of
innate immune responses [93–95] although the potential
mechanisms are still poorly understood. Kearley et al. [96]
found that cigarette smoke exposure (CSE) elevated the IL-
33 release from epithelial cells and altered the expression
of IL-33 cognate receptor ST2 in different immune
cells. They found that smoke exposure enhanced ST2
expression by macrophages and NK cells, but diminished
it in group 2 innate lymphoid cells (ILC2s), contributing to
strengthened IL-33-dependent pro-inammatory responses
of macrophages and NK cells upon infections. These results
indicate complicated inuences of smoking on innate
immune system. Innate immune cells, including dendritic
cells (DCs), natural killer (NK) cells and macrophages etc.,
play important roles in the host defense against infections.
Effects of cigarette smoking on the innate immune cells
(Figure 1) are described below.
Smoking and toll-like receptors (TLRs)
TLRs are a class of proteins that play an essential
role in the innate immune system. They are single and
non-catalytic receptors generally expressed in innate
immune cells, including macrophages and dendritic
cells, and recognize structurally conserved molecules
that are derived from pathogens. Botelho et al. found
that CSE resulted in inammatory responses mediated
by neutrophils and monocytes, while activated CD4+ T
cells were presented in murine lungs after the prolonged
exposure, implying that innate immune cells are sufcient
to trigger the acute inammation in a response to smoke
stimulation [97]. The acute inammatory responses caused
by smoking was reported to depend on toll-like receptors
(TLRs) [98]. Furthermore, Doz and colleagues showed
that cigarette smoking (with two cigarettes twice in a
day for three days) caused acute airway inammation in
mice through TLR-4 and IL-1R1 signaling [99]. Cigarette
smoking also promoted inammatory responses and
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atherosclerosis by activating the H1R-TLR2/4-COX2
axis [100]. Study on patients with periodontitis revealed
that smoking enhanced the mRNA expression of TLR-2
and TLR-4 in the gingival tissue [101, 102]. Similarly,
increased expression of TLR-2 was observed in the lungs
of mice exposed to cigarette smoke [103]. These results
indicate that cigarette smoking induces inammation
via increasing the expression and responsiveness of
TLRs. On the other hand, it was revealed that maternal
smoking reduced the TLRs (TLR-2, TLR-3, TLR-4
and TLR-9) responsiveness of infants’ cord blood cells
compared with nonsmoking groups, possibly increasing
the risk of respiratory infections and asthma [104]. And
CSE caused a decrease in mRNA level of TLR-7 and
IRF-7 in human plasmacytoid DCs (pDC) infected by
respiratory syncytial viruses, demonstrating a suppressive
effect of cigarette smoke on pDC upon infection [105].
Taken together, cigarette smoking is likely to exacerbate
inammatory responses but attenuate immune defenses
against infections by regulating TLR signaling.
Dendritic cells (DCs)
DCs are derived from a hematopoietic lineage
of bone narrow and can induce immune responses to
pathogens via processing and presenting antigens [106].
Cigarette smoke alters the number, distribution and
development of DCs and Langerhans cells (LCs). It was
reported that active smoking correlated with augmented
numbers of DC/LC lineage and caused a dramatic increase
in the number of LCs in human alveolar parenchyma [95].
And cigarette smoking upregulated the expression of
CCR7, MHCII and CD86, and signicantly promoted the
trafcking and responses of airway DCs in mice sensitized
with OVA, facilitating the allergic airway inammation
[107]. Moreover, passive smoking enhanced the frequency
of murine pulmonary DCs and caused their accumulation
and activation, which relied on IL-1R1/IL-1α [108]. The
upregulation of DC numbers in individuals exposed to
cigarette smoke likely resulted from a rise in the cell
survival, which was supported by a previous study on
the responsiveness of human and murine DCs to smoke
exposure [109]. Thus, smoking possibly aggravates the
airway inammation through increasing both the number
and function of DCs in humans as well as mice.
Mounting evidence has indicated that cigarette
smoke or its extract also negatively regulates the function
and maturation of DCs. It was demonstrated that CSE
was signicantly associated with the reduced stimulating
capacity of DCs in mice with asthma [110], and that
murine DCs treated in vitro with carbon monoxide (CO),
a component of tobacco smoke, prevented accumulation
of pancreatic autoreactive CD8+ T cells in mice with
autoimmune diabetes [111]. Furthermore, CSE led to
the reduced pulmonary DCs and suppression of DC
maturation in murine lymph nodes, accompanying with
the decreased expression of MHC II and costimulatory
molecules (CD80 and CD86) and an attenuated capacity
of inducing T cell proliferation [112]. The smoke exposure
for a longer than 24 hours resulted in suppression of
functional development of DCs with downregulation of
MHCII, CD83, CD86 and CD40, as well as a decline
in CD45 expression on human DC cell line L428 [113].
Similar effects of cigarette smoke were reported in
human studies. The prevalence of mature DCs (CD83+)
and migratory DCs (CCR7+) was decreased while the
percentage of immature DCs (CD1a+) was obviously
increased in the lung tissues of COPD patients compared
with healthy non-smokers [114]. Moreover, smokers with
COPD had lower mRNA expression of CD83 and CCR7
than healthy non-smokers [114]. Plasmacytoid DCs were
present in tissues that were in close association with the
external environment and important for immune defenses
against viruses [115]. Cigarette smoke extract was shown
to reduce the expression of IFN-α and TLR-7 in pDC
from healthy human volunteers and in pDC infected
by respiratory syncytial virus, indicating that smoking
attenuates the antiviral function of pDC [116, 117].
In conclusion, cigarette smoking profoundly
impacts the development and function of DCs and, hence,
inammation. However, ndings concerning the impacts
of cigarette smoke on DCs are contradictory given that
smoking can either suppress or promote DC development
and function in both humans and mice. It has not been
well dened likely due to the complex compositions of
cigarette smoke, the exposure time and quantity of smoke
and the interactions between DCs and other immune cells
in animal models and humans. Further investigations are
necessary to determine the exact effects of smoking on DC
generation and function in a specic disease setting and at
a particular location.
NK cells
NK cells are similar to cytotoxic lymphocytes
expressing perforin, granzymes, TNF-α and IFN-γ [118],
and are a critical component of innate immune cells. NK
cells can rapidly and effectively respond because they also
exhibit a memory feature [119]. Motz et al. [120] assessed
the inuences of smoking on NK (CD335+) cells in
COPD mice and revealed that smoke exposure promoted
the expression of IFN-γ and CD107a in NK cells upon
stimulation, and enhanced NK cell responses. Murine NK
cells were also primed by cigarette smoke to express more
Th-17 cytokine IL-17A [121]. Meanwhile, CSE for over
four days activated CD69+ NK cells in murine lung and
induced their responses [128]. Further analysis of human
data showed that smokers with or without COPD had an
increase in the frequency of circulating NK (CD56+CD3-)
cells compared with former smokers with COPD and
healthy nonsmokers [122, 123]. On the other hand,
previous investigations also demonstrated an obvious
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reduction of NK (CD16+) cells in the peripheral blood of
healthy smokers and the smokers exposed occupationally
to organic solvents compared with nonsmokers [124, 125].
Cigarette smoke was reported to suppress the expression
of IFN-γ and TNF-α in human NK (CD56+CD3-) cells
stimulated by poly I:C while smoking-conditioned
medium (SCM) reduced the cytotoxicity of NK cells that
had a lower perforin production [126, 127]. Similarly,
Mian et al. found that cigarette smoke apparently
attenuated the activation and cytolytic capacity of human
NK cells with decreased expression of activation marker
CD69 [128].
Taken together, smoking still exerts dual effects on
the frequency and function of NK cells in both mice and
humans. The actual inuences of cigarette smoking on NK
cells may vary, depending on the differential pathological
conditions or disease settings and subsets of NK cells with
different surface markers. Different subsets of NK cells
may paradoxically respond to cigarette smoke in a given
setting at a given time.
Macrophages
Macrophages respond to exogenous pathogens
via phagocytosis and digestion, and recruit/activate
lymphocytes via their antigen-presenting ability
[129]. Ko and others reported that both smoking and
nicotine treatments could enhance the expression of
proinammatory chemokine IL-8 in macrophages of both
humans and mice [130–132]. Metcalfe et al [133] found
that cigarette smoke extract inhibited the responses of
COPD-derived alveolar macrophages to TLR signaling
and Haemophilus inuenza stimulation. These results
indicated that smoke-treated human macrophages
and IL-8 produced by these macrophages facilitated
inammation, although studies on murine macrophages
demonstrated that smoking remarkably suppressed the
phagocytosis of macrophages and enhanced bacterial
survival [134]. Another report showed a similar trend
in phagocytic function of human macrophages THP-
1 treated with cigarette smoke extract [135], with an
increase in M2 macrophages. M2 macrophage is regarded
as a subset of anti-inammatory cells that can attenuate
inammation, whereas M1 macrophage is referred to as
pro-inammatory cells [136]. Finally, it was found that
bone marrow-derived mast cells exposed to cigarette
smoke promoted the polarization of murine macrophages
into M2 subset [137].
In summary, smoke treatments stimulate human
macrophages to release IL-8, facilitating inammation
rather than directly enhancing their function while
cigarette smoking suppresses the phagocytosis of
murine macrophages. However, smoking promotes M2
polarization of both human and murine macrophages.
Further studies are needed to fully understand impacts of
smoking on the function of macrophages, especially in
humans.
MOLECULAR MECHANISMS
UNDERLYING SMOKING-ASSOCIATED
IMMUNOPATHOLOGY
Cigarette smoke is an important source of hazardous
chemicals, including nicotine, reactive nitrogen species
(RNS), reactive oxygen species (ROS), free radicals, nicotine
and polycyclic aromatic hydrocarbons. They cause oxidative
stress, DNA damage, inammation and various cancers [3,
138, 139]. The molecular mechanisms behind the smoking-
induced effects on immune cells are still poorly understood.
Early investigation revealed that cigarette smoke initiated
the MAPK signaling pathways, which in turn regulated the
activation of transcription factors (TFs) and affected DNA-
binding capacity of more than 20 TFs, including nuclear
factor-kappa B (NFκB) [140]. The functional alterations
of TFs contributed to transcriptional changes of their target
genes, including inammatory cytokines and chemokines.
Furthermore, nicotine was also reported to exert anti-
inammatory effects on activated immune cells via nicotinic
acetylcholine receptors (nAChRs) mediated molecular
pathways. Nevertheless, the exact molecular mechanisms
underlying smoking-associated immunopathology remain
largely unknown.
NFκB
Activation of NFκB with oxidative stress plays a key
role in inammation [141]. It was reported that cigarette
smoke induced degradation of IκB-α and activation of
nuclear factor-kappa B (NFκB) in lymphocytes and
other types of cells, resulting in increased expression of
cyclooxygenase-2 and iNOS [142, 143]. An analysis using
protein/DNA array showed that CSE strengthened the
transcriptional activity of NFκB via promoting its nuclear
translocation and DNA binding activity in human A549 cells
[140]. Lerner et al [144] demonstrated that cigarette smoke
facilitated the expression of cytokine IL-8 and attenuated
differentiation of human monocytes via activating NFκB
pathway. Furthermore, Reynolds and colleagues found that
CSE enhanced the activation of Ras and NFκB, and that
downregulation of the receptor for advanced glycation end-
product (RAGE) resulted in the reduced activation of NFκB
in alveolar epithelial cells [145]. Thus, it was suggested that
cigarette smoke stimulated alveolar epithelial cells to express
more cytokine IL-1β and chemokine CCL5 via RAGE-
mediated Ras-NFκB pathway, possibly contributing to
leukocyte recruitments. On the contrary, others demonstrated
that CSE suppressed the activation of NFκB in human
and murine tracheobronchial epithelial cells infected by
Haemophilus inuenza (H. inuenza), and these ndings
were supported by a study using animals infected with
H. inuenza [146]. Mian et al. also observed that smoke-
conditioned media signicantly suppressed the activation
of NFκB and IRF-3 in nonsmokers’ PBMCs treated with
poly I:C [147], while cigarette smoke extract was shown
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to dramatically elevate the DNA binding activity of AP-1
rather than NFκB in endothelial cells of human umbilical
core vein [148].
Taken together, previous studies indicate smoking
also exerts dual roles in regulating NFκB activation in
both humans and animals. The net effects of cigarette
smoking on NFκB activity differ widely, depending on
cell types and extracellular environment with or without
exogenous pathogens, which possibly contributes to a
decline in immunity against bacterial infections but an
increase in pulmonary inammation.
ERK
There are three major types of MAP Kinase
pathways, including ERK1/2, JNK/SAPK and p38
pathways [149]. Iles et al. found that 4-hydroxynonenal
(HNE) induced by cigarette smoke in pulmonary epithelial
cells enhanced the phosphorylation of ERK, JNK and
c-Jun and the binding capacity of AP-1 with upregulation
of Heme oxygenase-1 (HO-1) [150]. Similar ERK-c-Jun
pathway induced by CSE was reported by others. Li et al.
[151] revealed that CSE induced ERK phosphorylation,
which in turn phosphorylated c-Jun in smooth muscle
cells, contributing to cyclin D1 upregulation. They also
demonstrated the involvement of MEK/ERK1/2 MAPK
pathway in the diminished expression of cystic brosis
transmembrane conductance regulator (CFTR) induced by
cigarette smoke in human bronchial epithelial cells [152].
In addition to acting on epithelial cells and smooth muscle
cells, CSE treatments also enhanced ERK phosphorylation
and suppressed IL-12p70 expression in mature DCs, while
the ERK phosphorylation in turn increased nuclear TF
c-Fos, leading to the reduction in IL-23 protein levels
[153]. It remains to be dened whether cigarette smoke
affects ERK phosphorylation in adaptive immune cells.
P38 MAPK
Both in vitro and animal studies have shown that
cigarette smoke exposure (CSE) exerts its effects through
p38 MAPK signaling pathway. It was reported that CSE
apparently elevated the phosphorylation of p38 MAPK
in mice with smoke-induced pulmonary inammation
[154, 155]. Furthermore, Moretto et al. [156] found that
CSE enhanced both mRNA and protein expression of
IL-8, which was important for neutrophil chemotaxis,
accompanying with phosphorylation of p38 MAPK
and MEK2 in human pulmonary cells. Treatments with
inhibitors of p38 MAPK or MEK2 accelerated the
degradation of IL-8 mRNA. Thus, they suggested that
cigarette smoking augments IL-8 expression in pulmonary
structural cells through p38 MAPK/MEK pathway,
resulting in neutrophil recruitments into the lungs and
inammatory sites. Additionally, some investigations [157,
158] demonstrated that both p38 MAPK and ERK1/2
pathways were concurrently implicated in the secretion
of IL-8 and pulmonary inammation induced by cigarette
smoking.
In conclusion, tobacco smoking activates MAPK
signaling in both murine and human pulmonary resident
cells and leukocytes, and hence induces the expression of
proinammatory cytokines such as IL-8.
Histone modication
In addition to effects on NFκB and MAPK
signaling pathways, tobacco smoke also alters the cellular
chromatin via histone modication [159]. Previous studies
established an association of tobacco smoking with
augmented acetylation of histone 4 and phosphorylated-
histone 3 in human and mice [154, 160]. Yang et al.
[161] revealed that CSE attenuated the activity of histone
deacetylase (HDAC) and reduced the production of
HDAC1, HDAC2, and HDAC3 in human macrophages.
Furthermore, expression of SIRT1, a type of histone/
protein deacetylases [162], was suppressed by cigarette
smoke in inammatory cells of murine lungs as well
as macrophage cell lines, resulting in abrogation of the
interaction of SIRT1 with RelA/p65 and acceleration of
RelA/p65 acetylation [163]. Since chromatin structures
regulated by histone acetylation and deacetylation affected
gene transcriptions [164], smoke-induced alterations
in histone modication could lead to aberrant gene
transcriptions in various immune cells. Taken together,
smoking alters the cellular chromatin of both murine and
human macrophages via histone modication.
Impacts of nicotine on molecular signaling
pathways
Nicotine has been shown to be an
immunosuppressive agent that can modulate innate and
adaptive immune responses [165, 166] through interacting
with nAChRs on the surface of immune cells, including
macrophages, T and B lymphocytes [167]. Recently,
considerable work has been done to show that α7 nAChR,
one type of nAChRs, plays a crucial role in nicotine’s
anti-inammatory effects. The activation of α7 nAChR
by nicotine in murine macrophages interacted with
Jak2 and then induced the phosphorylation of STAT3,
which subsequently inhibited the transcription of pro-
inammatory cytokines [168]. Furthermore, activated
α7 nAChR suppressed the phosphorylation of IκB in
human monocytes, resulting in inhibition of nuclear
translocation of NFκB [166, 169]. Besides, nicotine
may regulate additional signaling pathways beyond
activation of nAChRs. Early studies showed that nicotine
facilitated the release of alpha-melanocyte-stimulating
hormone (alpha-MSH) in frog melanotrophs through
inducing inositolphospholipid breakdown and increasing
the intracellular Ca(2+) concentration, indicating the
involvement of non-cholinergic nicotine receptor in
nicotine mediated effects [170]. It was also reported
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that nicotine treatment enhanced Ca(2+) channels and
suppressed nitric oxide (NO) signaling pathways in
smooth muscle cells of rats [171]. Moreover, interleukin-1
receptor-associated kinase M (IRAK-M), a negative
regulator of innate TLR-mediated immunity, was involved
in the anti-inammatory effects of nicotine through α7
nicotinic receptor in human macrophages [172]. Although
the major evidence has revealed that nicotine functions via
both nAChRs and non-nAChRs in immune cells, the exact
signaling pathways of nicotine are still largely unclear and
more studies are required to fully explore its molecular
mechanisms.
CONCLUSION
Ample evidence has shown that both innate
immunity and adaptive immunity are susceptible to
cigarette smoke, which interrupts immunological
homeostasis, causes various diseases, and exerts
paradoxical effects on immune and tissue cells through
regulating NFκB and MAPK signaling as well as histone
modication. In particular, cigarette smoke acts as a
double-edged sword that either exacerbates pathological
immune responses or attenuates the normal defensive
function of the immune system, possibly owing to the
complexities and functional diversities of cigarette
smoke components and individuals’ medical condition.
Nevertheless, smoking plays a harmful rather than
benecial role in either case. Perhaps, tobacco smoke
manufactured from different parts of the country may
differ in actual chemical components. It is unknown why
smoking is always deleterious rather than benecial,
even though it exerts dual effects on immune responses.
For instance, cigarette smoke generally weakens
immunity against infections but paradoxically promotes
autoimmunity. We speculate that the weakened immunity
with prolonged chronic infection results in cross-reactive
autoimmunity against both a pathogen and cross-reactive
self-tissue. It is also possible that cigarette smoke exerts
differential effects on immunity in the context of various
regional immunopathology and diseases. Although
previous studies have revealed some of the cellular and
molecular mechanisms responsible for immunoregulation
induced by cigarette smoke, the exact mechanisms
underlying smoking-associated immunopathology remain
mostly unclear, which warrants further investigations.
CONFLICTS OF INTEREST
The authors declare that there is no any conict of
interest in this review.
GRANT SUPPORT
This study was partially supported by a grant from
National Natural Science Foundation of China (NSFC
81471550).
Author contributions
FQ, CLL, and HL prepared the literature and wrote
the manuscript; YQZ, SZH and SH prepared the literature;
XL and ZD edited the manuscript.
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... In addition, smoking impacts the immune system by affecting the immune B cells responsible for antibody production after vaccination. Despite various observations of the effects of tobacco smoke on B lymphocytes [68], smoking plays a harmful rather than beneficial role in most studies, as it attenuates the normal defensive function of the immune system. In a systematic review on COVID-19 risk factors, smoking was also likeliest correlated with a negative progression and adverse outcomes [69]. ...
... The effect of cigarette smoking on immunity has been widely studied. It is usually associated with impaired function of immune cells, including B lymphocytes producing antibodies, often despite an increased number of B cells [68]. However, it must be stressed that when assessing the effect of smoking on the immune system response, other factors, such as smoking history or intensity, and genetic factors, must be taken under consideration. ...
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Background: This study aimed to investigate the early and longitudinal humoral response in Healthcare Workers (HCWs) after two doses of the BNT162b2 vaccine and to assess the association between metabolic and anthropometric parameters and the humoral response after vaccination. Methods: The study included 243 fully vaccinated HCWs: 25.50% previously infected with SARS-CoV-2 (with prior history of COVID-19-PH) and 74.40%-uninfected, seronegative before the first vaccination (with no prior history of COVID-19-NPH). IgG antibodies were measured, and sera were collected: prior to the vaccination, 21 days after the first dose, and 14 days and 8 months after the second dose. Results: 21 days after the first dose, 90.95% of individuals were seropositive; 14 days after the second dose, persistent immunity was observed in 99.18% HCWs, 8 months after complete vaccination-in 61.73%. Statistical analysis revealed that HCWs with PH had a greater chance of maintaining a humoral response beyond eight months after vaccination. Increased muscle mass, decreased fat mass, and younger age may positively affect long-term immunity. Smokers have a reduced chance of developing immunity compared to non-smokers. Conclusions: Fully vaccinated HCWs with PH are more likely to be seropositive than fully inoculated volunteers with NPH.
... Innate immunity and adaptive immune mechanisms are known to be affected by cigarette consumption (Qiu et al., 2017). Previous studies have shown reduced IgG concentration in smokers (Gonzalez-Quintela et al., 2008;McMillan et al., 1997). ...
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Growing evidence suggests that sleep could affect the immunological response after vaccination. The aim of this prospective study was to investigate possible associations between regular sleep disruption and immunity response after vaccination against coronavirus disease 2019 (COVID‐19). In total, 592 healthcare workers, with no previous history of COVID‐19, from eight major Greek hospitals were enrolled in this study. All subjects underwent two Pfizer–BioNTech messenger ribonucleic acid (mRNA) COVID‐19 vaccine BNT162b2 inoculations with an interval of 21 days between the doses. Furthermore, a questionnaire was completed 2 days after each vaccination and clinical characteristics, demographics, sleep duration, and habits were recorded. Blood samples were collected and anti‐spike immunoglobulin G antibodies were measured at 20 ± 1 days after the first dose and 21 ± 2 days after the second dose. A total of 544 subjects (30% males), with median (interquartile range [IQR]) age of 46 (38–54) years and body mass index of 24·84 (22.6–28.51) kg/m2 were eligible for the study. The median (IQR) habitual duration of sleep was 6 (6–7) h/night. In all, 283 participants (52%) had a short daytime nap. In 214 (39.3%) participants the Pittsburgh Sleep Quality Index score was >5, with a higher percentage in women (74·3%, p < 0.05). Antibody levels were associated with age (r = −0.178, p < 0.001), poor sleep quality (r = −0.094, p < 0.05), insomnia (r = −0.098, p < 0.05), and nap frequency per week (r = −0.098, p < 0.05), but after adjusting for confounders, only insomnia, gender, and age were independent determinants of antibody levels. It is important to emphasise that insomnia is associated with lower antibody levels against COVID‐19 after vaccination.
... Many chemicals in tobacco have toxic effects, including polycyclic aromatic hydrocarbons (phenyltoluene), N-nitrosamines, heavy metals (nickel, cadmium, chromium, and arsenic), alkaloids (nicotine and its main metabolites, and infectious agents), and aromatic amines. Tobacco induced LSCC pathogenesis including inflammatory and immune changes, genetic alterations, oxidative damage, endothelial dysfunction, and cellular senescence (16). A significant difference was observed in the rate of drinking (45.2%, 71/221) and non-drinking (67.9%, 150/221) among the patients with LSCC admitted to the First Affiliated Hospital of Anhui Medical University. ...
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Background Laryngeal squamous cell carcinoma (LSCC) is the most common type of head and neck squamous cell carcinoma. However, there are currently no reliable biomarkers for the diagnosis and prognosis of LSCC. Thus, this study aimed to identify the independent risk factors and develop and validate a new dynamic web-based nomogram that can predict auxiliary laryngeal carcinogenesis. Methods Data on the medical history of 221 patients who were recently diagnosed with LSCC and 359 who were recently diagnosed with benign laryngeal lesions (BLLs) at the First Affiliated Hospital of Anhui Medical University were retrospectively reviewed. Using the bootstrap method, 580 patients were divided in a 7:3 ratio into a training cohort (LSCC, 158 patients; BLL, 250 patients) and an internal validation cohort (LSCC, 63 patients; BLL, 109 patients). In addition, a retrospective analysis of 31 patients with LSCC and 54 patients with BLL from Fuyang Hospital affiliated with Anhui Medical University was performed as an external validation cohort. In the training cohort, the relevant indices were initially screened using univariate analysis. Then, least absolute shrinkage and selection operator logistic analysis was used to evaluate the significant potential independent risk factors (P<0.05); a dynamic online diagnostic nomogram, whose discrimination was evaluated using the area under the ROC curve (AUC), was constructed, while the consistency was evaluated using calibration plots. Its clinical application was evaluated by performing a decision curve analysis (DCA) and validated by internal validation of the training set and external validation of the validation set. Results Five independent risk factors, sex (odds ratio [OR]: 6.779, P<0.001), age (OR: 9.257, P<0.001), smoking (OR: 2.321, P=0.005), red blood cell width distribution (OR: 2.698, P=0.001), albumin (OR: 0.487, P=0.012), were screened from the results of the multivariate logistic analysis of the training cohort and included in the LSCC diagnostic nomogram. The nomogram predicted LSCC with AUC values of 0.894 in the training cohort, 0.907 in the internal testing cohort, and 0.966 in the external validation cohort. The calibration curve also proved that the nomogram predicted outcomes were close to the ideal curve, the predicted outcomes were consistent with the real outcomes, and the DCA curve showed that all patients could benefit. This finding was also confirmed in the validation cohort. Conclusion An online nomogram for LSCC was constructed with good predictive performance, which can be used as a practical approach for the personalized early screening and auxiliary diagnosis of the potential risk factors and assist physicians in making a personalized diagnosis and treatment for patients.
... In assessment of infiltrating immune cells, CD4 + and CD8 + cells were conspicuous (see Fig. 4). Cigarette smoking was reported to affect the innate and adaptive immunity, especially T helper cells, as well as CD4 + and CD8 + cells [42]. Accordingly, an influence of smoking on these cell types might lead to an autoimmunity resulting in pulmonal (COPD) and oral (periodontitis) inflammation. ...
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Background The aim of this study was to detect potential crosstalk genes, pathways and immune cells between periodontitis and chronic obstructive pulmonary disease (COPD). Methods Chronic periodontitis (CP, GSE156993) and COPD (GSE42057, GSE94916) datasets were downloaded. Differential expressed genes (DEGs; p < 0.05) were assessed and screened for overlapping results, following functional pathway enrichment analyses (p < 0.05). The xCell method was used to assess immune cell infiltration relationship between CP and COPD. Features of the detected cross-talk genes were revealed using conventional Recursive Feature Elimination (RFE) algorithm in R project. Receiver-operating characteristic curves were applied to evaluate the predictive value of the genes. Furthermore, Pearson correlation analysis was performed on crosstalk markers and infiltrating immune cells in CP and COPD, respectively. Results A total of 904 DEGs of COPD and 763 DEGs of CP were acquired, showing 22 overlapping DEGs between the two diseases. Thereby 825 nodes and 923 edges were found in the related protein–protein-interaction network. Eight immune cell pairs were found to be highly correlated to both CP and COPD (|correlation coefficients |> 0.5 and p-value < 0.05). Most immune cells were differently expressed between COPD and CP. RFE identified three crosstalk genes, i.e. EPB41L4A-AS1, INSR and R3HDM1. In correlation analysis, INSR was positively correlated with Hepatocytes in CP (r = 0.6714, p = 0.01679) and COPD (r = 0.5209, p < 0.001). R3HDM was positively correlated with Th1 cells in CP (r = 0.6783, p = 0.0153) and COPD (r = 0.4120, p < 0.01). Conclusion EPB41L4A-AS1, INSR and R3HDM1 are potential crosstalk genes between COPD and periodontitis. R3HDM was positively correlated with Th1 cells in both diseases, while INSR was positively correlated with Hepatocytes in periodontitis and COPD, supporting a potential pathophysiological relationship between periodontitis and COPD.
... Smoking is described as a possible protective factor for PD, and smokers frequently need corticosteroids due to pulmonary maladies (106,107). Moreover, cigarette smoke induces chronic inflammation, which results in immune cell exhaustion and generally attenuates the function of many immune responses (108). Therefore, smoking can be considered an immuneinhibitory activity (109,110). ...
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Parkinson’s disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD.
... For instance, smoking and alcohol consumption affect certain immune cell compositions in the innate immune response (e.g., natural killer cells, macrophages) as well as in the adaptive immune response (e.x., T-helper cells, T regulatory cells). This in turn facilitates the progression of virus and increase the virus load along the respiratory tract, as a result 39 . Also, the T-cell composition vary with sex depending on a number of factors such as environmental factors, nutrition status and the composition of the microbiome 40 . ...
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Respiratory viruses including Respiratory Syncytial Virus, influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cause serious and sometimes fatal disease in thousands of people annually. Understanding virus propagation dynamics within the respiratory system is critical because new insights will increase our understanding of virus pathogenesis and enable infection patterns to be more predictable in vivo, which will enhance our ability to target vaccine and drug delivery. This study presents a computational model of virus propagation within the respiratory tract network. The model includes the generation network branch structure of the respiratory tract, biophysical and infectivity properties of the virus, as well as air flow models that aid the circulation of the virus particles. As a proof of principle, the model was applied to SARS-CoV-2 by integrating data about its replication-cycle, as well as the density of Angiotensin Converting Enzyme expressing cells along the respiratory tract network. Using real-world physiological data associated with factors such as the respiratory rate, the immune response and virus load that is inhaled, the model can improve our understanding of the concentration and spatiotemporal dynamics of the virus. We collected experimental data from a number of studies and integrated them with the model in order to show in silico how the virus load propagates along the respiratory network branches.
... In addition, smoking has been reported to have anti-estrogenic activity, as reduced estrogen levels and early menopause have been found in smokers compared to non-smokers [29]. Predisposition to chronic pain may also depend on nicotine action on the immune system, as smoking has been reported to stimulate the release of inflammatory mediators by T lymphocytes, exacerbating the musculoskeletal conditions underlying the onset of pain [30]. Interestingly, a correlation between smoking and pain intensity has been found, as evidenced by the higher intensity of chronic pain, reduced function, lower sleep quality, and worse mood found in smokers compared to non-smokers. ...
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Musculoskeletal pain is a condition that characterises several diseases and represents a constantly growing issue with enormous socio-economic burdens, highlighting the importance of developing treatment algorithms appropriate to the patient’s needs and effective management strategies. Indeed, the algic condition must be assessed and treated independently of the underlying pathological process since it has an extremely negative impact on the emotional and psychic aspects of the individual, leading to isolation and depression. A full understanding of the pathophysiological mechanisms involved in nociceptive stimulation and central sensitization is an important step in improving approaches to musculoskeletal pain. In this context, the bidirectional relationship between immune cells and neurons involved in nociception could represent a key point in the understanding of these mechanisms. Therefore, we provide an updated overview of the magnitude of the musculoskeletal pain problem, in terms of prevalence and costs, and summarise the role of the most important molecular players involved in the development and maintenance of pain. Finally, based on the pathophysiological mechanisms, we propose a model, called the “musculoskeletal pain cycle”, which could be a useful tool to counteract resignation to the algic condition and provide a starting point for developing a treatment algorithm for the patient with musculoskeletal pain.
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Introduction: We aimed to compare demographics and clinical characteristics between patients with inflammatory arthritis (IA) with vs. without neutralizing anti-drug antibodies (nADAb) against tumor necrosis factor inhibitors (TNFi). A secondary aim of the study was to explore if current smokers were more frequently nADAb-positive. Methods: TNFi-treated outpatients with IA were recruited and a broad range of disease activity measures were assessed. nADAb were assessed using a reporter gene assay. Comparisons between nADAb-positive and -negative patients were done in unadjusted analyses as well as in adjusted logistic regression and general linear models. Results: A total of 282 patients with IA currently under treatment with TNFi were included. nADAb were identified in 11 patients (nine treated with infliximab, one with etanercept and one with certolizumab pegol). Patients with nADAb reported significantly worse joint pain, patient's global assessment, Health Assessment Questionnaire, Bath Ankylosing Spondylitis Disease Activity/Functional Index and Short-Form-36 physical functioning scale score than patients without nADAb (p < 0.04, adjusted analyses). 28-joint Disease Activity Score, Simplified Disease Activity Index and Maastricht Ankylosing Spondylitis Enthesitis score were also significantly worse in the nADAb-positive patients (p < 0.04, adjusted analyses), as were serum calprotectin, C-reactive protein and numbers of circulating peripheral leukocytes (p ≤ 0.001). A significantly higher proportion of nADAb-positive patients were current smokers (46 vs. 15%), in unadjusted as well as adjusted analyses (p ≤ 0.008). Conclusions: nADAb-positive patients were more frequently smokers and had significantly worse disease activity, physical function, and inflammatory markers, than patients without nADAb. The association between smoking and nADAb positivity warrants further examination.
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Background Tobacco smoke is the leading cause of morbidity and mortality in modern times. The combustion products in tobacco smoke contain a variety of toxic substances.FindingsThese substances have far-reaching effects on the immune system, altering both cell-mediated and humoral responses of the immune system. Hence, they affect the development, cytokine production, and effector function of both innate immune cells, including dendritic cells (DCs), macrophages, and natural killer (NK) cells, and adaptive immune cells, such as cytotoxic CD8+ T cells, CD4+ Th cells, regulatory T cells, and B cells, resulting in proinflammatory responses and/or immune cell dysfunction.Conclusion However, although tobacco products have been shown to impair humoral and cell-mediated immunity, neither the extent of this impairment nor its mechanisms are clearly understood.
Chapter
De primaire functie van het immuunsysteem (afweersysteem) is om ons te beschermen tegen infecties en tumoren. Maar het doet meer. Het immuuunsysteem reageert op verstoringen van de homeostase door invloeden van buiten of binnen het lichaam. Het neutraliseert oorzaken van verstorende prikkels en herstelt het natuurlijke evenwicht. Hierbij werkt het immuunsysteem nauw samen met het endocriene en het neurale systeem. Het immuunsysteem houdt zo een dynamisch evenwicht in stand. De potentie van het immuunsysteem is zo groot en sterk dat er veel controlemechanismen nodig zijn om te zorgen dat de respons niet buiten proportie is. Een reactie van immuunsysteem is steeds als ‘gas geven met de rem erop’.
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Background Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder characterized by poorly reversible airway obstruction and its pathogenesis remains largely misunderstood. Local changes of regulatory T-cell populations in the lungs of COPD patients have been demonstrated although data concerning their pathologic role are contrasting. The aim of our study was to evaluate the relative percentage of regulatory T-cells in the peripheral blood of current and former smoker subjects, affected or not by COPD. Furthermore, the effect of different concentrations of budesonide and formoterol, on regulatory T-cells has been investigated. MethodsT regulatory lymphocytes were isolated and assessed as CD4+CD25highCD127- cells by flow cytometry and cultured for 48 hours in the absence or in the presence of budesonide and/or formoterol at different doses. ResultsCD4+CD25highCD127- regulatory T-cells percentage was significantly reduced in COPD patients, both current and former smokers, with respect to volunteers. Furthermore, CD4+CD25highCD127- cells of COPD patients showed a not statistically significant response to drugs compared to healthy subjects. DiscussionOur results evidenced a different behaviour of CD4+CD25highCD127- Treg cells in COPD patients after in vitro treatments. Conclusions Based on our data, we suggested a possible role of CD4 CD25highCD127 T-cells in COPD pathogenesis.
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Background: CD8+ T cells (Cytotoxic T cells, Tc) are known to play a critical role in the pathogenesis of smoking related airway inflammation including chronic obstructive pulmonary disease (COPD). However, how cigarette smoke directly impacts systematic CD8+ T cell and regulatory T cell (Treg) subsets, especially by modulating muscarinic acetylcholine receptors (MRs), has yet to be well elucidated. Methods: Circulating CD8+ Tc/Tregs in healthy nonsmokers (n = 15), healthy smokers (n = 15) and COPD patients (n = 18) were evaluated by flow cytometry after incubating with anti-CD3, anti-CD8, anti-CD25, anti-Foxp3 antibodies. Peripheral blood T cells (PBT cells) from healthy nonsmokers were cultured in the presence of cigarette smoke extract (CSE) alone or combined with MRs agonist/antagonist for 5 days. Proliferation and apoptosis were evaluated by flow cytometry using Ki-67/Annexin-V antibodies to measure the effects of CSE on the survival of CD8+ Tc/Tregs. Results: While COPD patients have elevated circulating percentage of CD8+ T cells, healthy smokers have higher frequency of CD8+ Tregs. Elevated percentages of CD8+ T cells correlated inversely with declined FEV1 in COPD. CSE promoted the proliferation and inhibited the apoptosis of CD8+ T cells, while facilitated both the proliferation and apoptosis of CD8+ Tregs. Notably, the effects of CSE on CD8+ Tc/Tregs can be mostly simulated or attenuated by muscarine and atropine, the MR agonist and antagonist, respectively. However, neither muscarine nor atropine influenced the apoptosis of CD8+ Tregs. Conclusion: The results imply that cigarette smoking likely facilitates a proinflammatory state in smokers, which is partially mediated by MR dysfunction. The MR antagonist may be a beneficial drug candidate for cigarette smoke-induced chronic airway inflammation.
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Smokers develop metastatic prostate cancer more frequently than nonsmokers, suggesting that a tobacco-derived factor is driving metastatic progression. To identify smoking-induced alterations in human prostate cancer, we analyzed gene and protein expression patterns in tumors collected from current, past, and never smokers. By this route, we elucidated a distinct pattern of molecular alterations characterized by an immune and inflammation signature in tumors from current smokers that were either attenuated or absent in past and never smokers. Specifically, this signature included elevated immunoglobulin expression by tumor-infiltrating B cells, NF-κB activation, and increased chemokine expression. In an alternate approach to characterize smoking-induced oncogenic alterations, we also explored the effects of nicotine in human prostate cancer cells and prostate cancer-prone TRAMP mice. These investigations showed that nicotine increased glutamine consumption and invasiveness of cancer cells in vitro and accelerated metastatic progression in tumor-bearing TRAMP mice. Overall, our findings suggested that nicotine was sufficient to induce a phenotype resembling the epidemiology of smoking-associated prostate cancer progression, illuminating a novel candidate driver underlying metastatic prostate cancer in current smokers.
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Tobacco use, primarily associated with cigarette smoking, is the largest preventable cause of cancer mortality, responsible for approximately one-third of all cancer deaths. Approximately 85% of lung cancers result from smoking, with an additional fraction caused by secondhand smoke exposure in nonsmokers. The risk of lung cancer is dose dependent, but can be dramatically reduced with tobacco cessation, especially if the person discontinues smoking early in life. The increase in lung cancer incidence in different countries around in the world parallels changes in cigarette consumption. Lung cancer risks are not reduced by switching to filters or low-tar/low-nicotine cigarettes. In patients with cancer, continued tobacco use after diagnosis is associated with poor therapeutic outcomes including increased treatment-related toxicity, increased risk of second primary cancer, decreased quality of life, and decreased survival. Tobacco cessation in patients with cancer may improve cancer treatment outcomes, but cessation support is often not provided by oncologists. Reducing the health related effects of tobacco requires coordinated efforts to reduce exposure to tobacco, accurately assess tobacco use in clinical settings, and increase access to tobacco cessation support. Lung cancer screening and coordinated international tobacco control efforts offer the promise to dramatically reduce lung cancer mortality in the coming decades.
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Developmental intermediates of human natural killer (NK) cells are found within secondary lymphoid tissue (SLT), and five distinct stages of these intermediates have been identified. While it is well documented that developing NK cells are reliant on interleukin (IL)-15 as a survival factor, it is likely that additional cytokines and growth factors are required for complete NK cell differentiation. Microarray transcriptional profiling of purified stage 1–4 cells from human tonsil and stage 4 and 5 cells from peripheral blood (PB) identified a developmental window of interleukin-1 receptor 1 (IL-1R1) messenger RNA (mRNA) expression restricted to stages 2 and 3. We confirmed this finding by quantitative RT-PCR, and analysis of IL-1R1 surface protein expression revealed that, on average, 81% of stage 3 immature NK cells are IL-1R1(+), whereas the majority of cells from stages 1, 2, and 4 are IL-1R1(−). When cultured in vitro with IL-1β, a physiologic ligand for IL-1R1, cells from all four stages died within 48 hours, consistent with an absolute requirement for IL-15 as a survival factor. However, the combination of IL-1β and IL-15 led to a significant and reproducible 4.64±−0.68–fold increase in stage 3 cell number over that seen with IL-15 alone (p < 0.0005). This phenomenon was completely restricted to stage 3 immature NK cells, and is attributed to increased proliferation. The effects of IL-1β were abrogated by a molar excess of IL-1 receptor antagonist (IL-1RA), a physiologic competitor for IL-1R1 binding. Collectively, our data indicate that IL-1R1 expression fluctuates dramatically during NK cell development, and that unique responses of IL-1R1(+) stage 3 cells to IL-1β and IL-15 govern the expansion of these immature NK cells. Our findings support a model in which IL-1β promotes stage 3 proliferation and survival in vivo, driving stage 3 cells to be the most prevalent NK cell intermediates within SLT.
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Smoking is associated with prostate cancer mortality. The Scandinavian smokeless tobacco product snus is a source of nicotine but not the combustion products of smoke, and has not been studied with respect to prostate cancer survival. The study is nested among 9,582 men with incident prostate cancer within a prospective cohort of 336,381 Swedish construction workers. Information on tobacco use was collected at study entry between 1971 and 1992, and categorized into (1) never users of any tobacco, (2) exclusive snus: ever users of snus only, (3) exclusive smokers: ever smokers (cigarette, cigar, and/or pipe) only, and (4) ever users of both snus and smoking. Hazard ratios for prostate cancer-specific and total mortality for smoking and snus use based on Cox proportional hazards models adjusted for age, calendar period at diagnosis, and body mass index at baseline. During 36 years of follow-up, 4,758 patients died - 2,489 due to prostate cancer. Compared to never users of tobacco, exclusive smokers were at increased risk of prostate cancer mortality (HR 1.15, 95% CI: 1.05-1.27) and total mortality (HR 1.17, 95% CI: 1.09-1.26). Exclusive snus users also had increased risks for prostate cancer mortality (HR 1.24, 95% CI: 1.03-1.49) and total mortality (HR 1.19, 95% CI: 1.04-1.37). Among men diagnosed with non-metastatic disease, the HR for prostate cancer death among exclusive snus users was 3.17 (95% CI: 1.66-6.06). The study is limited by a single assessment of tobacco use prior to diagnosis. Snus use was associated with increased risks of prostate cancer and total mortality among prostate cancer patients. This suggests that tobacco-related components such as nicotine or tobacco-specific carcinogens may promote cancer progression independent of tobacco's combustion products. This article is protected by copyright. All rights reserved.
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Hematopoietic stem cells (HSC) continuously replenish all types of blood cells through a series of lineage restriction steps that results in the progressive loss of differentiation potential to other cell lineages. This chapter focuses on the recent advances in understanding one of the earliest differentiation steps in HSC maturation, the diversification of the lymphoid and myeloid cell lineages, which make up the two major branches of hematopoietic cells. We will discuss the progress in identifying and characterizing progenitor populations that are downstream of HSCs. Prospective isolation of cell populations at the various maturational stages is a key in understanding the sequential biological events that take place during the course of differentiation of HSC into each hematopoietic cell type. The role of transcription factors, cytokines, and bone marrow microenvironments in lymphoid versus myeloid cell fate decisions will also be discussed.
Article
Objective: Cigarette smoking is the main cause of chronic obstructive pulmonary disease (COPD) and may modulate the immune response of exposed individuals. Mast cell function can be altered by cigarette smoking, but the role of smoking in COPD remains poorly understood. The current study aimed to explore the role of cigarette smoke extract (CSE)-treated mast cells in COPD pathogenesis. Methods: Cytokine and chemokine expression as well as degranulation of bone marrow-derived mast cells (BMMCs) were detected in cells exposed to immunoglobulin E (IgE) and various doses of CSE. Adoptive transfer of CSE-treated BMMCs into C57BL/6J mice was performed, and macrophage infiltration and polarization were evaluated by fluorescence-activated cell sorting (FACS). Furthermore, a coculture system of BMMCs and macrophages was established to examine macrophage phenotype transition. The role of protease serine member S31 (Prss31) was also investigated in the co-culture system and in COPD mice. Results: CSE exposure suppressed cytokine expression and degranulation in BMMCs, but promoted the expressions of chemokines and Prss31. Adoptive transfer of CSE-treated BMMCs induced macrophage infiltration and M2 polarization in the mouse lung. Moreover, CSE-treated BMMCs triggered macrophage M2 polarization via Prss31 secretion. Recombinant Prss31 was shown to activate interleukin (IL)-13/IL-13Rα/Signal transducers and activators of transcription (Stat) 6 signaling in macrophages. Additionally, a positive correlation was found between Prss31 expression and the number of M2 macrophages in COPD mice. Conclusion: In conclusion, CSE-treated mast cells may induce macrophage infiltration and M2 polarization via Prss31 expression, and potentially contribute to COPD progression.