Atherosclerosis 265 (2017) 258e265

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Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Review article

Pathogenesis of thromboangiitis obliterans: Gene polymorphism and

immunoregulation of human vascular endothelial cells
Xiao-lei Sun a, b, Betty Yuen-Kwan Law a, Ivo Ricardo de Seabra Rodrigues Dias a,
Simon Wing Fai Mok a, Yan-zheng He b, **, Vincent Kam-Wai Wong a, *
a
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
b
Department of Vascular and Thyroid Surgery of the Affiliated Hospital of Southwest Medical University, Sichuan Province, China

a r t i c l e i n f o a b s t r a c t

Article history: Thromboangiitis obliterans (TAO) is a nonatherosclerotic, segmental, inflammatory vasculitis, which
Received 19 June 2017 commonly affects the small- and medium-sized arteries of the upper and lower extremities. Despite its
Received in revised form discovery more than a century ago, little progress has been made in its treatment. Unless the patho-
24 July 2017
genesis is elucidated, therapeutic approaches will be limited. The purpose of this review article is to
Accepted 17 August 2017
collate current knowledge of mechanisms for the pathogenesis of thromboangiitis obliterans and to
Available online 18 August 2017
propose potential mechanisms from a genetic and immunoreactive point of view for its inception.
Therefore, we discuss the possibility that the pathogenesis of this disease is due to a type of gene
Keywords:
Thromboangiitis obliterans
polymorphism, which leads to an immunological inflammatory vasculitis associated with tobacco abuse,
Buerger's disease highly linked to T cells, human vascular endothelial cells (HVECs), and the TLR-MyD88-NFkB pathway,
Polymorphism distinct from arteriosclerosis obliterans and other vasculitides.
MyD88 © 2017 Elsevier B.V. All rights reserved.
Type 2 helper T cells
IL-33

1. Understanding thromboangiitis obliterans (TAO) long-term management of TAO is 25% after 5 years past diagnosis,
38% after 10 years and 46% after 20 years [5]. Smoking is considered
TAO, also known as Buerger's disease, was first described in a the main precipitating factor [4,6], thus TAO is more common in
patient by von Winiwarter in 1879 [1]. Buerger, for whom the male patients 35e50 years of age.
disease is named, performed a detailed and accurate systematic
study of TAO in 1908 [2]. Although the disease has been named for
2. Smoking as a potential key risk factor for pathogenesis of
more than 100 years, its pathogenesis has not yet been elucidated
TAO
and research progress is slow. TAO is now generally recognized as
an incurable disease in vascular surgery [3], and can cause the
The disease was, at first, thought to occur mainly in Jews, but
necessity for limb amputations in young and middle-aged people,
since then, the worldwide distribution is found to be extremely
particularly smokers [4].
uneven. Overall, the incidence of TAO in the Middle East and the
TAO, affecting arteries and veins of upper and lower distal limbs,
Far East has a higher prevalence. The proportion of TAO among
is a kind of segmental vasculitis. The pathology is characterized by
patients with peripheral arterial disease in the late 20th century
non-suppurative diffuse vascular involvement of inflammatory,
varies greatly (Fig. 1) [7e14]. In recent decades, while the overall
proliferative and thrombotic occlusion changes with clinical fea-
incidence of TAO decreased, possibly due to a decreasing smok-
tures of limb ischemia, pain, intermittent claudication and migra-
ing population and more rigorous diagnostic methods and tools
tory thrombophlebitis, which can cause severe limb ulcers or
[4,7], an increase in the incidence of TAO in women has been
necrosis, and ultimately lead to amputation. Amputation risk in
observed, likely due to the increasing numbers of female smokers
[7,15,16].
The major risk factor for TAO has been proposed to be smoking
* Corresponding author.
** Corresponding author.
[17]. Most TAO patients have a history of smoking, which can cause
E-mail addresses: heyanzheng_11@163.com (Y.-z. He), kawwong@must.edu.mo vasospasm and a hypercoagulable state [18]. Clinical practice has
(V.K.-W. Wong). proved that smoking cessation can slow down disease progression

http://dx.doi.org/10.1016/j.atherosclerosis.2017.08.009
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 X.-l. Sun et al. / Atherosclerosis 265 (2017) 258e265 259

Fig. 1. The incidence rate and distribution of thromboangiitis obliterans (TAO) worldwide.
The incidence rate and distribution of TAO worldwide is uneven. In general, higher prevalence of TAO is found in the Middle East and the Far East region. The proportion of TAO
among patients with peripheral arterial disease (PAD) in the late 20th century varies greatly, of which India, South Korea and Japan and Israel have a higher proportion of PAD
disease [7e14].

and reduce the odds of requiring amputation, while smoking in-
creases the chances of amputation [19]. However, decreasing the
number of cigarettes per day does not have any effect on the
outcome of the disease [20]. So far, complete abstinence from the
use of all tobacco is the corner stone of management. Even though
there are different pharmacological agents and methods [21e41],
such as prostacyclin [23] and Bosentan [39], bypass surgery or
interventional revascularization (Fig. 2) applied under the condi-
tion of acute and severe limb ischemia with distal outflow in some
cases [28], autologous peripheral blood stem cell transplantation
[35] as TAO therapy (Table 1), high rate of recurrence exists and the
exact pathogenesis of TAO and its association with smoking re-
mains unclear [42].
Jin et al. [43] investigated the relationship between smoking
and TAO in rat experiments. The site around the femoral artery
of 20 rats was injected with tobacco extracts, and then the pa-
thology results by scanning electron microscopy showed that
seven rats displayed changes compared with typical TAO. Thus,
it can be concluded that the incidence of smoking was one of the
risk factors in TAO genesis. However, smoking alone did not
necessarily lead to TAO in rats. Recently, Kearley et al. [44] re-
ported that smoke exposure could be used to stimulate mouse
lungs to produce an immune response, resulting in increased
production of IL-33 and increased expression of IL-33 receptor
ST2 in T helper type 2 cells (Th2), which is one of the key im-
mune response leading to TAO [45]. In addition, the production
of IL-33 was also found to be up-regulated in severe chronic
obstructive pulmonary disease (COPD) patients, who were
usually smokers, suggesting smoking as a risk factor for TAO
[44,46,47].
3. Major factors contributing to the pathogenesis of TAO
3.1. Infection and TAO
Studies showed that nearly two-thirds of patients with TAO had
severe periodontal infections [48]. Iwai et al. [49]detected seven
kinds of bacterial DNA in oral samples and in occluded arteries,
using PCR in 14 cases of TAO patients afflicted by periodontitis, and
found that 13 of these cases had the same bacterial infection,
implying an association between TAO incidence and chronic oral
infections. Cytomegalovirus infection might also be associated with
the pathogenesis of TAO [50]. However, Klein-Weigel and Richter
[32] argued that the possible association between periodontal
disease and TAO pathogenesis was not very convincing, as the
prevalence of periodontal infection was also high in the typical risk
group, and similar associations had been reported for arterioscle-
rotic diseases and even rheumatoid arthritis [51]. In this regard, we
would propose a bold hypothesis that there might be abnormal
gene expression related to innate immunity in TAO patients, thus
weakening immunity and leading to infection.
3.2. Gene polymorphism and TAO
Immune genetic analysis on TAO patients found that the inci-
dence of HLA A-9 and HLA B-5 in TAO patients was higher than that
in healthy persons [52], whereas the incidence of HLA-B12 was
lower. However, these studies, and others that also demonstrate
HLA genes expression changes in TAO patients, show that the genes
affected and how their expression is affected vary from population
to population [52]. The MyD88 (myeloid differentiation factor 88)-
dependent pathway is one of the most important signaling

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Fig. 2. Typical computed tomography angiography (CTA) and angiographic feature of TAO.
The TAO patient is 31 years old, male, who has smoked more than 10 years, 20 cigarettes per day. CTA demonstrates segmental distally located multisegmental vessel occlusions of
the right limb (A and B). In the endovascular intervention, with retrograde access via the distal dorsalis pedis artery and the “SAFARI” technique subintimal arterial flossing with
antegrade-retrograde intervention (C), a method for recanalization of chronic total occlusions (CTOs) when subintimal angioplasty fails, the occlusive arteries were revascularized
(DeF). However, three months later, the arterial occlusions recurred.

pathways of innate immunity in Toll-like receptors (TLRs). Chen
et al. [53] found that, in a comparative study of the single nucleo-
tide polymorphism (SNP) rs7744 in the MyD88 gene 30 -untrans-
lated region in Japanese TAO patients, TA (Takayasu's arteritis)
patients and healthy controls, the GG genotype frequency in pa-
tients with TAO was significantly lower than that in the healthy
group (p ¼ 0.011), with no significant difference between the TA
group and the healthy group, which put forward the idea of
research on the TLR signaling pathway and its mutations, and their
correlation with TAO. Moreover, Adigüzel et al. [54] found that the
occurrence of endothelial nitric oxide synthase (eNOS) gene of
894 T/T genotype frequency correlated with the decline of the
occurrence of TAO; thus, it was proposed that the T allele of eNOS
gene 894G/T polymorphism played a protective role against the
development of TAO. Chen et al. [55] found that the frequencies of
CD14 TT genotype, HLA-DRB1*1501 and HLA-DPB1*0501 were
significantly higher in TAO patients than in healthy controls.
Recently, Shi et al. [56] undertook a case-control study to identify
genetic factors potentially involved in the pathogenesis of TAO and
found that the SNPs rs376511 in IL17RC (p < 0.0001), rs7632505 in
SEMA5B (p < 0.0001), and rs10178082 (p < 0.0001) correlated with
a significant risk of TAO in the Uyghur population in China. These

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 X.-l. Sun et al. / Atherosclerosis 265 (2017) 258e265 261

Table 1
The advantages and disadvantages of current therapeutic methods to Thromboangiitis obliterans (TAO).

Therapeutic method Advantages Disadvantages

Smoking cessation Overwhelming positive effect towards the prevention of limb amputation Effective, but not curative [21], and hard for smokers to cease
[19]. tobacco abuse [22].
Prostanoid therapy E.g. iloprost, a prostacyclin analogue. Effective for ulcer healing or relief of Clinical routine effectiveness of iloprost remains controversial
ischaemic pain [23]. [24].
Antiplatelet drugs and Widely used [21]. No proven evidence of effectiveness of platelet function
oralanticoagulants inhibitors, such as aspirin or clopidogrel, in TAO [24].
Vasodilating drugs Calcium channel-blockers or pentoxifyllin were reported to reduce No proven evidence of effectiveness in Buerger's disease (TAO).
vasospasm and improve walking distance [25].
Analgesia Effective analgesia is crucial as ischemic and neuropathic pain in TAO is Does not stop the progress of TAO or change the rate of the
usually severe [26]. clinical consequence of amputation [27].
Revascularization Includes bypass procedures, endovascular therapy, Higher recurrence rate of arterial occlusions and are impossible
procedures thrombendarteriectomies, omentum transfer, local thrombolysis, and so on. in the majority of cases due to the distal localization of arterial
Temporarily improves clinical ischemia in successful cases [28]. occlusions and the absence of recipient vessels [29].
Sympathectomy Preferred over open surgical reconstruction or bypass procedures with Currently there is no proven indication for effectiveness of
improved self-consciousness of pain or ischemia [30]. sympathectomy in TAO [31].
Immunosuppressive drugs Widely used in former times [32]. Side effects and there are no indications forimmunosuppressive
drugs in TAO [33].
Wound management Intermittent pneumatic compression might be of additional value [34]. Recovery ability and resistance to bacteria is worse in ischemic
andinfection Protects the ischemic limb against suffering from serious complications, wounds.
such as wound/soft tissue/bone infections and systemic inflammatory
response syndrome (SIRS).
Progenitor cell therapy Proven practicability and safety. Significant improvement of pain, ulcer size, The time lag of 4e8 weeks until improvement of
better amputation-free survival as well as claudication-free walking microcirculation becomes evident might be problematic in
distance [35]. cases of severe ischemia, demanding a more urgent
improvement of perfusion [36]. Controlled and comparative
studies are lacking.
Immunoadsorption (IA) A quick way to ameliorate infectious risks in TAO patients. A fast Only a single pilot study with a small number of patients has
improvement of pain, a steep incline of transcutaneous arterial oxygen been performed [38].
tension (TcPO2) levels, an improvement in ulcer healing, and a high return-
to-work rate in patients [37].
Bosentan An endothelin receptor blocking agent. Positive and promising results in the More clinical trials are needed.
treatment of TAO patients [39].
Traditional Chinese There are many traditional Chinese medicines applied in cardiovascular Little is known of their effects in TAO disease.
medicine diseases, such as Salvia miltiorrhiza, safflower injection, etc. An anti-oxidant
role [40] or inducement of moderate autophagy [41] have been reported as
protective effects in vascular endothelial cells and smooth muscle cells.

studies suggest that susceptibility to TAO is, in part, controlled by
genes involved in the innate and adaptive immunity. Recently,
Javierre et al. [57] connected non-coding disease variants to puta-
tive target promoters, and highlighted promoter interactions in
genomic regulatory mechanisms of common diseases, casting a
new light into research on gene polymorphism in TAO
pathogenesis.
4. Molecular mechanisms in the development of TAO
4.1. Human vascular endothelial cells (HVECs) injury and TAO
The etiology of TAO, leading to inflammation, thrombosis, hy-
perplasia and other symptoms, is most likely initiated by HVEC
injury [58]. Arterial endothelial cells from TAO animal models un-
der scanning electron microscopy showed that the extent of dam-
age and the extent of lesion development positively correlated with
the extent of arterial endothelium injury, which may be the initi-
ating link of pathogenesis of TAO [59]. Typical cardiovascular risk
symptoms, such as hyperlipidaemia, hyperglycaemia or hyperten-
sion are not found in TAO patients. One of the acute manifestations
of TAO is vasospasm, mainly due to local endothelial dysfunction
[60]. But the mechanism of HVEC injury in TAO is still unknown and
is currently focused on the following aspects:
(a) NFkB-iNOS-NO oxidative stress induced injury pathway: a
study aiming to reveal the relationship between oxidative
stress and TAO showed that the oxidative stress level was
significantly higher in TAO patients when compared to
healthy smokers and non-smokers [61]. He et al. [62] pointed
out that oxidative stress may occur through the activation of
endothelial NFkB-iNOS-NO pathway, resulting in excessive
release of nitric oxide (NO), which can react with superoxide
anion, and generate strong oxidation of nitrite anion, causing
lipid peroxidation and direct injury to the endothelial func-
tion, but can also increase the expression of adhesion mol-
ecules and inflammatory factors. Studies have shown that
infection of Porphyromonas gingivalis could lead to IkB-alpha
degradation and NFkB p65 nuclear translocation, thus acti-
vating the NFkB signaling pathway, increasing oxLDL uptake
by HUVECs, and further damaging HUVECs [63].
(b) Hemodynamic effect: changes in hemodynamics are also
involved in endothelial injury. Shyy et al. [64] showed that
the effect of blood flow on the endothelial cell surface G
proteins can activate the process of phosphorylation in
vascular endothelial cells, leading to the rearrangement of
vascular endothelial cells along the flow direction and acti-
vation of the NFkB signaling pathway, thereby causing
changes in vascular structure and function.
4.2. T cell-related immune injury and TAO
Recent studies suggest that TAO is an autoimmune disease [65],
but it is hard to explain all of the immune disorder processes
involved in TAO immunopathogenesis, due to a lack of sufficient
evidence [66]. In the serum of TAO patients, a variety of immune
complexes (anti-endothelial cell antibodies, anti-neutrophil

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antibodies, anti-cardiolipin antibodies) were, thus, significantly

higher than that in a healthy subject [67]. Kobayashi et al. [68]
analyzed the cell infiltration in arteries from TAO patients using
immunohistochemistry and found the presence of a large number
of intimal CD4 (þ) and CD8 (þ) T lymphocytes and a small amount
of CD20 (þ) B lymphocytes in the vessel walls, and macrophage
infiltration was also observed in thrombosis and vessel intima. They
also found that CD68 (þ) macrophage and S-100 (þ) dendritic cell
infiltration in the intimal layer of the arterial walls, and far more
CD3 (þ) T cells than CD20 (þ) B cells. Cui et al. [69] observed, under
the scanning electron microscope, that there were deposits of im-
mune complexes, and macrophage and neutrophil infiltration in
the occluded blood vessels of TAO patients. Dellalibera-Joviliano
et al. [45] found that, regardless of the current smoking status,
proinflammatory (IL-1b, TNF-a and IL-6), Th1 (IFN-g and IL-12), Th2
(IL-4, IL-5 and IL-13) and Th17 (IL-17 and IL-23) cytokines in the
serum of TAO patients were significantly increased compared to the
control groups (non-smokers, ex-smokers and active smokers),
suggesting that Th1 and Th2 cells are involved in the pathogenesis
of TAO, along with TAO susceptibility in smokers being due to ge-
netic modifications or, as suggested by the increased levels of IL-17
and IL-23, autoimmune disorders.
4.3. IL-33 secretion in human vascular endothelial cells (HVECs)
and TAO
IL-33, which is constitutively expressed in the nucleus of
endothelial and epithelial cells [70], is the most recently discovered
member of the IL-1 cytokine family and is identified as a ligand for
the IL-1 receptor (IL-1R) family member ST2 [71]. It is reported that
IL-33 acts during the early events of the inflammatory process, and
has a major role in host responses to different pathogens and al-
lergens [71]. Kim et al. [72] studied more about the factors asso-
ciated with plasma IL-33 levels in patients with COPD and found
that plasma IL-33 level in patients with stable COPD was related to
eosinophil count and chronic bronchitis phenotype, and current
smoking status was not related to a high IL-33 level. Besides the
pulmonary source of IL-33, Chen et al. [73] reported that pressure
overload-induced systemic circulating IL-33 could be abolished by
endothelial-specific deletion of IL-33, which revealed that endo-
thelial cell secretion of IL-33 is crucial for translating myocardial
pressure overload into a selective systemic inflammatory response.
Our preliminary results demonstrated that, while plasma IL-33
level of TAO patients were higher than that of control groups
(p ¼ 0.0001), TAO patients who were active smokers showed a
higher level of IL-33 when compared to a healthy control group
(Fig. 3, preliminary and unpublished data, Clinical Trial Registration
NO. ChiCTR-CRC-17011428 on http://www.chictr.org.cn/index.
aspx). Our clinical data, therefore, supports the hypothesis for a
role of IL-33 in the pathogenesis of TAO. However, the mechanistic
role of smoking on IL-33 level and TAO requires further
investigation.
Endothelial cells were recently shown to be important func-
tional targets for IL-33, which acts as an essential regulator of
allergic inflammation, including corticosteroid-refractory endo-
thelial cell responses and functions [74]. Stojkovic et al. [75]
recently reported that IL-33 could enhance the thrombotic capac-
ity of human umbilical vein endothelial cell (HUVEC) via ST2-and
NFkB-dependent mRNA and protein expression of tissue factor
(TF). Damaged endothelial cells release IL-33 to induce the immune
system and attract Th2 cells, thereby increasing local IL-4, IL-5 and
IL-13 [70,71,76]. Chalubinski et al. [77] reported that IL-33 elevated
endothelial cell surface ICAM-1 expression to promote leukocyte
adhesion and reversibly destabilized the endothelial barrier but, in
conjunction with IL-4-induced apoptosis of endothelial cells,
Fig. 3. Determination of activity of interleukin (IL)-33 in plasma of control individuals
and patients with thromboangiitis obliterans (TAO).
(A) The level of plasma IL-33 of TAO patients (n ¼ 7) is significantly increased
compared to that of control individuals (n ¼ 34), p ¼ 0.0001. (B) The level of plasma IL-
33 of active smokers with TAO (n ¼ 5) is also higher than the non-smokers control
(n ¼ 22, p < 0.0001), former smokers control (n ¼ 7, p ¼ 0.0068) and active smokers
control (n ¼ 5, p ¼ 0.0120). The measurements were evaluated with ELISA (human IL-
33 ELISA kit from BOSTE, China). The horizontal bars represent the mean þ SEM. The t-
test and one-way ANOVA test were carried out.
resulted in an extended and uncontrolled destabilization of the
endothelial barrier, which may eventually lead to aggravation of
inflammatory injury. However, IL-33 signaling also exerted car-
dioprotective effects. For example, IL-33 could ameliorate the
development of atherosclerosis in mice by inhibiting the conver-
sion of macrophages into foam cells [78], and promoting a shift
from Th1- to Th2-type immune response [79]. Ashlin et al. [80]
reported that IL-33 could stabilize developing atherosclerotic pla-
ques via ERK1/2, JNK (JNK1/2 and c-Jun) and PI3K signaling path-
ways, but not p38 MAPK. All these have summarized the role of IL-
33 in TAO.
4.4. IL-33 combines with its receptor ST2 via MyD88-dependent
TLR signaling pathway
IL-33 receptor complex consists of ST2 and the IL-1R accessory
protein (IL-1RAcP) composition [81]. IL-33 is a specific ligand for
ST2L (a transmembrane protein). The structure of ST2L consists of
three extracellular immunoglobulin domains and an intracellular
Toll/IL-1 receptor (TLR) domain [82]. IL-33 binds to its receptor ST2
to activate IL-1-related protein kinase (IRAK), tumor necrosis factor
receptor associated factor 6 (TRAF6), MAPK and NFkB through
MyD88, thereby regulating gene transcription, resulting in subse-
quent biological functions [82,83].
MyD88 single nucleotide polymorphism (SNP) in TLR signaling
pathway was studied in TAO patients, suggesting a correlation be-
tween the MyD88-dependent TLR signaling pathway and TAO
pathogenesis [53]. In addition, the MyD88-dependent TLR signaling
pathway is involved in the process of HVECs injury. For example,
Pahwa et al. [84] reported that high glucose stimulation induced
ROS increase as well as increasing TLR2 and TLR4 mRNA and protein
expression, activating MyD88-dependent and MyD88-independent
TLR signaling pathways, increasing monocyte adhesion and local
inflammatory response in aortic endothelial cells, which may lead
to injury. Echavarria et al. [85] found that angiopoietin-1 reduced

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 X.-l. Sun et al. / Atherosclerosis 265 (2017) 258e265 263

Fig. 4. The signaling pathway and pathogenesis of thromboangiitis obliterans (TAO).

Smoking might induce the tracheal epithelial cells of TAO patients susceptible to MyD88 gene mutation and stimulate IL-33 secretion from epithelium. The expression of IL-33
receptor ST2 is also upregulated in a panel of immunocellular components (including dendritic cell, Th2 cell, M2 macrophage, mast cell, and eosinophil). (A) Dendritic cells
stimulate Th1/Th2 polarization of naive T cell skewed towards the Th2 lineage upon IL-33 activation; (B) Th2 cells further mediate the transformation of fibroblasts into fibrocytes;
(CeE) IL-33 also activates M2 macrophages, mast cells, and eosinophils. The IL-33-activated cells infiltrate into the blood vessel walls and release inflammatory mediators damaging
HVECs and causing acute thrombosis in the vessel cavitym which leads eventually to TAO development.

inflammation response to LPS exposure in HUVECs by upregulating
miR-146b-5p expression, which inhibits the MyD88-IRAK1-TRAF6
signaling pathway. Aplin et al. [86] reported that in mouse aortic
vascular injury associated with angiogenesis there was over-
expression of TLRs and activation of TLR signaling pathways as well
as upregulation of downstream gene sequences, while in MyD88
knockout mouse cell culture, the activation of angiogenesis after
aortic injury was depressed, suggesting the involvement of MyD88
in TAO.
5. Conclusion and perspectives
We consider very important the finding of a disease-linked
polymorphism in the TLR signaling pathway's key factor MyD88,
which mediates many key innate immunity mechanisms, in TAO
patients [53]. Of course, we suspect that other regulatory factors of
the TLR signaling pathway (e.g. IRAK, TRAF6, ERK1/2, etc.) may also
suffer from gene polymorphisms that may increase susceptibility to
TAO but, as of yet, the exact mechanism that induces the patho-
genesis of TAO has not been elucidated.
This finding, in conjunction with the findings of smoking as a
predisposing factor of TAO [17], the significant immune and in-
flammatory cell infiltration, including Th2 cells, in the amputated
limb blood vessels of TAO patients [68,87], circulating IL-33, a
potent chemokine for Th2 cells [76], being induced in response to
smoke [44] and HVECs being capable of releasing IL-33 [70,71,76],
leads us to propose a hypothesis where smoking might induce the
vascular endothelial cells of TAO patients susceptible to MyD88
gene mutation to secrete more IL-33, accompanied by an increase
of IL-33 receptor ST2 expression on circulatory Th2 cell mem-
branes, thus leading to Th2 cell infiltration in blood vessel walls,
damaging HVECs with elevated expression of ICAM-1, E-selectin,
etc., which induces leukocyte aggregation in response, enhances
the inflammatory response, acute thrombosis in vessel cavity and
finally induces the occurrence of TAO (Fig. 4).
Thus, immuno-modulators to restore Th1/Th2 balance [88],
such as Toll-like receptor-9 (TLR9) activators, like CYT003-QbG10
and QAX-935, which are newly developed, and chemoattractant
receptor-homologous molecule expressed on Th2 cells antagonists,
like OC0000459, BI-671800 and ARRY-502, whose safety and
effectiveness was revealed in clinical trials [89], might be worthy
additions to the immunotherapy of TAO. Increasing evidence sug-
gests that autophagy occurs in peripheral arterial disease (PAD)
[90]. Exposure of endothelial cells in culture to stress factors such as
oxidized lipoproteins or advanced glycation end-products induces
autophagy [91,92], which is protective against endothelial cell
injury [93]. Selective autophagy induction-targeted drugs might be
another option to protect endothelial cells from inflammatory
injury in TAO.
In summary, this paper first attempts to provide an overview of
the pathogenesis of TAO from the environmental, genetic, immu-
nological and inflammatory aspects, and tries to hypothesize a new
comprehensive and systematic doctrine of TAO pathogenesis. Thus,
it might be possible to screen out-smoker populations susceptible
to TAO earlier, to prevent or avoid the pathogenesis of the disease. It
could not only ameliorate medical and social costs, but may also
open up new directions for the diagnosis and treatment of TAO.
Conflict of interest
The authors declared they do not have anything to disclose
regarding conflict of interest with respect to this manuscript.
Financial support
This work was supported by the Youth Innovation and Medical
Research of Sichuan Province (YIMRSP) grant from the Sichuan
Medical Association Fund of China (Project code: Q15043/

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264 X.-l. Sun et al. / Atherosclerosis 265 (2017) 258e265
SMA(2016)/NO.2), and the Science and Technology Development
Fund of Macao, FDCT (Project code: 084/2013/A3).
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