A scope systematic review to clarify immune response to tobacco in Buerger

doi:10.21203/rs.3.rs-4157270/v1

Background

Progressive Thromboangiitis Obliterans (TAO) is a progressive and segmental inflammatory disorder known as Buerger's disease that affects the medium and small arteries of the upper limbs. The major risk factor for Buerger's disease is cigarettes and tobacco products, which can activate several inflammatory and pre-inflammatory parameters.

Methods

For this systematic review, based on the accepted criteria of Prisma, we searched from 2017 to 2022 in PubMed, Web of Science, science direct and followed the results of Google Scholar cytokines. We reviewed the literature on these smoking-related immune parameters in Buerger's disease as a potential treatment for this disease.

Results

In TOA patients, IL-17, RORγt, HMGB1 and RAGE mRNA expression are positively correlated with symptom severity. TLR family is associated with changes in the TOA population as a significant difference in TLR4 in the resting and acute phases. TLR9 may also be responsible for the secretion of IL-8 TNF involves in inflammation, muscle weakness, and pain in TOA. significant difference of IL-33 levels between TOA patients, healthy smokers and non-smokers of this cytokine.

Conclusion

Our results suggest that Buerger's disease can be considered an autoimmune disease caused by smoking. Buerger increase pro-inflammation markers in TOA and reduce angiogenetic factors. We recommend that pro-inflammatory cytokines should be considered in treatment and diagnosis programs and further research should focus on them.

Buerger's disease

Tobacco

Thromboangiitis Obliterans

tumor necrosis factor

toll-like receptors

Non-atherosclerotic, obstructive, thrombotic, and segmental inflammation of the medium and small vessels of the lower and upper limbs is a condition known worldwide as TOA and called Buerger's disease(1, 2). The cause of this disease is still unknown, but tobacco is strongly suspected to be one of the main causes(3). Despite the inflammatory nature of this disease, there is a difference between it and similar vasculitis conditions, so the vessel wall and elastic properties have different conversion in TOA, which has encouraged researchers to look for a more precise and specific cause in its pathophysiology (4, 5).Diagnosing systems such as Shionoya and Olin occur before the age of 50 years. Migratory phlebitis along with infrapopliteal artery occlusion, excluding other causes other than atherosclerotic smoking and a history of tobacco use completes the diagnostic process of Buerger's disease(6–8) .Self-aggressive effector T cells are involved in the pathogenesis of cell-mediated autoimmune diseases. In particular, IFN-γ producing Th1 cells have long been implicated in the pathogenesis of many organ-specific autoimmune diseases(9). Treg cells help limit the immune response by producing immunosuppressive cytokines such as IL-10 and TGF-beta. Th17 cells are widely implicated in autoimmune diseases, producing IL-17A and IL-17F cytokines and also secreting IL-21 and IL-22(10, 11). Drug therapies have been assessed to treat patients with Buerger's disease, including anticoagulants, thrombolytics, vasodilators, and anti-inflammatory drugs. However, most are ineffective(12). Angiogenesis stimulation(13), and sympathectomy (14)are prominent surgical options in these patients, but the distal ischemic conditions have almost made these cases ineffective in the main treatment. The search for cytokines and immune regulators involved in inflammation and coagulation has led researchers to an autoimmune state in Buerger's disease(15–17) and prompted us to perform a systematic review of previous studies and to summarize the immune system pathways studied in TOA. Previous studies have focused on the treatment of TOA, while its physiological pathway is not well understood; according to the results of our review, this is the first systematic study of the physiological pathway of injury in Buerger's disease. In this systematic review, we aim to answer the following research question based on the PICO (Patient, Intervention, Comparison and Output) criteria, how tobacco changes immune system activity in TOA patients?

This systematic study was written based on the accepted criteria of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

o Search strategy

Our systematic review assessed articles in PubMed, Scopus and web of science, and we extracted the keywords we used from the MESH database. We completed our search between February 2015 and August 2022. We examined our own title in the Cochrane Data Base to find similarities and review similar systematic studies.

keywords searched as:

Thromboangiitis Obliterans
Buerger's disease
Tobacco
Smoking

o Eligibility criteria, study selection, and data extraction

Buerger was investigated based on the international definition of ICD 11 (International Classification of Diseases) accepted in 2022. Article that examined congenital brain abnormalities were excluded from the articles.

All kinds of original articles, including observational, comparative, clinical trials, etc were included. .
case report articles, reviews and non-English articles excluded from our findings.
We did not exclude animal articles from the study
Articles that examined the effect of a treatment protocols on burgers and excluded the effect of tobacco in population or ignore immune parameters

After reviewing the articles that measured the relationship between smoking, tobacco and Buerger, we were looking for an effective factor in order to create a stronger correlation between smoking and TOA, finally, by reviewing the article and the opinion of all the authors, we paid attention to all substances related to tobacco.

o Certainty of evidence assessment

In order to comply with the principle of non-bias, we used the Cochrane Manual for Systematic Reviewers 5.1.0 for clinical studies and reviewed the studies in terms of allocation concealment, blinding of participants, study personnel and outcome assessors.

o Data Collection Process

Two authors reviewed the studies separately, and all stages were conducted according to the PRISMA criteria. In case of disagreement in selecting a study, the responsible author resolved the issue.

The following information was extracted from the final statistical population.

first author
Type of study
Population
smoking habit and type
Diagnosis Method
Side risk factors
Age means
geographical location
Immunity parameters

Two authors blindly reviewed the studies in the selection phase. In the first step, we examined the immune parameters measured in Buerger's disease. The articles were read by two authors, and in case of disagreement, the differences were resolved under the refereeing of the responsible author. Studies were searched, abstracts of articles were screened and then eligibility was evaluated. The full text was read by two authors and the immunity factors (cytokines, interleukins and etc.) measured in the studies were followed in tobacco studies (due to prove the effectiveness of tobacco in immune system changes). Then the above steps were repeated again. If two different articles had almost the same result and were measured through the same method, the older article was excluded from the study and the newer study was cited.

Eventually, we compared the changes of the parameters obtained by tobacco with the changes in Buerger's disease. Results matched by searches in Cochrane and Google Scholar to find any contradiction article against our results and mentioned according to the principle of non-bias criteria (Fig. 1).

All articles were patient-based and 7 articles were conducted in Iran, 4 in China and one in Korea. Systematic reviews and meta-analyses were not available, all clinical trials were not ethically prohibited, and randomized trials were assessed based on Consort checklists(11, 18–28).

o Cytokines level changed by tobacco to increase tissue inflammation

The most important of immunologic factors investigated in studies related to Berger's disease were TLR4, TLR2, C-Reactive Protein (CRP), neopterin, IL-33, ST2 receptor, IL-17, IL-23, IL-6, TNF-α, IFN-γ, IL-4, IL-10, high mobility group box 1 (HMGB1), IL-22, TLR9, IL-8, IL-1, human leukocyte antigen (HLA) class I (HLA-A, HLA-B), HLA class II (HLA-DRB1, HLA-B), CD4.

There was a significant difference of IL-33 levels between TOA patients, healthy smokers and non-smokers of this cytokine, two other IL-33-related compounds, including Neopterin, and so considering a positive correlation between IL-33 and TLR4 and a negative correlation with IL-17. Neopterin as a parameter along TLR 4, increased in the group of patients. Neopterin is produced by human monocytes/macrophages and dendritic cells upon stimulation with IFN-γ, which is released by activated T-helper lymphocytes(29, 30). IL-17, IL-22, and IL-23 were significantly high in the group of TOA patients, which eventually increases Th 17 and the inflammation of the vessels progress towards further damage(7, 11). In TOA patients, IL-17, RORγt, HMGB1 and RAGE mRNA expression are positively correlated with symptom severity. IL-23 is a member of the IL-12 family, including pro-inflammatory cytokines that strengthen Th 17, and can positively correlate with IL-17 and IL23 in JK Byun's study, along with other parameters such as IL-6, TNF-α, IFN-γ, HMGB1 to justify TOA(20).

o Tobacco induced apoptosis in TOA in TLR signaling

TLR4 activates the innate immune response by recognizing pathogen-associated molecular patterns or danger-associated molecular patterns (mainly endogenous signals for cell death and tissue damage)(19). As we expect to see TLR4 responses in inflammatory pathways, studieshave Mohareri has shown that the TLR family is associated with changes in the TOA population as a significant difference in TLR4 in the resting and acute phases. Activation of TLR9 may also be responsible for the secretion of IL-8, which may explain the neutrophil infiltration in the SG of TOA patients.

Peroxynitrite may act as an intracellular signal for the production of IL-8, one of the key regulators of leukocyte trafficking in inflammation. This is based on the multifold increase of HMGB1 (its nuclear protein present in all cell types that regulates inflammation) and TLR9 in the SG of the TOA population. However, the increased expression of TLR 4 in SG was violated by Haimei Liu, whose results showed that Sage phenolic acids have anti-inflammatory properties and potential mechanisms involved in the TLR4/NF-kB signaling pathway and may be effective in the treatment of inflammation-related vascular diseases(31). IL-8 has an anti-inflammatory role in the immune system, but it is known as a strong angiogenic factor(32, 33), nevertheless, the effect of bypass treatment on the serum levels of IL-6, IL-8 and TNF-α in TOA patients was studied in comparison with drug treatment (hydrochloric acid nicardipine, enteric-coated trental and aspirin). This study showed a high reduction of IL-8 by western medicine or by revascularization and the decrease in the bypass group was more significant(22).

o TNF reduce reperfusion in TOA by tobacco

We concepted that cytokine induced TOA, one of the most effective inflammatory parameters in Buerger is TNF. It can be said that the hottest discussion in our available studies has been TNF-α, along with IL-6 and IL-1(23, 34). The roles of TNF include involvement in inflammation, muscle weakness, and pain in TOA. Macrophages and CD 4 + cells play a role in its production TNF-α has a strong effect on Th cell polarization and function(35–37), focusing on the fact that treatment with prostaglandin sodium and cilostazol in Li ZF study, was able to reduce IL-1 along with TNF [44, 48]. IL-6 also regulates the specific differentiation of CD4 + T cells(38), alongside TGF-β, it is essential for the differentiation of Th17 and in regulating the Th17/Treg balance(39–41), which is pathological in the development of various diseases such as autoimmunity and chronic inflammation. IL-6 and TNF were decreased after bypass surgery in the TOA(24, 34), which may be related to the reduction of the degree of ischemia after bypass surgery. This increase of CD 4 + in addition to CD 8 + in TOA patients is somewhat justified and shows the range of regulators in TOA.

We found traces of antibodies such as immunoglobulin M, that exerts inflammatory conditions in autoimmune diseases such as RA through various pathways(42, 43). Rheumatoid factor IgM and ANA were increase between the group of TOA patients and healthy people, but there was no significant difference between the severity of TOA and their serum levels.

To assess the autoimmune cause of Buerger's disease, we needed more evidence because the statistical population obtained was fragmented, but by putting these pieces together, we can deduce a single and acceptable result that the immune system plays an important and major role in Buerger's disease. The expression of cytokines along with HLA and TNF for the balance of the regulators of the immune system and the activation of pro-inflammatory agents are put together like a puzzle, while the role of immunoglobulins and interleukins in completing this cycle is obvious. However, in order to draw a correct conclusion, we examined the traces of these elements in the articles related to tobacco and followed the results in the immune system.

It seems that the groups suffering from COPD tolerated a high level of TNF-α in their serum by increasing the pressure of tobacco, which ultimately caused the sensitivity and inflammation of their lung tissue to be more severe than that of non-smokers(44, 45). As we noted in TOA, this effect was possible with cytokines such as IL-1 and IL-6(46, 47). It seems that tobacco can express a group of HLAs corresponding to what we observed in TOA (class II). IL-33 levels are significantly higher in smokers(48–50). IL-33, a member of the IL-1 family, was originally reported to be constitutively expressed in the nucleus of tissue and structural cells. However, upon tissue injury or damage, IL-33 can be rapidly released to bind to its ST2 receptor in response to wound healing and inflammation(51). The interaction of TLR4 and IL-33/ST2 signaling in autoimmune patients can induce a Th2 response. The existence of a single nucleotide polymorphism (SNP) in MyD88 as a key factor of TLR4 signaling pathway in TAO patients with smoking can induce the expression of IL-33 by vascular endothelium and thus change the immune response from Th1 to Th2 type. Therefore, it seems that the high level of IL-33 in the active phase of TAO leads to a Th2-type immune response, which may not be a favorable response if an intracellular pathogen is involved in the pathogenesis of TAO. In the silent phase of TAO, the mean levels of IL-33 were significantly higher in CRP-negative patients than in CRP-positive patients. Therefore, IL-33 seems to play an anti-inflammatory role in TAO patients. If TAO is an infectious disease, this anti-inflammatory effect of IL-33 may be detrimental. On the other hand, it may be helpful if TAO is an autoimmune disease. The results of the investigations showed that the regulation pattern of IL-33/sST2 in TAO is different from that in autoimmune vasculitis such as SLE(19). Th17 cells are a subset of T helper cells that play a key role in inflammation by activating neutrophils. Studies have shown that Th17 cells may play a role in autoimmune diseases, particularly with the cross-activity of HMGB1 and IL-17 in patients with TOA. Increased levels of HMGB1 play a key role in vascular lesions in patients with Buerger's disease (11, 20). IL-17 induces the secretion of pro-inflammatory cytokines such as IL-6 and TNF-α from macrophages. These pro-inflammatory cytokines amplify their effects by forming a positive feedback loop with IL-17. Elevated levels of IL-17 and IL-23 indicate that autoimmunity is responsible for the aforementioned changes in Buerger's disease. IL-17 along with IL-1 (52) and IL-22 showed a similar behavior, but most of the values were measured in the context of diseases such as COPD in TOA patients, finally they had TNF-α next to them, which guarantees their behavior as the correlation with this cytokine in TOA (53–55).

It appears that different TLR pathways are affected by smoking and tobacco, but studies have yielded conflicting results. TLR4 activates the innate immune response by recognizing pathogen-associated molecular patterns or danger-associated molecular patterns (mainly endogenous signals for cell death and tissue damage)(56). The TLR family plays a different role, as we expect TLR4 responses in inflammatory pathways(57, 58). Changes in the levels of TLR 4 and 2 have been seen in studies, and the inhibition of the TLR 4 pathway is more powerful, as reported by Haimei Liu. had led us to the contradiction of data with the effects of tobacco on this pathway(59–61). The role of peroxynitrite as an intracellular signal for the production of IL-8 in leukocyte trafficking ensures TOA inflammation(62), Nevertheless, we have encountered various contradictions around IL-8 that introduce it as a useful parameter harmful one. If we consider its angiogenic role, it can be said that it may be a suitable therapeutic target in TOA(63), although many studies are still needed to determine whether tobacco and nicotine inhibit or enhance the path of this cytokine in TOA(47).

So far, the main cause of Burger has been tobacco, and according to these arguments, it is clear that almost most of the parameters found in the TOA articles could be attributed to tobacco. If we want to judge that these changes are related and that the immune system mediation is the creator of Buerger, it is very early and requires more extensive research on the certainty of the effect of tobacco, nicotine and cigarettes on the immune system and on the other hand the certainty of these changes in TOA. However, with the few articles available to us, we have been able to compensate to some extent. TNF antagonists are considered an important therapeutic agent to prevent inflammatory pathways in patients with arthritis, thrombocytopenia, and aplastic anemia(64, 65).In addition, interleukins 17, 33, 23, 22, 6, 8 have many studies in other diseases such as cancer based on their involvement in regulating the immune system, inflammation and the pathogenesis of autoimmune diseases(66–69).

HMGB1 is a protein produced in inflammatory and necrotic tissues. This protein increases the expression and function of cytokines and also increases cell migration and cell adhesion. That is, what we found in TOA and as we observed (HMGB1) was associated with an increase in Burger's disease(70–72). Immune system changes in TOA suggest similar changes in inflammation and autoimmune disease, and this has been partially confirmed by tracking these changes in the immune system induced by tobacco.

As should mentioned, it appears that Buerger's disease can be considered as an autoimmune disease. The immune system induces inflammation and tissue ischemia in Thromboangiitis Obliterans, and on the other hand, tobacco's ability to influence this pathway. The parameters in TOA were similar to the same parameters that are seen in autoimmune diseases and inflammatory conditions. Literature on Berger's is not strong enough in terms of numbers, which has made the pathogenesis of this disease somewhat unclear. In this review, we had few articles available, however, we followed up the results with tobacco and nicotine products. We definitely cannot consider Berger's as an autoimmune disease. If TOA were more similar to conditions such as vasculitis, this possibility would be stronger, but its special condition and, as we said, the ambiguity of its nature make this judgment difficult. our investigation confirms the possibility of TOA that being autoimmune, although we should consider that it can be affected by genetics and geographical factors, which can determine the severity of the disease.

The changes of cytokines and proinflammatory markers in TOA are towards autoimmune disorders, and this indicates the extremely important role of the immune system in the course of tissue death and reduced perfusion in Buerger. More inflammatory factors can be measured in TOA, and related tissue markers may also be useful in the management of this disease. We hope that future studies will evaluate the safety aspect in TOA pathology more.

TAO Thromboangiitis Obliterans

TLR Toll-like receptors

IL Interleukin

IFN Interferon

TGF Transforming growth factor

HLA Human leukocyte antigen

HMGB1 High mobility group box 1

COPD Chronic obstructive pulmonary disease

SG Sympathetic Ganglia

IgM Immunoglobulin M

ANA Antinuclear antibodies

COPD Chronic Obstructive Pulmonary Disease

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Author contribution statement

M.S.: study design, supervise the steps of study implementation and prepared the first draft of the manuscript, M.S., N.KH., and R.M.: study design and data collection, KH.A and S.AH: study design and consultation preparing the first draft of the manuscript. KH.A. Final manuscript revision. All authors contributed to the finalization of the article.

Acknowledge

This work was done in collaboration with the immunology department of Hormozgan University of Medical Sciences, for which we are very grateful to all the respected professors, especially the assistant professor Dr. Afshin Samie. In accordance with the Taylor and Francis guidelines on use of copyright material (https://authorservices.taylorandfrancis.com/editorial-policies/plagiarism/), an abstract related to this manuscript has been presented at the 4th National Congress and the 1st International Congress on Tobacco and Health of Hormozgan University of Medical Sciences.

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Table 1

	CASE POPULATION		CONTROL POPULATION		AGE	GEOGRAPHICAL tLOCATION	Kind of population	STUDY KIND
Mehran Mohareri (2018)	MAN: 51 28 acute phases 23 quiescent phases		MAN:31		CASE: acute phase group 40.6 ± 1.1 quiescent phase group 43 ± 1.8	Iran	Human-Caucasian	Case-control
Mehran Mohareri (2018)	FEMALE: -		FEMALE:		CONTROL: 40.3 ± 0.5	Iran	Human-Caucasian	Case-control
Hiva Sharebiani(2020)	MAN: 50 patients 22 were in acute phase 28 patients in quiescent phase		MAN: 20 healthy smokers 19 non-smoker controls		CASE: acute group 40.6 ± 1.1 quiescent phase 43 ± 1.8	Iran	Human-Caucasian	Case-control
Hiva Sharebiani(2020)	FEMALE: -		FEMALE:		CONTROL: smoker 40.3 ± 0.5 non-smoker 41.6 ± 1.4	Iran	Human-Caucasian	Case-control
J K Byun (2021)	MAN: 15 patients		MAN: 6 healthy donors		CASE: 43.27	Korea	Human	Clinical trial
J K Byun (2021)	FEMALE: -		FEMALE:4 healthy donors		CONTROL: 36.4	Korea	Human	Clinical trial
Shayan Keramat (2019)	MAN: 60 patients		MAN: 30		CASE: 42 ± 7	Iran	Human-Caucasian	Case-control
Shayan Keramat (2019)	FEMALE: -		FEMALE:		CONTROL: case matched	Iran	Human-Caucasian	Case-control
Behzad Mousazadeh (2019)	MAN: 24 patients		MAN: -		CASE: 42 ± 7	Iran	Human-Caucasian	Case -control **According to the side effects of sympathectomy, our biobank included no tissue from SG resection from healthy people. Thus, the cDNA of the SG of hyperhidrosis patients was used as the control for calculating the fold change of gene expression based on the Pfaffl method.
Behzad Mousazadeh (2019)	FEMALE: -		FEMALE:		CASE: 42 ± 7	Iran	Human-Caucasian
Shifeng Wu (2018)	MAN: 65patients		MAN: 33		CASE: 39.18 ± 7.45	China	Human	Case -control
Shifeng Wu (2018)	FEMALE: -		FEMALE:		CONTROL: 39.21 ± 7.38	China	Human	Case -control
Zheng-Fei Li (2020)	MAN: 67patients treated with revascularization combined with prostaglandin sodium and cilostazol		MAN: 50 patients treated with sodium and cilostazol		CASE: 55.3 ± 8.6 CONTROL: 54.7 ± 9.4	China	Human	Randomize-control trial
Zheng-Fei Li (2020)	FEMALE: -		FEMALE:		CASE: 55.3 ± 8.6 CONTROL: 54.7 ± 9.4	China	Human	Randomize-control trial
Zheng Wei (2018)	MAN: 20patients	MAN: 20patients			CASE: 42	China	Human	Case -control
Zheng Wei (2018)	FEMALE: -	FEMALE:			CONTROL: 38	China	Human	Case -control
Fatemeh Dehghani Firouzabadi (2020)	MAN: 70 patients	MAN: unspecified			CASE: 39.8	Iran	Human	Case -control
Fatemeh Dehghani Firouzabadi (2020)	FEMALE: -	FEMALE:			CONTROL: unspecified	Iran	Human	Case -control
Mahdi Farzadnia(2017)	MAN: 19 patients	MAN: -			CASE: 40.9 ± 5.1	Iran	Human-Caucasian	Randomize-control trial
Mahdi Farzadnia(2017)	FEMALE: -	FEMALE:			CONTROL: -	Iran	Human-Caucasian	Randomize-control trial
Abbas Shapouri-Moghadam (2021)	MAN: 80 patients Mild (n = 11) Moderate (n = 46) Severe (n = 23)	MAN: -			CASE: Mild (48.68) Moderate (42.43) Severe (40.43)	Iran	Human	Randomize control trial
Abbas Shapouri-Moghadam (2021)	FEMALE: -	FEMALE:			CONTROL: -	Iran	Human	Randomize control trial
Fuchen Song (2018)	MAN: 13 patients	MAN: 12		CASE: 32–56 years		China	Human	Case -control
Fuchen Song (2018)	FEMALE:10 patients	FEMALE:8		CONTROL: 32–56 years		China	Human	Case -control

Table 2

C-reactive protein (CRP).soluble decoy receptor ST2 (sST2),enzyme-linked immunosorbent assay (ELISA),soluble receptors for advanced glycation end (sRAGE),high-mobility group box 1 (HMGB1),soluble vascular cell adhesionmolecule-1 (sVCAM-1),soluble intercellular adhesion molecule-1 (sICAM-1) cluster of differentiation 8 (CD8),real-time polymerase chain reaction (PCR),anti-nuclear antibodies (ANA),anti-cyclic citrullinated peptide(anti-CCP),antiphospholipid antibodies (APA),anti-cardiolipin antibodies (ACLA),anti-double stranded DNA (anti-dsDNA),extractable nuclear antigen (ENA),Mean Platelet Volume(MPV)
Table 2 First author / year published / Doi number	Diagnosis Method	Immunity parameters	Results Highlights	Other results
Mehran Mohareri (2018) DOI: 10.2147/VHRM.S172047	ELISA method	• TLR 4 • TLR2 • CRP • Neopterin	The mean level of sTLR4 acute phase patients 3.3 ± 0.59 ng/mL, quiescent phase 1.98 ± 0.18 ng/mL, and in the control group 4.55 ± 0.87 ng/mL no significant difference between the levels of sTLR2 was found The neopterin level was significantly higher in the patients in the acute phase of the disease in comparison with the patients in the quiescent phase and the controls. 73.1% of patients were positive for CRP and 26.9% were negative. 73.1% of patients were positive for CRP and 26.9% were negative.	TAO might be Gram-negative bacteria, which can be hidden or immunologically suppressed in the quiescent phase of TAO
Hiva Sharebiani(2020) DOI:10.2147/JIR.S253980	ELISA	• IL-33 • sST2	Interestingly, IL-33 in the acute phase group was significantly higher than in the patients in the quiescent phase of the disease the mean serum level of IL-33 in the patients with gangrene was significantly higher than in the patients with non-healing ulcers	TAO an infectious disease as opposed to an autoimmune disease the active phase of TAO might be due to changing the type of immune response from mainly Th1 to Th2 toward an intracellular pathogen
J K Byun (2021) DOI: 10.26355/eurrev_202106_26046	• Ficoll-Hypaque • ELISA	• IL-17 • IL-23 • IL-6 • TNF-α • IFN-γ, • IL-4 • IL-10 • HMGB1 RAGE	levels of inflammatory cytokines and production of pathogenic Th cells were found to be higher in Korean patients with Buerger’s disease.	IL-17 and HMGB1 cytokines contribute to the pathogenesis of Buerger’s disease, ADAM10 alleviates inflammation in Buerger’s disease via the HMGB1 and RAGE/NF-κB signaling pathways
Shayan Keramat (2019) Doi: 10.2147/JIR.S218105	ELISA	• IL-22 • IL-23 • IL-17	The serum levels of IL-17, IL-22 and IL-23 were significantly higher in the TAO patients in comparison with the controls	particularly in the patients with neutrophilia and a low level of MPV, suggest that the trigger of TAO development may be an infectious pathogen
Behzad Mousazadeh (2019) Doi: 10.1186/s12948-019-0114-2	• PCR • real-time PCR Green • CT (∆∆CT)	• HMGB1 • TLR4 • TLR9 • RAGE	The gene expression of HMGB1 and TLR9 increased by about 25- and 2-fold changes in the SG of the TAO patients, there was no change in the gene expression of TLR4 or RAGE. Inflammation in the SG of TAO patients is more likely a sterile inflammation, and its trigger may be mitochondrial DNA (mtDNA).	Cadmium in cigarettes could be responsible for the induction of mtDNA release to the cell cytoplasm.
Shifeng Wu (2018) Doi: 10.3892/etm.2018.5877	ELISA	• IL-6 • IL-8 • TNF-α	Changes in inflammatory cytokines in the groups Before treatment, no significant differences in the serum levels of inflammatory cytokines were found between the groups Compared with the pre-treatment levels, the serum levels of IL-6, IL-8 and TNF-α were significantly reduced in both groups, and the decreases of serum levels of IL-6, IL-8 and TNF-α were more significant in the treatment group	suggesting that the treatment of TAO with revascularization can better improve limb blood supply and immune injury.
Zheng-Fei Li (2020) Doi: 10.3892/etm.2020.9362	ELISA	• VEGF • IL-1 • TNF-α	Serum VEGF concentration in group A was clearly higher than that in group B, and IL-1 and TNF-α levels were much lower than those in group B After amputation: The serum VEGF concentration in the study group before treatment was significantly lower than that in the control group while IL-1 and TNF-α levels were significantly higher another group.	pretreatment serum VEGF, IL-1 and TNF-α had a positive diagnostic value for poor prognosis of patients with amputation, and low concentration of VEGF and higher concentration of IL-1 and TNF-α are the risk factors for amputations in patients with TAO.
Zheng Wei (2018) Doi: 10.1016/j.cellsig.2018.01.015	ELISA	• IL-6 • sICAM-1 • sVCAM-1	IL-6/STAT3 pathway contributes to the pathogenesis of TAO by regulating cellular adhesion molecules and cytoskeleton of vascular endothelial cells	Targeting IL-6/STAT3 pathway may provide a potential approach for the management of TAO
Fatemeh Dehghani Firouzabadi (2020) DOI: 10.1002/iid3.325	Polymerase chain reaction (PCR)	• HLA class I (HLA-A HLA‐B) • II (HLA-DRB1HLA‐B)	HLA-A locus, the frequency of the A03:01 and A29 was significantly higher in patients compared with the healthy control In the HLA-B locus, the frequency of the B55:0B15:03 and B49:01 was increased in patients. but did not reach statistical significance the HLA-DRB1 locus, the DRB104 and DRB116 were significantly increased whereas the DRB101:01 was significantly reduced in patients compared The frequency of the DRB108:01 and DRB113:02 were increased in the control group but this was not significant	Genetic marker in the HLA region along with some environmental such as smoking and immunological factors may increase the risk of HLA-associated susceptibility genes in Buerger's patients.
Mahdi Farzadnia(2017) Doi: 10.1055/s-0037-1604410	• QIAGEN RNeasy • IHC • real-time PCR • Ct method (ΔΔCT)	• CD4 • CD8	lymphocyte infiltration was observed in all of the histological sections, ranging from scattered to moderate lymphocyte infiltration. CD8 marker expression in all of the samples with the expression of CD4 markers in only four tissue samples was demonstrated.	Inflammation of the sympathetic ganglia plays a role in the pathophysiology of TAO and its outcome
Abbas Shapouri-Moghadam (2021) DOI:10.5543/tkda.2021.19014	ELISA	• IgM • ANA • anti-CCP • APA • ACLA • anti-dsDNA • ENA	In all the patients, the serum levels of ANA and IgM RF were higher than 1 U and 15 IU/mL, progression of the disease from mild to moderate did not affect these markers significantly	The findings of this study indicate that BD may closely be correlated to transient autoimmune phenomena,
Fuchen Song (2018) Doi:10.3892/etm.2018.6436	ELISA	• IL-1β • IL-6 • TNF-α	The mRNA expression levels of IL-1β, IL-6 and TNF-α in TAO group were significantly higher than those in control group, the levels in cilostazol group were significantly decreased compared with those in TAO group	Cilostazol can significantly reduce the TAO-induced abnormal increase in ICAM-1, VCAM-1 and inflammatory factor expression in plasma in patients. It was proven that cilostazol has a good anti-TAO effect.

No competing interests reported.

A scope systematic review to clarify immune response to tobacco in Buerger

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

Background

Methods

o Search strategy

o Eligibility criteria, study selection, and data extraction

o Certainty of evidence assessment

o Data Collection Process

Results and findings

o Cytokines level changed by tobacco to increase tissue inflammation

o Tobacco induced apoptosis in TOA in TLR signaling

o TNF reduce reperfusion in TOA by tobacco

Discussion

Conclusion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1