A Systematic Review of Interleukin-17 in Oral Lichen Planus: From Etiopathogenesis to Treatment

Abstract

Lichen planus (LP) is a chronic autoimmune disease of skin and mucous membranes. World Health Organization has announced oral lichen planus (OLP) as a premalignant lesion. The exact etiology of OLP remains unknown; however, different mechanisms may be involved in its immunopathogenesis. The upregulation of cytokines, chemokines, and adhesion molecules is consistent with a persistent and erratic immunological response to OLP-mediated antigens generated by oral keratinocytes and innate immune cells. These molecules attract T cells, and mast cells to the disease site and regulate complex interactions among cells that lead to death of keratinocytes, degradation of basement membrane, and chronicity of the disease. It is believed that CD8+ and CD4+ T helper 1 (Th1) cells are the main lymphocytes involved in this process, although recent evidence suggests implication of other T helper subgroups, such as Th23, Th17, and regulatory T cells (Tregs), proposing a more complex cellular immunity process to be involved in its pathogenesis. The emphasis of this research review is on the function of IL-17 in the pathophysiology of OLP and how current discoveries may point to future treatment strategies. This research protocol will follow Preferred Reporting Items for Systematic Reviews (PRISMA 2020) checklist. An electronic search was conducted in PubMed, Scopus, Google Scholar, Embase, and Cochrane databases for articles published from 1960 to June 2022. Based on the eligibility criteria, 21 articles were enrolled. In comparison to healthy controls, the findings of this review demonstrated greater expression of IL-17 and Th-17 in the blood, saliva, and tissues of OLP and LP patients. Additionally, there was a strong link between the relative levels of IL-17 and IL-23 expression. Treatment with monoclonal antibodies against Th-17/Tc-17, IL-12/IL-23, and IL-23 would result in significant long-term improvement of LP symptoms.

Oral lichen planus (OLP) is a non-infectious, immune-mediated, recurrent, chronic inflammatory, mucocutaneous disease,¹ which is the reason for a high number of dental visits.² It reportedly affects 0.5% to 4% of the world’s population.^3-5 In general, OLP is a disease of adulthood, rarely occurring in children. Middle-aged women are more likely to experience it.⁶ OLP is often not particularly severe, but there is a chance that it might become malignant.⁷ Patients who have OLP for 10 years, for instance, have a 0.5%–2% risk of oral cancer.^3,7,8 Smokers and alcoholic patients are at higher risk of malignant transformation.^9,10 Lichen planus (LP) more commonly affects the skin, mucous membranes, scalp, and nails.¹¹ Although cutaneous and mucosal forms of LP have similar histopathological characteristics, they can be differentiated based on their heterogeneous clinical behaviors.¹⁰ Subacute or chronic progressive polygonal papules^12-14 define cutaneous lesions. Bilateral white bands or plaques on the gingiva, buccal mucosa, and tongue are symptoms of oral lesions.¹⁵ Histologically, LP is characterized by apoptosis of keratinocytes, acanthosis, hypergranulosis, and lymphocyte-rich infiltration of superior dermis.^14,16-18 The oral cavity is the most common site of development of LP, and it often develops on the gingiva, buccal mucosa, palate, and tongue.¹⁹ Some studies reported significantly worse periodontal status in OLP patients compared with healthy controls.^20,21 Some other studies reported significantly higher plaque and calculus in patients with atrophic-erosive gingival OLP, which was associated with higher periodontal destruction.^22,23 Furthermore, owing to the significant gingival and periodontal involvement in such individuals and its detrimental consequences on oral health, some studies advise periodontists to actively participate in the care of OLP.²⁴ Clinical manifestations of OLP can be categorized into six groups of papular, reticular, plaque-like, atrophic/erythematous, erosive/ulcerative, and bullous lesions.² Papular, reticular, and plaque-like lesions are asymptomatic. Reticular form is the most common, which is often asymptomatic. The erosive type has a lower prevalence.²³ In contrast, atrophic/erythematous, erosive/ulcerative, and bullous types are symptomatic and have a wide range of symptoms such as intraoral pain, burning sensation, bleeding, impaired sense of taste, and sensitivity to hot and spicy foods, which adversely affect the quality of life of patients.^25-28 OLP pathogenesis seems to include both specific and non-specific antigens.²⁹ OLP’s etiology has not been fully explained. Its pathogenesis is multifaceted, and it is caused by intricate interplay between innate and acquired immune responses.^30,31 Several factors were proposed as the possible etiologies for OLP, such as genetics, and infectious agents (bacterial and viral infections, such as the herpes simplex virus, human immunodeficiency virus, human papilloma virus, and hepatitis virus).^32-37 Moreover, the frequency of fungal infections with Candida albicans and Candida glabrata is higher in OLP patients.³⁸ It should be noted that although viruses and fungi colonize the oral environment, bacterial species are the main inhabitants of the oral cavity.³⁹ It is still unclear what role bacteria had in the formation of OLP. Helicobacter pylori was the sole microbe known to have a potential involvement in the pathogenesis of OLP for a considerable length of time.^40,41 Auto-immunity related to other auto-immune diseases, immunodeficiency, stress, over-reaction to drugs or some restorative materials,⁴² trauma, and systemic conditions, such as diabetes mellitus, and hypertension were proposed as possible etiologies for OLP.^37,43

Infiltration of T lymphocytes is highly important in initiation and progression of OLP, which elicits inflammatory responses in lamina propria and epithelial layer and causes apoptosis of keratinocytes in oral epithelium.⁴⁴

T-helper cells had two separate subgroups before to 2005, each of which had unique cytokine characteristics and immune system roles.⁴⁵ Interferon C and tumor necrosis factor (TNF)-alpha, which are often produced by T-helper 1 (Th1) cells, are involved in macrophage activity and the distinction between chronic infections and autoimmune disorders. T-helper 2 (Th2) cells produce interleukin (IL)-4, IL-5, and IL-3, which have a role in allergic reactions and protection against helminth parasites.¹⁵ In 2005, a third subgroup of T-helper 17 (Th17) was identified, which is characterized by production of IL-17 and plays a fundamental role against extracellular pathogens.⁴⁶ This cytokine mediates a correlation between innate and acquired immunity. IL-17 is a pro-inflammatory cytokine and a strong stimulant for recall, activation, and migration of neutrophils, production of interferon (IFN)-alpha, and IL-B by macrophages, and chemotaxis of eosinophils.^47,48 The Th17 family includes IL-17A-F. IL-17 is mainly released by Th17. It is produced by regulatory T cells (Tregs), mast cells, natural killer cells, neutrophils, macrophages, and T αβ γδ lymphocytes.^49,50 Pathogenesis of various different auto-immune and inflammatory illnesses is attributed to Th17 cytokines. It causes the production of chemokines from a variety of cutaneous cell types, including keratinocytes, macrophages, and endothelial cells under inflammatory circumstances, which promotes tissue regeneration and the chemotaxis of pro-inflammatory effector cells to the skin.⁴⁹ In LP, the cells producing IL-17 are often present in the inflammatory skin infiltrate beneath the skin basement membrane zone at the site of apoptosis of epidermal keratinocytes.⁵¹ IL-17 may be implicated in other skin diseases, such as atopic dermatitis, alopecia areata, systemic lupus erythematosus, and bullous pemphigoid.^52,53 IL-17 may decrease the diversity of oral bacteria and provide an opportunity for the activity of other opportunistic infections, trigger the activity of innate immunity, and lead to disease flare-ups.³²

Th17 cells protect extracellular bacterial and fungal pathogens, such as Klebsiella pneumoniae, Citrobacter rodentium, Candida albicans, and Staphylococcus aureus.⁵⁴ Th17 cells can secrete several cytokines such as IL-17, IL-21, IL-22, and IL-26.⁵⁵ These cytokines induce a severe inflammatory response and stimulate different cells to release chemokines.⁵⁶ According to reports, IL-17 influences the microenvironment of tumors, the development of inflammatory infectious illnesses, and auto-immune disorders.⁵⁷ Preservation and proliferation of Th17 cells are associated with expression of IL-23, a cytokine that plays a main role in development of autoimmune diseases and regulates IL-17 production.^58,59 Recently, it was found that IL-23/IL-17 axis plays a fundamental role in the pathogenesis of different inflammatory and autoimmune diseases.⁴⁹

In summary, the role for IL17 is stimulated by the following emergent evidence:

First, T lymphocytes play a major role in the etiology of OLP disease by (include their relationship to IL-17).

Second, IL-17 is associated with a wide spectrum of “activities” including: IL-17 is a pro-inflammatory cytokine that: 1) secretes several cytokines, 2) is a strong stimulant for recall, activation, and migration of innate immune cells, 3) mediates a correlation between innate and acquired immunity, 4) plays a fundamental role against extracellular pathogens, decreases the diversity of oral bacteria, and protects extracellular bacterial and fungal pathogens.

Third, prevailing evidence base suggests that IL-17 deficiency may contribute to pathogenesis of autoimmune and inflammatory diseases.

Fourth, this cytokine was increasingly examined in the patients with OLP and justifying examination of the emerging evidence base.

Husein-ElAhmed and colleagues⁶⁰ conducted a systematic review and meta-analysis in 2022 to assess the reliability and validity of the studies conducted in this area. However, in this study, studies involving saliva and tissue analysis were excluded, and the role of IL-17 in oral lichen planus was not examined in a structured manner. Therefore, the aim of the current systematic review of the literature was to comprehensively assess the present evidence from the association of serum, salivary levels, and cells expressing interleukin-17 with oral lichen planus by emphasizing cellular mechanisms from etiopathogenesis to treatment approach to provide effective guidance for conducting better studies by the researchers and helping clinicians make better decisions in managing patients.

Materials and Methods

We studied IL-17’s part in the pathogenesis of OLP. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA 2020) checklist was strictly adhered to in this study procedure. Ethics approval and patient consent were not required as this study is an overview based on published reviews.

Eligibility Criteria for this Review

Type of studies: We have included case-control studies on the changes in IL-17 in oral mucosa clinical samples, peripheral blood, and saliva samples of OLP patients with no time limitation set.

Participants: Patients who were diagnosed with OLP based on WHO criteria were included. There were no limitations in age, race, nation, sex, and nationality of participants, as well as treatment plan and type of OLP.

Index tests and Outcome measures: Any subtype of OLP and type of medium aimed at evaluating the role of IL-17 in pathogenesis of OLP was considered eligible.

Exclusion criteria: Studies with unavailable full-text or irrelevant results, those not meeting the WHO criteria for a confirmed diagnosis of LP, those assessing indirect effect of IL-17 on development of LP, systematic reviews, and studies without a control group were excluded were excluded.

Inclusion criteria: Only articles in English about the role of IL-17 in pathogenesis of OLP were included. Data extraction included author’s name, country of origin, year of publication, age, gender and number of patient, subtype of OLP, and type of medium.

Search Methods for Identification of Studies

The search for relevant review studies was conducted by authors. A systematic search was performed using PubMed, Scopus, Google Scholar, Embase, and Cochrane databases for articles published from 1960 to June 2022. The references of relevant articles were searched to identify additional potential studies (Table 1).

Table 1.

Characteristics of included studies

Author /Date /Country	Aim of study	Medium	Diagnosed with OLP(n), Female/male ratio	Age Min-max (average)	Conclusion
Shaker, 20111 Egypt	Possible role of IL-17 in LP	Serum	P (30)14/16, C (20)14/6	42.7±15.4 (16–68) 28.4 ± 8.2 (18–45)	Increased level of IL-17 in LP patients with a history of viral hepatitis
Sanxiang, 201279 China	Possible role of Th17 in OLP lesions and blood circulation of OLP patients	Serum + cell	P(R=22)14/8, P(E=18) 13/5, C(15)9/6	46.8±12.2 49.2±10.4 43.9±11.8	Important role of increased ratio of Th17 cells in local lesions and peripheral blood in OLP pathogenesis
Wang, 201423 China	Comparison of expression level of IL-17 in periodontal tissue of patients with chronic periodontitis and OLP, patients with chronic periodontitis alone, and patients with OLP alone	Serum	HC (10)6/4, OLP (15)9/6, CP (15)10/5, CP-OLP (15)9/6	39.6±8.9, 40.3±9.1, 41.2±11.0, 42.4±10.6	Increased expression of IL-17 in periodontal tissues in patients with chronic periodontitis and OLP
Shen, 201482 China	Assessment of expression of IL-17 in LP and OLP	Cell	OLP (P=42)21/21 (C=10)5/5 LLP (P=38)17/21 (C=10)5/5	50.1 ± 10.6/45.2 ± 12.1/50.0 ± 15.9/49.6 ± 13.7	Increased expression of IL-17 in LP and OLP lesions
Pouralibaba, 201388 Iran	Assessment of serum level of IL-17 in erosive and non-erosive LP patients	Serum	P(NE=24)12/12 E=24)10/14 C(24)11/13	36.97 ± 6.15 33.26 ± 7.52 37.06 ± 6.93	Higher inflammation and atrophy along with high serum levels of IL-17 in patients with erosive OLP compared with non-erosive OLP and healthy controls
Lu, 201416 China	Does IL-23/IL-17 axis is involved in OLP and does it have any application in treatment?	Serum+ cell	OLP(E=13)10/3 R=14)11/3 C (10)8/2	43.9 ±11.3 42.3 ± 12.6 40.8 ± 15.3	Over-expression pattern and selective regulatory roles of IL-23/IL-17 axis in in OLP
Monteiro, 201426 Brazil	Assessment of the expression of IL-17 and IL-23 cytokines in reticular and erosive OLP	Cell	OLP (E=18) (R=23) IFH(10)		No significant difference in number of IL-17 lymphocytes and possession of strong positive epithelial immunity for IL-17 in OLP
Wang, 201532 China	Differences in genetic profile of salivary microbiota between two subgroups of OLP	Saliva	P(E9/R=9), C(16)		Presence of a positive significant correlation between the concentration of salivary IL-17 concentration and clinical score of disease
Shen, 201690 China	Potential role of IL-17 and targeting its mRNA in OLP	Cell	P (50)31/19 C (19)11/8	21-70/20-40	Potential role of IL-17 and targeting its mRNA in pathogenesis of OLP
Liang, 20163 China	Expression and correlation of miR-155 and mRNA IL-17 in peripheral blood of female OLP patients	Serum	P(E=123) (NE=138) C(254)	46.5 (7.5) 47.2 (8.0) 46.6 (7.8)	Possible important role of miR-155 and mRNA IL-17 in OLP pathogenesis and their possible use as potential biomarkers for prediction of degree of severity of lesions
Atwa, 201653 Egypt	Possible correlation of serum and tissue levels of IL-17 and detection of their possible role in OLP etiopathogenesis	Serum	P (20)12/3, C (10)11/4	36-48/35-42	Increased serum and tissue expression of IL-17 and IL-17 receptors in OLP
Shirazian, 201789 Iran	Comparison of salivary level of IL-17 in OLP patients and healthy controls	Saliva	P(E=20/R=6)22/4, C (26)22/4	50.81±12.6 49.42±5.3	No significant difference in the mean level of IL-17 between reticular and erosive OLP and healthy controls
Kumaran, 2019105 India	Assessment of expression of IL-17 in pigmented lichen planus	Cell	P (Lpp=30)20/10 (LP=10)5/5 (post lp=10)7/3 C(10)	34.3 ± 11.8 29.3 ± 10.9 36.0 ± 19.7	Maximum expression of IL-17 in LP
Solimani, 201912 Germany	Targeting IL-17+ T cells and clinical improvement of OLP and LP	Serum+cell	P(5)	25-72	Clinical improvement of LP and OLP by targeting Th-17/Tc17 cells
Ismail, 2019.111 Australia	Clinical resolution of erosive OLP with tildrakizumab and its effect on IL-23/IL-17 axis		P(1)	59	More prominent role of IL-17/IL-23 in OLP pathogenesis
El-Refai, 201944 Egypt	Level of IL-17 as the main cytokine and diagnostic marker for OLP	Serum+Saliva	P(OLP=15/PV=15) C(15)32/13		Presence of high serum and salivary levels of IL-17 in OLP patients compared with healthy controls
Ge X, 20209 China	Reinforcement of STAT4 renin phosphorylation to promote the production of IL-17 by keratinocytes	Cell	P(14) reticular 8/6	middle-aged/8-week	Increased expression of IL-17 in oral keratinocytes and its potential targeted therapy in OLP
Żychowska, 202011 Poland	Serum and tissue levels of IL-17 in cutaneous lichen planus	Serum+Cell	CLP: p (52)30/22 C(27)12/15	51:6±15:55/45:59±10:15	Confirming increased serum concentration and expression of IL-17 in cutaneous LP and its role in LP immunopathogenesis
Mahmoud, 202178 Egypt	Correlation of IL-17 and vitamin D with LP	Serum	P: LP (30)15/15 C(30)18/12	42.00±13.975/39.90±10.848	Confirming the role of IL-17 in LP pathogenesis and its correlation with disease severity
Hassan, 20212 Egypt	Efficacy of topical corticosteroids in treatment of erosive/atrophic lichen planus and IL-17 level	Saliva	P(R=10/E=20) C(10)	25-60	Higher salivary level of IL-17 in erosive/atrophic OLP patients than reticular OLP, and higher IL-17 levels in both forms compared with healthy controls
Abdeldayem, 202291 Egypt	Salivary expression of lncRNA DQ786243 and IL-17 in different types of OLP	Saliva	C(13) P(R=13) (E=13) (U=13	42.92±7.54 48.69 ± 6.09 43.23 ± 13.24 48.85 ± 6.99	Increased salivary expression of lncRNA DQ786243 and IL-17 in OLP compared with healthy controls and their positive correlation with severity of OLP

Abbreviations: LP, Lichen planus; OLP, Oral lichen planus; P, Patient; C, Control; E, Erosive; R, Reticular; NE, Non erosive; PV, Pemphigus vulgaris; CLP, Cutaneous lichen planus; U, Ulcerative

Selection of Studies

Two reviewers (AF and BH) independently evaluated the articles retrieved from electronic database search and manual search in three steps. In the first step, the duplicates were removed by EndNote 20 software followed by a manual recheck. The second phase included screening publications by looking at their titles and abstracts to weed out research that was not relevant. The final phase included reading each piece in its entirety to ensure it qualified for inclusion. The two reviewers then presented their findings about each article’s eligibility. After reaching a consensus, the studies were included in the final phase for consultation with a third reviewer.

Data Extraction and Management

A draft data extraction sheet was developed using Microsoft Excel 2013 (Microsoft Corp, Redmond, WA, www.microsoft.com). Two reviewers independently extracted research information from the included article, such as author, publication year, journal nation, categories of included studies, number of included studies, age, gender, and patient counts, subtype of OLP, and medium type.

Results

Identification

A total of 65 records were retrieved from the electronic search of PubMed, Scopus, Embase, Cochrane, and Google Scholar databases. Moreover, manual search of the bibliographies yielded five more records (n=70). After the elimination of duplicates, 38 records were selected for screening (n=38).

Screening

In this step, screening of the articles was performed based on their title and abstract. Moreover, three studies were excluded, since they were not in English, seven were excluded (full text of four studies was not available, and three studies were excluded, since their results were not relevant, or were systematic reviews). Of the 27 remaining studies, 6 were disregarded because they lacked a control group, failed to fulfill WHO standards for OLP, or looked at IL-17’s potential indirect influence on OLP. Subsequently, 21 papers total were included in this evaluation. The reasons for exclusion of studies are explained in PRISMA 2020 flow diagram of the study (Figure 1). Table 1 presents the details of included studies.

Figure 1.

PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources.

Included

Among 21 studies included in this review, one was a clinical trial, and two were letters to editors (The score of the evidence based on the type of study: II.1).⁶¹ The remaining were case-control studies, among which, two studies showed no significant difference in the mean level of IL-17 between healthy controls and the patients with reticular and erosive forms of OLP; one study reported higher salivary level of IL-17 in erosive/atrophic OLP patients compared with reticular OLP patients, and higher level of IL-17 in both of them compared with healthy controls. All other studies reported significantly higher serum and salivary levels of IL-17 in OLP patients compared with healthy controls. The assessment of IL-17 was conducted in serum in six articles, serum and tissue in four articles, serum and saliva in one article, tissue in five articles, and saliva in four articles.

Discussion

OLP is a common, recurring, chronic, inflammatory and immunological disease. It is among the main research topics in oral medicine in terms of its high mucosal prevalence, symptomatic nature, painful and relatively stable lesions, and xerostomia,⁶² which can significantly deteriorate the quality of life of patients, as well as its unknown etiopathogenesis and absence of a definite treatment for it.⁶² Researchers have largely focused on the involvement of several inflammatory cytokines due to the immunological and inflammatory aspect of this illness. ThCD4 cells are the primary cytokine-producing cells, and cytokines are the primary mediators of immune responses.⁶³ All T helper cells differentiate from CD4+ T cells following activation via T cell receptor.⁶³ Signaling mediated by Th cells is not only important for protective immunity, but also can induce inflammatory responses to self-antigens or non-hazardous allergens, which lead to development of autoimmune diseases or allergic reactions as such.⁶⁴ Th cells produce effective cytokines and play vital roles in the generation of acquired immune responses to infections.⁶³ Different kinds of T helper cells are available depending on their cytokine profile, with Th1 and Th2 cells that primarily generate IFN-Y and IL-4, respectively, being the first to be discovered.⁶⁵ Differentiated subclasses of T helper cells play a role in protective immunity against various infections.⁶⁵ T helper cells can produce the majority of known cytokines such as lymphotoxin-alpha for Th1 and IL-5, IL-9, IL-13, and IL-24 for Th2.⁶³ Moreover, all subclasses of T helper cells can produce IL-2, IL-6, IL-10, IL-21, TNF-alpha, and granulocyte-macrophage-colony stimulating factor.⁶³ T helper cells are professional cytokine producers, and can respond to different types of cytokines produced by other cells, such as IL-1, IL-7, IL-12, IL-15, IL-18, IL-23, IL-27, IL-33, and IFN-1, among others.⁶³ In the process of differentiation, T helper cells can respond to their own cytokines, such as IFN-Y and IL-4, resulting in a strong positive feedback or inhibitory effects.⁶³ T helper cell subclasses each perform a specific immunological role in the context of protective immunity.⁶⁶ Th1 cells play a major role in the host’s defense against intracellular pathogens such bacteria, viruses, and protozoa.⁶⁷ They are also to blame for the emergence of certain organ autoimmunities. One main function of Th1 cells is activation of macrophages via the production of IFN-Y.⁶⁷ Th2 cells are critical to mediate immune responses against extracellular parasites, such as helminth parasites. These cells are involved in pathogenesis of inflammatory diseases such as asthma and allergies. Th2 cells change the B cell immunoglobulin to IgG1 and IgE by production of IL-4.⁶⁸ By production of IL-5, they attract eosinophils.⁶⁹ They induce the movement of smooth muscle cells and mucus production by epithelial cells by the release of IL-13.⁷⁰ IL-4 and IL-13 can also induce alternative activation of macrophages.⁷¹

The third population of T helper cells, i.e., Th17 that produce IL-17, were identified a few decades later. Th17 cells release three main cytokines of IL-17A, IL-17F and IL-22.⁷² Five other members of this family include IL-17B, IL-17C, IL-17D, and IL-17E.⁷³ Although some of them were well identified, they have not been extensively studied. IL-17A was more commonly studied compared with others. Neutrophil recruitment and activation are IL-17’s primary functions.⁷³ Additionally, it may cause several cell types to create inflammatory cytokines like IL-6. A crucial cytokine for producing antimicrobial peptides, pro-inflammatory cytokines, and chemokines in mucous membrane barriers is IL-22.⁷⁴ Evidence shows that although IL-17 is a pro-inflammatory cytokine, it can aid in immunity homeostasis. The absence of its signaling can lead to irregular and exaggerated production of other pro-inflammatory cytokines.⁷³ Although it was first believed that Th17 cells are the main source for release of IL-17, it was later found that IL-17 can be produced by other cell types, the most important of which are the innate immunity cells. Innate immunity cells producing IL-17 are responsible for fast release of IL-17 in response to the pathogens or tissue injury, enabling fast production of IL-17 in response to bacteria.⁵⁶ Other IL-17 producing cells include (I) LTi cells (key components required for the synthesis of lymphatic structures) that quickly produce IL-17A after challenge with Zymosan (a yeast cell wall component);⁷⁵ (II) a subclass of TCD8+ cells, known as TC17 cells, that participate in host defense mechanisms against viruses by the production of IL-17 and can play a role in auto-immunity;^76,77 and (III) bacteria that activate the NF-kB signaling pathway by release of TNF-alpha, which lead to renin production by keratinocytes and lymphocytes. Renin phosphorylates the STAT4 and indirectly affects IL-17 transcripts.⁹ The induction of controlled differentiation of CD4+ T cells to Th17 cells is conducted by a series of cytokines including IL-6, IL-1B, IL-21, IL-23, and tumor growth factor-B, which eventually result in activation of Th17. Excessive release of such cytokines is associated with pathological conditions.^23,78 Additionally, IL-17 stimulates the production of several inflammatory molecules, including cytokines, chemokines, defensins, and matrix metalloproteinases, by activating epithelial, endothelial, fibroblastic, chondrocyte, and osteoblast cells.^55,79 It was well confirmed that IL-17 is a main stimulant of several inflammatory and autoimmune conditions. High levels of IL-17 were detected in diseases such as multiple sclerosis, psoriasis, asthma, Crohn’s disease, and rheumatoid arthritis.^55,80,81 Evidence shows that Tregs play a fundamental role in the induction and maintenance of immunological tolerance and inhibition of immune responses. On the other hand, Tregs are regulated by Foxp3, and the level of expression of Foxp3 increases in OLP lesions, compared with normal oral mucosa. Higher number of Foxp3+ cells in OLP may indicate increased number of Tregs to control exaggerated immune response.^82,83

It was shown that Th17 and Tregs may change the fate of their lineage and show high levels of plasticity in different forms¹² including (I) under non-pathological conditions, Th17 cells help in correct function of epithelial barrier and protection against fungal (Candida) and bacterial (staphylococci) pathogens;^84,85 (II) under pro-inflammatory conditions, these cells can differentiate to T regulatory type I cells (Tr1) in the intestines;⁸⁶ (III) these cells may differentiate to Tregs upon resolution of inflammation; (IV) as mentioned earlier, different cells can produce IL-17. Evidence shows that Th17 acquire the capacity to produce cytokines released by other T helper cells, such as IFN-Y by a T-bet dependent method;⁸² (V) as shown in experimental models of inflammatory bowel disease and multiple sclerosis, it can reinforce the immune responses causing inflammatory diseases by acquiring INF-Y or production of granulocyte-macrophage colony stimulating factor, and IL-17 derived from Th17, which creates a positive feedback cycle in combination with IL-6 and tumor growth factor-beta and results in further increase in Th17 cells.^84,87 Although it is applied to Th1 and Th2 cells, these cells are relatively stable in contrast to Treg and Th17 cells.¹²

Cytokines are essential for the growth, character, and persistence of immune responses throughout the pathogenesis of OLP.²³ Various illness phases, genetic variations across populations, and various ELISA kits used may all be associated to contentious findings in the literature.⁸⁸ Several studies showed significant upregulation of IL-17 in tissue, serum, and saliva samples of OLP patients compared with healthy controls.^{2,9,11,15,16,23,32,44,78,79,82,88-91} Considering T-cell-mediated immune response in pathogenesis of OLP, presence of IL-17 and its regulatory role in OLP is not surprising. It participates in the pathogenesis of OLP through the following mechanisms: (I) reinforcement of T lymphocyte reactions and production of inflammatory mediators such as IL-6, IL-8, and IL-1B,^15,78 (II) regulation of production of matrix metalloproteinase-9 (that breaks type IV collagen leading to impairment of the basement membrane and apoptosis of keratinocytes),^92,93 (III) reduction in diversity of oral bacteria (providing an opportunity for opportunistic pathogens to stimulate the innate and acquired immune system and lead to disease flare-up),⁸⁸ (IV) and increased hypersensitivity reactions (through degranulation of mast cells).⁸⁹ Th17 cells are imperative to coordinate the immune responses elicited by extracellular bacteria and fungi.⁵⁶ Atrophic and ulcerative gingival LP may be improved with good oral hygiene,⁹⁴ and chlorhexidine therapy can alleviate the symptoms of lichenoid responses,⁹⁵ leading researchers to hypothesize that the microbiota may play a role in OLP pathogenesis. It was clearly demonstrated that the bacterial diversity of collected saliva from OLP patients was significantly different from that of healthy controls, and shifted community composition had a close correlation with IL-17.³² It appears the stress imposed by OLP, even in early stages of disease, has a significant effect on the microbial community of the saliva, because reticular and erosive OLP have a different microbial structure than that in healthy controls.³² Despite that bacterial diversity is unchanging, reticular OLP patients’ bacterial richness is much lower than that of healthy controls.³² Patients with erosive OLP have different patterns in both richness and alpha diversity as the illness progresses.³² The reduction of biodiversity can be a highly important parameter in disease progression.³² Ecologically, the reduction in biodiversity makes the host susceptible to invasion of different species, such that extraoral pathogens can easily colonize the oral cavity.⁹⁶ For instance, higher frequency of the diagnoses of Candida infection was reported in OLP patients, and an inverse correlation was confirmed between the Candida load with the diversity of salivary microbiota.^97,98 Moreover, some oral symbiotic bacteria are opportunistic pathogens, and loss of their antagonists may allow them to become the dominant species.³² By producing mononuclear cells and neutrophil granulocytes, these cells may trigger an inflammatory response while also defending the host against fungal and bacterial infections of the mucosal membranes. It was reported that richness and biodiversity of salivary microbiota have an inverse correlation with level of IL-17. Thus, it is assumed that decreased richness, and diversity may be induced, at least partly, by the cleaning effect of inflammatory response due to IL-17.³²

Based on the literature, salivary level of IL-17 in erosive/atrophic OLP is higher than that in reticular form, and its level in both conditions is higher than that in healthy controls. This finding may indicate higher level of disease activity in erosive OLP patients.^26,44,79,88

MiRNA-155 plays a pivotal role in the immune system of mammals especially in the regulation of T-helper differentiation. A cell experiment revealed that miRNA-155 can inhibit the release of pro-inflammatory mediators, such as IL-8, IL-6 and TNF-alpha by MyD88.^3,99 Relative expression of miRNA-155 significantly increases in OLP patients. Moreover, relative expression of both mRNA IL-17 and miRNA-155 in OLP patients was significantly higher than that in healthy controls and in erosive OLP patients compared with non-erosive OLP patients. Thus, it may be concluded that mRNA IL-17 and miRNA-155 are potential paraclinical markers for prediction of degree of OLP severity.³

Since IL-23 is the primary upstream inducer of IL-17, it is important to do more research to determine if IL-23 upregulation regulates IL-17 synthesis in the local environment of OLPs.¹⁰⁰ Dendritic cells and macrophages are two antigen-presenting cells that mostly generate IL-23.¹⁰¹ Recent immunological discoveries have supported this claim. Although IL-23 has no significant effect on differentiation of Th17, it is imperative for proliferation and stability of Th17 cells, their migration to pathological tissues, and production of IL-17, and promotes the pathogenesis of Th17 cells.^102,103 Based on the present evidence, a new model is proposed for the interaction of T cells and keratinocytes in OLP pathogenesis in which IL-23/IL-17 axis is involved. Moreover, keratinocytes in OLP produce high amounts of IL-23 via an unknown mechanism.¹⁶ Then, IL-23 released from keratinocytes may help in accumulation of Th17 cells and over-production of IL-17 in local OLP lesions.¹⁶ Subsequently, IL-17 inversely forces the keratinocytes to selectively produce inflammatory mediators. Resultantly, they create a complex immune network in the inflammatory environment of OLP lesions. These findings suggest that IL-23 overexpression may be a primary event in the pathogenesis of OLP and may be maintained at a high level as the disease advances. Thus, it may be suggested that over-expression of IL-23 may be functional, and help (at least partly) in the accumulation of Th17 cells and increase the level of IL-17 in OLP lesions.¹⁶ Therefore, IL-23/IL-17 axis may indicate a new signaling pathway in the interactions of keratinocytes and CD4+ T cells, which may be involved in OLP pathogenesis.¹⁶ Furthermore, the results of studies revealed that the effects of IL-17 on oral keratinocytes were selective but not extensive, indicating the unique regulatory role of IL-23/IL-17 axis in local environment of OLP lesions.¹⁶ This result suggested that over-expression of IL-17 in OLP lesions was associated with other, as yet unidentified regulatory mechanisms, in addition to lymphocytic infiltration, which calls for further research.¹⁶ The analysis of studies showed a positive correlation between the expression of IL-23 and IL-17 at both protein and mRNA levels in reticular OLP, indicating upregulation of IL-23 by an increase in level of IL-17 in early stages of OLP. On the other hand, the absence of a correlation between IL-23 and IL-17 expression in erosive OLP may be in terms of continuously high levels of IL-23 but variable levels of IL-17, pointing to the presence of potential regulatory mechanisms other than IL-23 in expression of IL-17 in erosive OLP.¹⁰³ Due to differences in their structure and function, oral mucosa and the skin both exhibit unique clinical symptoms of LP. In terms of keratinization patterns, resistance to external pressure and wet vs dry conditions, oral mucosa and skin vary from one another. Moreover, oral mucosa compared with the skin is exposed to higher levels of antigens, such as foods, bacteria, viruses, and fungi. This antigenic load may interfere with immunocompetent cells.¹⁰⁴ It was shown that Foxp3+ cells significantly increase in OLP compared with cutaneous LP, while IL-17+ cells in OLP are comparable to those in LP. This result showed there are considerably more Tregs in OLP than in LP.⁸² Treg cells protect the integrity of the natural microflora by preventing unchecked immune reactions to allergens or infections. Thus, difference in number or function of Foxp3+ of Teg cells affect the clinical course of these two types of LP. It appears that the function of oral microbiota is another explanation for the changes in the number of Treg cells in OLP.¹⁰⁵ Treg cells suppress T cells by cell-cell contact, which is independent of cytokines, which is believed to play a pivotal role in central tolerance to self-antigens. It is assumed that Th17 cells may be among the effective T cells on Tregs independent of IL-17. Altogether, these data explain the difference in clinical behaviors of OLP and LP and indicate that different immunopathogenic mechanisms may be involved in OLP and LP.⁹⁰ Vitamin D insufficiency, on the other hand, may be linked to LP because of its anti-proliferative, pro-apoptotic, pro-differentiating, and anti-angiogenic qualities,¹⁰⁶ and it may be crucial in controlling inflammation and cytokine production. It may have antimicrobial and immune-regulating effects¹⁰⁷ and prevent the proliferation of Th1 lymphocytes.¹⁰⁸ Moreover, vitamin D suppresses the inflammation caused by lipopolysaccharides in OLP via regulating the kB nuclear factor pathway and inhibits the production of IFN-Y and IL-1 by oral keratinocytes through regulating lipopolysaccharide-induced hypoxia-inducible factor-1α.¹⁰⁹ Although it has been suggested that vitamin D regulates IL-17 synthesis by preventing IL-17 gene expression from being directly transcribed, no direct relationship between serum vitamin D levels and IL-17 levels in tissues or blood has been discovered.⁷⁸ This finding can be attributed to the multifactorial pathogenesis of LP, in which a number of factors may affect the expression of vitamin D and IL-17.

Since OLP is often resistant to clinical treatment, great attention has been directed to alleviate the symptoms.^13,110,111 Currently, systemic and local immunosuppressive medications such as glucocorticoids, cyclosporine, azathioprine, methotrexate, or immune system modulators like acitretin assist in alleviating clinical symptoms and are often administered.¹² The present review showed the IL-17/IL-23 pathway was the most studied topic. Since this axis plays a key role in the pathogenesis of many chronic inflammatory diseases, and over-expression of IL-23 and IL-17 in OLP compared with normal oral mucosa has been confirmed, novel treatments for OLP mainly aim to block this pathway.

At present, the following medications have gained approval for the treatment of inflammatory disorders, such as psoriasis vulgaris, psoriatic arthritis, and Crohn’s disease: Secukinumab (anti-IL-17), ustekinumab (anti-IL-12/IL-23), guselkumab (anti-IL-23), and tildrakizumab (anti-IL-23) (12, 111). Since IL-17 and IL-23 suppression is equally successful for treating OLP and LP, researchers made the assumption that these medications could also be helpful for treating OLP that is resistant to therapy. The results showed that targeted therapy of Th17/Tc17 cells in LP either by suppression of IL-17A with secukinumab or inhibition of Th17/Tc17 axis with ustekinumab or guselkumab would result in a significant long-term effect. Thus, treatment with ustekinumab and guselkumab may be more effective than secukinumab in the inhibition of Th17/Tc17 and subsequently Th1 cells in LP.^12,17,88,111

The results in this review showed that the studies conducted on the relation between IL-17, and oral lichen planus are diverse. If a researcher wants to continue looking into this marker, they need to be aware of what information is already out there, where more research is needed (e.g., differences between races), and where it is still unknown (e.g., variations in lichen planus types, comparisons of sampling techniques, therapeutic interventions). Therefore, this study was conducted on this marker, as present studies in this field were inconclusive about the role of this marker in oral lichen planus.

Limitation

We only reviewed studies that had WHO criteria to confirm the diagnosis of OLP, which led to a reduction in the number of articles.

Conclusion

This review study found the following results:

• (I)The expression of IL-17 and Th17 is higher in serum, saliva, and tissues of OLP and LP patients compared with healthy controls.
• (II)Relative expression level of IL-17 has a significant correlation with IL-23.
• (III)Treatment with monoclonal antibody against Th-17, Tc-17, IL-12/IL-23, and IL-23 axes would result in significant long-term resolution of LP symptoms.
• (IV)Relative expression level of IL-17 has a direct correlation with the severity of inflammation, and the level of this cytokine in erosive OLP is higher than that in reticular OLP, and in reticular OLP is higher than that in healthy controls. Furthermore, it has a higher level in different types of LP than LLP.
• (V)Expression level of IL-17 in inflammatory conditions, such as periodontitis and auto-immune diseases, such as Pemphigus vulgaris is higher than that in OLP or pemphigus vulgaris alone.
• (VI)No significant correlation was found between the level of IL-17 with the duration or extent of disease.
• (VII)IL-17 had no significant correlation with age or gender.
• (VIII)There is an inverse correlation between IL-17 and vitamin D levels, but it is not statistically significant.
• (IX)In different types of LP, no significant correlation was found between the level of IL-17 and severity of itching or simultaneous involvement of skin, nails, and oral mucosa.
• (X)A positive correlation exists between level of expression of IL-17 with inc RNA DQ786243 and pain