Etiopathogenesis of Oral Lichen Planus: A Review

Abstract

Background

Oral lichen planus (OLP) is a chronic immune-mediated disease affecting the mucous membranes of the oral cavity, regarded as a potentially malignant disorder.

Methods

We performed a narrative review of the literature compiling key hypotheses on the etiopathogenesis of OLP, addressing recently raised aspects and questions yet to be elucidated.

Results

The etiopathogenesis of OLP is complex and not fully understood, with evidence suggesting a multifactorial cause. Lesions appear to be triggered by the recognition of one or more antigens, provoking a dysregulated T-cell-mediated immune response against oral keratinocytes. Genetic and environmental factors significantly influence the orchestration of various immune and non-immune cells, cytokines, and molecules involved in this pathological process.

Conclusions

Understanding recent theories on the etiopathogenesis of OLP is crucial forguiding future research on its diagnosis and treatment, as well as on preventing its malignant transformation.

Introduction

Oral lichen planus (OLP) is a chronic immune-mediated disorder affecting the mucous membranes lining the oral cavity and a potentially malignant disorder [1, 2]. It affects approximately 1.01% of the global population, with significant regional variations that possibly reflect differences in diagnostic criteria, population and environmental factors; the prevalence is higher in european studies and lower in studies from India. OLP predominantly affects middle-aged women and occurs in 70% of cases in which the disease also affects the skin [3–6]. Oral lichen planus can manifest in various clinical patterns, characterized by periods of relapse and remission; cases involving burning, pain, or discomfort can significantly reduce patients’ quality of life [3, 7]. Although first recognized in the 19th century, the etiopathogenesis of OLP remains incompletely understood [4, 7]. Consequently, a permanent cure has yet to be developed. Current management of OLP focuses on alleviating symptoms and healing erosive and ulcerative lesions [3, 8]. Treatment traditionally involves the use of corticosteroids, and new advances have focused on Janus kinase (JAK) inhibitors, interleukin blockers, and other immunomodulators for resistant cases [9]. Available evidence suggests a multifactorial cause, with lesions triggered by antigen recognition that results in a dysregulated immune response against keratinocytes, heavily influenced by genetic and environmental factors [5, 10]. This review aims to summarize the principal mechanisms proposed to date for the etiopathogenesis of OLP, updating the understanding of the complex interactions among different cell types involved in this pathological process.

The Trigger of the Disease

The basal layer of the oral epithelium consists of cuboidal or columnar keratinocytes [11]. Their interaction with T lymphocytes forms the immunological basis of OLP [12]. Keratinocytes are essential for tissue homeostasis, maintaining the epithelial barrier and composing the basement membrane by secreting type IV collagen and laminin V. The integrity and function of the keratinocyte barrier depends on tight junction proteins such as ZO-1, ZO-2 and ZO-3. ZO-1 has been shown to be significantly reduced in the OLP, suggesting that loss of adhesion between keratinocytes facilitates immune cell infiltration and contributes to chronic inflammation [13–15].

Dendritic cells (DCs) are located between keratinocytes but are not connected to them by cell junctions [16]. Moreover, DCs are antigen-presenting cells (APCs) of myeloid origin, playing a fundamental role in the adaptive immune response by recognizing, capturing, and responding to antigens [16–19]. Various subsets of DCs interact specifically with T cells [17]. One subtype, Langerhans cells (LCs), are motile cells in the suprabasal layers of the stratified epithelium of the oral mucosa, forming the dominant APC population by expressing langerin/CD207 and CD1a [20–22].

The most widely accepted theory for OLP initiation suggests that DCs recognize one or more intrinsic or extrinsic antigens, triggering and perpetuating an immune response; however, this hypothesis has yet to be proven (Fig. 1). Consequently, T lymphocytes infiltrate the sub-epithelial zone of the oral epithelium in a band-like pattern, resulting in keratinocyte degeneration through liquefaction. However, these antigens remain unidentified [7, 23–25]. The role of heat shock proteins (HSPs) in OLP is multifaceted, contributing both to immune activation and as a potential marker of cellular stress. Increased expression of HSP60 and HSP70 genes, particularly in erosive OLP, has led to debate about their role as autoantigens [26]. Recently, Pan et al. [19] demonstrated that the HSP90 complex activates DCs via toll-like receptor (TLR9)/IFN-α, differentiating naïve T cells into Th17, which increases inflammation. As HSP overregulation is associated with dysplasia and oral squamous cell carcinoma, they may be involved in OLP’s etiopathogenesis and malignant progression. However, it remains unclear whether HSPs act as disease initiators or as a secondary response to cellular damage. This distinction highlights the need for further studies to clarify their precise role in OLP [14, 26].

Fig. 1.

Schematic diagram of the hypotheses concerning the etiopathogenesis of oral lichen planus (OLP) and its malignant transformation. (1) Presence of microorganisms: It has been posited that oral bacteria invade the epithelium and lamina propria, triggering T cell infiltration. (2) Migration of dendritic cells (DCs) to regional lymph nodes: DCs undergo maturation, presenting antigens to naïve T cells via the major histocompatibility complex and, together with costimulatory signals, induce clonal expansion of T cells. Chemokine gradients attract T cells to the lesion site, with adhesion molecules in blood vessels facilitating their movement. CD4 + T cells are drawn to lesional fibroblasts, which also inhibit apoptosis. CCL5 recruits mast cells, which assist the migration of CD4 + T cells through the lesion. Angiogenesis is promoted by fibroblasts, mast cells, and hypoxic conditions. (3) Formation of the inflammatory microenvironment in OLP: Below the basement membrane, CD4 + T cells predominate and are organized in a band-like pattern. Conversely, CD8 + T cells are more prevalent in the intraepithelial region and adjacent to basement membrane rupture areas. The etiopathogenesis of OLP is affected by the imbalance between cell types with inflammatory/anti-inflammatory actions, such as Th1/Th2, Th17/Treg, and M1/M2 macrophages. Dendritic cell release exosomes to activate immune cells, sustain chronic inflammation, and influence matrix metalloproteinase (MMP) production pathways. (4) Apoptosis (A) and pyroptosis (P) of keratinocytes: CD8 + T cells induce keratinocyte apoptosis, leading to epithelial damage characteristic of the disease. Apoptosis is initiated by mechanisms activating the caspase cascade and can be amplified by MAIT cells. In pyroptosis, activated caspases cleave gasdermins to form membrane pores, releasing pro-inflammatory cytokines. MMP-9 and reactive oxygen species cause disruption of the basement membrane. (5) Oral squamous cell carcinoma: OLP is regarded as a lesion with the potential for malignant transformation, with current hypotheses emphasizing the role of chronic inflammation and genetic factors in this process

Meta-analyses indicate that emotional factors such as anxiety, depression, and stress contribute to the occurrence and development of OLP. Indeed, patients with OLP often have elevated levels of these conditions [3, 27]. However, this association is inconsistent, and these symptoms may be effects rather than causes of OLP [14, 28]. Stress and anxiety are associated with the release of neuroendocrine hormones, unbalancing Th1 and Th2 lymphocyte cytokines and contributing to autoimmune diseases and OLP [29]. Many studies indicate a positive correlation between OLP and certain medications (antihypertensive, hypoglycemic, anti-inflammatory, and antimalarial) and restorative materials, such as amalgam, metallic mercury, and nickel [3, 30]. Such elements, as well as systemic conditions such as hypothyroidism, appear to alter immune function, potentially contributing to the onset and progression of OLP. It is important to differentiate OLP from oral lichenoid lesions (OLL), which can be challenging due to their similar clinical appearance, especially in primary care settings. OLL is a hypersensitivity reaction that is usually unilateral and triggered by identifiable factors such as medications or dental materials. Histologically, OLL shows moderate to intense immune cell infiltration, degeneration of basal cells with colloid bodies, and different degrees of dysplasia [31, 32]. However, there is still a lack of robust evidence directly assessing the impact of emotional factors on OLL and OLP.

Meta-analyses have indicated an association between the hepatitis C virus and OLP [33]. Other viruses may also be implicated as etiological factors, including human papillomavirus 16 and 18, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, Varicella-zoster virus, and hepatitis B virus [3, 5, 34]. However, the direct involvement of these viruses in OLP’s etiopathogenesis remains unconfirmed [33]. The oral microbiota in OLP differs from that in healthy mucosa, although no microorganism meets the criteria for a causal relationship [35, 36]. It has been proposed that oral bacteria invade the epithelium and lamina propria, triggering T-cell infiltration, exacerbating inflammation, and acting as antigens for OLP [36, 37]. Escherichia coli is commonly found in OLP tissues, invading oral keratinocytes [35, 38]. Choi et al. [30] demonstrated that zinc deficiency and E. coli infection contribute to OLP pathogenesis in C57BL/6 mice. Additionally, Prevotella, Fusobacterium, and decreased lactic acid bacteria levels may be related to disease progression [15, 39, 40]. In this sense, evidence suggests that microbial dysbiosis can both contribute to the development of OLP and be a result of the disease, generating an intricate cycle that requires further investigation.

In OLP pathogenesis, environmental and genetic factors influence the host immune response, affecting epithelial integrity and inflammatory signaling pathways, which increases disease susceptibility [41, 42]. Genetic polymorphisms in cytokines such as IL-4, IL-6, IL-10, IL-18, IL-8, IFN-γ, TNF-α, TLR3, and MMP-9 have been reported in OLP patients [42–47]. Recently, Zhu et al. [48] identified differentially expressed genes related to activated memory CD4 + T-cells (Amyloid Beta Precursor Protein, IL-1B, and Transferrin) in OLP. Vo et al. [49] determined genetic signatures associated with hyperkeratosis, wound healing, barrier defects, and infection responses. New data shows the upregulation of KRT17, an epithelial protein promoting autoimmune diseases such as psoriasis [50]. Similarly, increased expression of genes involved in T cell and DC regulation, such as TCIRG1, DCG1, and NRIP1, was observed [41].

Cutaneous lichen planus (LP) affects the skin, scalp, nails, and various mucous membranes and shares pathogenic mechanisms with OLP, despite exhibiting distinct genetic associations [51]. The severity of OLP appears to be influenced by the concomitant presence of LP, as recently demonstrated [52]. Although there is overlap in molecular findings between the two lesions, direct extrapolation from LP to OLP must consider site-specific differences in immune regulation and tissue response [53].

In summary, the etiopathogenesis of OLP consists of a complex orchestration of immunological, environmental, and genetic factors that ultimately produce sustained T-cell activation and destruction of basal keratinocytes. Limited information on the clinical factors that determine the course of OLP hinders effective and personalized treatment. Topics such as the exact role of HSPs and the degree of contribution of the oral microbiota in the etiopathogenesis deserve further investigation. Genetic studies with adequate sample sizes, including diverse ethnic groups, are needed because some results remain inconclusive.

T Cell Activation

Langerhans cells are elevated in OLP [54]. Upon activation, LCs detach from the epithelium due to decreased E-cadherin expression and migrate to regional lymph nodes, where they complete their maturation process [21, 55, 56]. This transition, where DCs mature within the epithelium and migrate to the submucosa, is a key immunopathological feature of OLP [7]. In lymph nodes, LCs present antigens to naïve T cells via the major histocompatibility complex (MHC) on their surface [24]. MHC-I is present on all nucleated cells and primarily presents endogenous peptides, while MHC-II, found on APCs, presents primarily exogenous antigens [57]. T cells have on their surface the T cell receptor (TCR), a protein complex formed by variable chains TCRα and TCRβ, and multiple invariable accessory chains, which recognize peptide antigens presented by MHC molecules [57, 58]. The primary immune response is initiated by activating naïve T cells by binding their TCR-CD3 complex and coreceptor CD4 or CD8 with MHC-I or MHC-II on DCs. Costimulatory interactions, including the binding of B7.1/B7.2, CD54, and CD40 on DCs with CD28, CD18/CD11a, and CD154 on lymphocytes, also participate in this activation [10]. This induces the clonal expansion of T cells and the secretion of cytokines critical for amplifying the immune response, such as IL-2, IL-6, and IL-12 [7, 10, 17]. The interaction between naïve T cells and DCs also occurs within the lesion [23]. Moreover, T cells that have not been activated are transported to the lesion, where they are activated by tissue APCs. Mast cells can also activate T cells through the expression of MHC-II, CD80/86, and CD11a. Thus, a secondary immune response, which produces the clinical signs of OLP, occurs when LCs re-encounter the triggering antigen [10, 14, 59].

Keratinocytes play a significant role in the immune response of the oral mucosa, contributing to various stages of the pathogenesis of OLP. Keratinocytes mainly express MHC-I, but upon contact with IFN-γ, they begin to display MHC-II, temporarily acting as APCs and secreting several inflammatory mediators such as TNF-α, IL-1β, and CCL5. However, the exact role of keratinocytes as part-time APCs in OLP remains uncertain and requires further investigation [7, 10, 25]. MHC-II expression on keratinocytes may be an epiphenomenon resulting from inflammation. However, in some cases, it may indicate a central role of keratinocytes in driving immune dysregulation.

It has been suggested that alterations in histamine metabolism and transport in keratinocytes influence the progression of OLP by compromising epithelial integrity [60]. OLP tissues exhibit increased PA28γ compared to healthy controls [61]. A recent study by Wang et al. [7] indicated that high levels of PA28γ protein in keratinocytes elevate the expression of CD80, CD86, and MHC-II, thereby increasing DC maturation. Furthermore, PA28γ-overexpressing keratinocytes may facilitate the differentiation of CD4 + T cells toward the Th1 phenotype via the CCL5-CD44 pathway [7]. PA28γ appears to contribute to inflammatory progression regardless of OLP subtype; however, evidence of its role in OLP pathogenesis is still under development. It has also been proposed that activated keratinocytes release the cytokine thymic stromal lymphopoietin, promoting Th2 immune responses and increasing inflammation in the oral mucosa [62–63]. In conclusion, T cell activation in OLP depends on complex relationships between Langerhans cells, tissue APCs, mast cells, and keratinocytes. The effects of PA28γ on immune regulation and keratinocyte function is a potential research topic to explore new treatment strategies.

Formation of the Lesion Microenvironment

The transfer of T cells from lymph nodes to the OLP lesion is mediated by adhesion molecules present in the activated endothelium. Vascular adhesion molecules (e.g., ICAM-1 and VCAM-1) facilitate the interaction between lymphocytes and the vascular wall is increased in OLP tissues due to the action of pro-inflammatory cytokines such as TNF-α and IFN-γ. Additional molecules essential for this process include PECAM-1, ELAM-1, P-selectin, and CD34 [64, 65]. Furthermore, vascular endothelial cells release chemerin, attracting plasmacytoid DCs and natural killer cells (NK) to the lesion [23]. T cells subsequently migrate to the lesion, driven by chemokine gradients released by resident cells. Chemokines, a large family of small cytokines, orchestrate the migration of immune cells from the blood to specific tissues and their interaction with other cell types within these sites [66]. Chemokine-receptor axes such as CCL17-CCR4, CXCL10-CXCR3, CCL5-CCR5, and CXCR4-CXCL12 are significantly upregulated in patients with OLP [67–70]. The CXCR4-CXCL12 axis also activates DCs and memory T cells, while the CCL5-CCR5 axis triggers numerous inflammatory cascades and participates in mast cell degranulation [10, 69, 70].

Keratinocytes express CD54, facilitating the passage of T cells through the epithelium, where they accumulate below the basement membrane after infiltrating the lamina propria of the mucosa [10, 71]. CD4 + T cells are the primary cytokine producers and coordinate various immune response agents, such as B lymphocytes, macrophages, and CD8 + T lymphocytes [14, 72]. CD4 + T cells are classified into Th1, Th2, Th17, Treg, Th22, Th9, and Tfh subsets based on their cytokine production. The Th1/Th2 balance is crucial for the progression and maintenance of OLP chronicity, regulated by transforming growth factor beta (TGF-β). Th1 cells produce IFN-γ, IL-2, and TNF-α, which exacerbate the inflammatory process [17, 38, 73]. Shalaby et al. [74] recently showed that vitamin D supplementation significantly reduces IFN-γ levels compared to corticosteroid therapy alone in OLP. The authors propose that salivary measurements may serve as an interesting noninvasive tool to monitor disease progression and therapeutic response. Furthermore, a recent case series demonstrated the promising effect of deucravacitinib in interfering with TYK-2 signaling, thereby inhibiting the production of IL-12, a potent promoter of Th1/IFN-γ responses. Conversely, Th2 and regulatory T cells support the disease’s regression or less aggressive forms [9, 38]. Treg differentiation is influenced by TGF-β and IL-2, typically expressing Foxp3 and balancing pro-inflammatory and anti-inflammatory signaling by producing TGF-β, IL-10, and IL-35 [10, 17, 75, 76].

Th2 and Th17 cells predominate in the subepithelial band of OLP, while CD8 + T cells are more prevalent in the intraepithelial region and near areas of basement membrane disruption [14, 63]. Previous studies have highlighted the significance of Th17/Treg imbalance in the pathogenesis of OLP [38, 75]. The Th17 phenotype, retinoic acid receptor-related orphan receptor γt transcription factor, is implicated in several autoimmune diseases. IL-17, the characteristic cytokine of Th17 cells, initiates the production of additional cytokines, chemokines, and metalloproteinases (MMPs) and activates CD8 + T cells and tissue-resident cells [38, 77]. Additionally, Th17 cells release IL-26, IL-22, IL-6, IL-1, TNF-α, TGF-β, IL-21, and IL 23 [63, 71]. Differentiation into Th17 cells occurs in response to TGF-β and IL-6; however, its mechanism in OLP remains unclear [63, 75]. Recently, Pan et al. [19] showed that the polarization of naïve T cells toward the Th17 phenotype is promoted by activating DCs via TLR9/IFN-α, stimulated by heat shock protein 90 (HSP90). The interaction of Th17 cells with non-classical Th1 cells can result in a more aggressive form of OLP [10].

Other inflammatory cells also play roles in the interaction between T cells and keratinocytes. The Tfh subtype produces IL-21, a cytokine capable of promoting B cell proliferation [17]. Feng et al. [78] demonstrated that activated B cells are present in higher proportions in OLP tissue compared to healthy mucosa, suggesting they actively contribute to disease progression. Furthermore, γδ T cells, which are crucial for linking innate and adaptive immune responses, are overexpressed in OLP lesions, as shown by Huang et al. [79], their pro-inflammatory interaction with keratinocytes may contribute to the pathogenesis of OLP through the activation of the STING-TBK1 pathway [80].

The role of the PI3K/Akt signaling pathway in OLP has been extensively studied, as aberrant PI3K/AKT/MTOR signaling can disrupt the interactions between keratinocytes and T cells. This pathway is implicated in the production of MMPs from miRNAs present in exosomes [81, 82]. Exosomes, extracellular vesicles with a bilayer phospholipid membrane structure, hold potential as diagnostic biomarkers [83]. It has been proposed that these exosomes are released by LCs stimulated by pathogens [82]. Patients with OLP have shown significant increases in miR-4484 in salivary exosomes and miR-34a-5p in plasma exosomes [84, 85]. Exosomes also affect the Wnt/b-catenin and NF-kB pathways in OLP, activating immune cells and perpetuating chronic inflammation [82]. Furthermore, the overexpression of circHLA-C in OLP has been identified as another potential diagnostic marker implicated in immune regulation through antigen presentation and natural killer cell cytotoxicity [86].

Hypoxic conditions may significantly contribute to the pathogenesis of OLP. Increased cell proliferation in the inflamed regions of OLP is thought to generate hypoxia [87]. This hypoxia activates hypoxia-inducible factor 1-alpha (HIF-1α), which regulates the expression of galectin-3 (Gal-3), associated with inflammation and carcinogenesis. HIF-1α also controls MMP-9, which degrades the basement membrane, further promoting damage and inhibiting epithelial cell proliferation in OLP [82, 88, 89]. Reactive oxygen species, essential mediators of apoptosis stimulated by cytokines, accumulate in the basal layer, potentially inducing hypoxia, reducing local pH, and consequently increasing extracellular enzymatic activity that propagates tissue injury [90]. Hypoxia also stimulates vascular endothelial growth factor (VEGF), which is crucial for angiogenesis [20]. Angiogenesis plays a significant role in the pathogenesis of OLP, supporting its maintenance by transporting lymphocytes and oxygenating lesions [87, 91]. The angiogenesis rate is notably elevated in OLP, with disease severity correlating with elevated VEGF serum levels [92, 93]. Fibroblasts are key players in the innate immune system, regulating IL-6 and promoting angiogenesis in OLP. Activated fibroblasts further contribute to the chronicity of the condition by inducing CD4 + T cell proliferation and migration while inhibiting apoptosis [17].

Macrophages serve as the first line of immune defense, classified into M1 (pro-inflammatory) and M2 (anti-inflammatory or pro-reparative) types [94]. They are abundant in OLP, with a higher density of CD68⁺ macrophages (M1) than other conditions, including oral lichenoid lesions and oral fibrous inflammatory hyperplasia [54]. M1 macrophages are activated by IFN-γ from Th1 cells, contributing to sustained chronic inflammation in OLP through antigen presentation and the secretion of IL-1β, MMPs, and TNF-α [10, 17, 95]. TNF-α initiates keratinocyte apoptosis and contributes to basement membrane disruption by T cells [14]. Furthermore, TNF-α and IL-1β regulate adhesion molecules on endothelial cell surfaces, inducing keratinocytes to produce the chemokine CCL5 (RANTES), thereby increasing inflammation in OLP [17, 96]. Ferrisse et al. [21] suggested that the M2 subtype (CD163⁺) acts in tandem with M1 to balance the immune response. A higher M2 expression might indicate a favorable response to corticosteroid treatment. It was recently proposed that macrophages expressing STAT1/CD163 contribute to lesion pathogenesis by interacting with lymphocytes within the subepithelial inflammatory microenvironment of OLP [41]. However, the definitive role of macrophages in OLP development remains not fully understood.

Mast cells are components of both the innate and adaptive immune systems, participating in OLP pathogenesis in several ways. Mast cell presence significantly increases in OLP, attracted to the lesional microenvironment by CCL5 from T cells, and populating deeper areas of connective tissue near blood vessels and basement membrane destruction sites [10, 17, 97–99]. These cells may amplify inflammation, evidenced by the positive correlation between mast cells and inflammatory mononuclear cells [99]. Approximately 60% of mast cells undergo degranulation, releasing inflammatory mediators such as TNF-α, chymase, tryptase, IL-16, CCL4, and CCL5 that perpetuate the inflammatory response in lesions [10, 20, 99]. Moreover, mast cells release pro-angiogenic and angiogenic factors such as histamine, heparin, basic fibroblast growth factor (FGFb), VEGF, and TGF [100]. It has been suggested that mast cells contribute to basement membrane rupture by releasing chymases that activate MMP-9, thus facilitating cytotoxic T-cell movement into the oral epithelium and enhancing keratinocyte apoptosis by impeding survival signaling from the basement membrane [54, 101]. Innate immune agents, such as natural killer cells and innate lymphoid cells (ILCs), contribute to inflammation and immune dysregulation in OLP, but their exact role is not yet fully elucidated. NK cells are believed to contribute to the cytotoxic response against keratinocytes and influence the balance between inflammation and tissue repair. A significant increase in ILC1 and ILC3 was observed in OLP tissues, suggesting their involvement in chronic inflammation through the secretion of cytokines that modulate T cell responses [10, 17, 19, 102]. Understanding how different immune cells interact through the release of cytokines, adhesion molecules, and chemokines to link innate and adaptive immunity and maintain chronic inflammation may provide valuable insights for research into targeted therapeutic strategies (Tables 1 and 2).

Table 1.

Key proteins and their role in the pathogenesis of OLP

Protein	Role in Pathogenesis
ZO-1	Its reduction weakens the epithelial barrier, facilitating the infiltration of immune cells
HSP60 / HSP70	Autoantigens that activate DCs and promote inflammation
HSP90	It induces DC activation via TLR9/IFN-α, Leading to a differentiation naive T cells into Th17
E-cadherin	Responsible for cell-cell adhesion in the epithelium
MMP-9	It degrades the basement membrane, facilitating the migration of inflammatory cells
TNF-α	Induces keratinocyte apoptosis and increases the expression of adhesion molecules
IFN-γ	Stimulates the expression of MHC-II in keratinocytes and activates macrophages
VEGF	Promotes angiogenesis and facilitates the transport of inflammatory cells
IL-1	Promotes inflammation and stimulates the expression of adhesion molecules
IL-2	Stimulates proliferation and activation of T cells
IL-6	Differentiates Th17 cells and regulates chronic inflammation
IL-10	Anti-inflammatory; suppresses the immune response
IL-12	Stimulates the Th1 response and the production of IFN-γ
IL-17	Stimulates the production of cytokines and MMPs, increasing inflammation
IL-21	Stimulates B cell proliferation and Th17 response
IL-22	Stimulates inflammation
IL-23	Promotes the maintenance and expansion of Th17 cells
IL-26	Induces the release of pro-inflammatory cytokines and activates epithelial cells
IL-35	Promotes Treg-mediated immune suppression
IL-1β	Regulates inflammation and activates keratinocytes and macrophages
TGF-β	Regulates Th1/Th2 balance and Treg differentiation
PA28γ	Induces the expression of CD80, CD86 and MHC-II, promoting maturation of DCs
Galectin-3	Regulates inflammation and is associated with carcinogenesis
Histamine/ Heparin	Act as pro-angiogenic and angiogenic factors
PECAM-1 / ELAM-1 / P-selectin / CD34	Facilitate leukocyte migration, cell adhesion and angiogenesis
CCL5 (RANTES) / CCL17 / CXCL10 / CXCL12 / CCL4	Regulate the recruitment and activation of immune cells
HIF-1α	Regulates the hypoxia response and activates MMP-9, promoting epithelial damage
Granzyme B	Induces keratinocyte apoptosis through cytotoxic T cells​
Perforin	It forms pores in cell membranes, facilitating apoptosis

Table 2.

Cell types and their role in the pathogenesis of OLP

Cell Type	Role in Pathogenesis
Keratinocytes	Express MHC-I and MHC-II (when stimulated), release inflammatory mediators and undergo apoptosis/pyroptosis
Langerhans cells	Once activated, they migrate from the epithelium to the lymph nodes and present antigens to naive T cells
Dendritic cells	Present antigens to T lymphocytes
Näive T cell	Differentiates into effector subtypes following activation by APCs
Th1	Produces IFN-γ, IL-2 and TNF-α, exacerbating inflammation and promoting TCD8+activation
Th2	Modulates the inflammatory response and contributes to less aggressive forms of OLP
Th17	Secretes pro-inflammatory cytokines, amplifying inflammation and tissue destruction
Treg	Produces IL-10 and TGF-β, regulates inflammation and balances the immune response
TCD8+ cell	Induces keratinocyte apoptosis through perforin/granzyme B release, FasL/Fas interaction and TNF-α signaling
MAIT cell	Produce granzyme B contributing to apoptosis and possibly pyroptosis of keratinocytes
M1 macrophage	Promote chronic inflammation through antigen presentation and secretion of TNF-α and IL-1β
M2 macrophage	Have an anti-inflammatory or pro-reparative function
Mast cells	Amplify inflammation through the release of inflammatory mediators and angiogenic factors. They activate MMP-9 and contribute to the rupture of the basement membrane
Fibroblasts	Promote angiogenesis, induce proliferation and migration of CD4 + T and inhibit their apoptosis

Keratinocyte Cell Death

CD8 + T cells are highly effective cytotoxic immune cells against infected or tumorous tissues [103]. In OLP, CD8 + T cells induce keratinocyte apoptosis, resulting in epithelial damage characteristic of the disease [20]. CD4 + T cells release IL-2 and IFN-γ, which recruit and activate CD8 + T cells in the subepithelial regions of the lesion [17]. However, CD8 + T cells can also be directly activated by MHC-I recognition on damaged keratinocytes or DCs [17]. Apoptosis, a form of programmed cell death, involves the activation of caspase enzymes that degrade various cellular components, leading to the loss of plasma membrane integrity, cell shrinkage, chromatin condensation, and DNA fragmentation [104, 105]. Caspases can be activated via extrinsic or intrinsic pathways. The extrinsic pathway is initiated by cell surface ‘death receptors’ such as those from the TNF family, including TNF-1 and FasL, while the intrinsic pathway is associated with stress and various forms of intracellular damage. In OLP, apoptosis is triggered by distinct mechanisms culminating in the activation of the caspase cascade, specifically through caspase-1 and caspase-3 [20, 106, 107].

CD8 + T cells release perforin, forming pores in the keratinocyte membrane, thereby allowing granzyme B ingress into the cell. Granzyme B, a serine protease, initiates intracellular apoptotic pathways. Additionally, CD8 + T cells express the Fas ligand (FasL or CD95L), which interacts with the Fas receptor (CD95) on the surface of keratinocytes. A third mechanism involves the interaction of TNF-α released by T cells with its TNF-α1 receptor on keratinocyte surfaces [17, 20, 108]. CD4 + T lymphocytes undergo clonal expansion, releasing cytokines that, together with activations by mast cells, sustain the inflammatory state in the lesion [17, 101]. Recently, Bao et al. [109] proposed that CD4 + CD8αα+, a T lymphocyte subpopulation within epithelial mucosal barriers, participates in keratinocyte apoptosis and sustained inflammation. While CD8 + T-induced apoptosis is well-established, the role of CD4 + CD8αα+-induced apoptosis in OLP requires further investigation. The animal study by Peng et al. [110] suggested that apoptosis is modulated by the organic cation transporter 3, which influences fibroblast growth factor 2 expression, activating the NF-κB pathway and amplifying inflammation and keratinocyte death [60].

Apoptosis can also be amplified by mucosal-associated invariant T (MAIT) cells, a unique T cell population present in peripheral blood (~ 1–10%) whose TCR recognizes microbial metabolites. In OLP, MAIT cells are rapidly activated in the presence of antigens and cytokines, clustering in the connective tissue [12, 111]. Keratinocytes activate MAIT cells by expressing MHC class 1-related protein, presenting antigens for MAIT cell activation and subsequent granzyme B (GzB) production [12, 54]. Recent research by Wu et al. [112] indicates that MAIT cells exhibit different functional profiles as OLP progresses, showing an activated phenotype in early stages with high CD69 and CD38 expression and elevated PD-1 and GzB expression in advanced stages, implying that MAIT cells could help monitor OLP progression. It is proposed that keratinocytes in OLP might undergo pyroptosis, a form of programmed necrotic cell death [104, 105]. During pyroptosis, activated caspases cleave gasdermins, forming pores in the cell membrane, causing a rupture and pro-inflammatory cytokine release, which trigger a significant inflammatory response. Consequently, IL-1β release from keratinocytes activates the NF-κB signaling pathway in T cells, a critical event for their proliferation and activation, potentially contributing to OLP etiopathogenesis [104, 105, 113]. In summary, CD8 + T, CD4 + T and MAIT cells play a fundamental role in inducing apoptosis and pyroptosis of keratinocytes through several mechanisms. The destruction of keratinocytes leads to colloid body formation and exacerbates bacterial invasion and inflammation, worsening OLP deterioration [23, 110].

Malignant Progression of OLP

Currently, OLP is part of the group of oral potentially malignant disorders (OPMDs), which are defined as any abnormality in the oral mucosa significantly associated with an increased risk of developing oral squamous cell carcinoma (OSCC) [114]. In contrast, there is insufficient evidence to support the same status for cutaneous LP. The difference in the risk of malignant transformation may be related to factors such as: genetic differences between the two lesions; the chronicity and resistance to treatment imposed by OLP, whereas LP has a more transient character; influence of the inflammatory microenvironment of the oral cavity, where more carcinogenic factors could act, such as tobacco, alcohol and trauma [6, 51].

The malignancy rate of oral lichen planus (OLP) varies between studies, ranging from 1 to 2% [115–117]. This variation reflects differences in diagnostic criteria, which makes risk stratification difficult [118]. Recently, the World Health Organization (WHO) updated and classified oral epithelial dysplasia based on criteria that encompass multiple patterns of dysplasia, basal cell clusters, loss of cell polarity, teardrop-shaped epithelial projections, and changes in keratinization. From a cytological perspective, apoptotic mitoses, increased nuclear size, hyperchromasia, variation in cell shape, increased nuclear-cytoplasmic ratio, and individualized keratinization are considered. Lesions classified as high risk of malignant progression present at least four architectural alterations and six cytological alterations. Therefore, the use of standardized histopathological criteria is essential to improve the diagnosis of OLP, to assess its risk of malignancy, and to establish appropriate management [114].

It is known that there is a direct link between inflammation and malignant transformation, since both inflammation and cancer utilize common signaling pathways [41]. Approximately 20% of malignant neoplasms are related to chronic inflammation caused by infections, irritants, or autoimmune diseases [119]. Macrophages, mast cells, lymphocytes, and fibroblasts secrete cytokines, MMPs, and CCL5, which stimulate inflammation, potentially damaging genetic material and increasing the proliferation of defective cells [120, 121]. Evidence suggests that the macrophage migration inhibitory factor participates in malignant transformation by inducing the retention of macrophages at the lesion site [101]. CD163 + macrophages are associated with increased aggressiveness in oral cancers and have been found infiltrating OLP tissue [44, 122]. Recently, Zheng et al. [115] demonstrated a strong correlation between the risk of oral cancer and IL-13 levels. Hazza et al.’s study [89] proposed that hypoxia-adaptive pathways, including Gal-3, MMP-9, and the HIF-1α-mediated upregulation pathway, may play a significant role in the malignant transformation of OLP, as well as the process of neoangiogenesis [123]. The association between inflammation and cancer is complex. Pathways that support chronic inflammation do not necessarily lead to dysplasia. Cytokines and ROS appear to play a dual role, as they promote immunity and tissue repair, but if they act for a prolonged period, they could trigger oncogenic mutations [124]. Furthermore, degradation of the basement membrane could facilitate invasion of altered epithelial cells into the underlying connective tissue.

Genetic alterations may predispose patients with OLP to malignant progression. Xie et al. [125] suggested that mutations in TP53, CELSR1, CASP8, and KMT2D are essential in this process. TP53 is a tumor suppressor gene essential for cell cycle regulation and genomic stability. TP53 mutations are involved in approximately 60–70% of OSCC cases and in approximately 33% of OLP cases, and may serve as an early marker of malignancy [126]. The role of genetic alterations in malignant progression is complex and dependent on other factors, as not all OLP cases with these features progress to OSCC, highlighting the need for further research on this topic.

Risk stratification tools to identify patients with OLP at high risk for malignant transformation consider factors such as tobacco and alcohol use, tongue site involvement, erosive OLP subtype, advanced age, and erythematous clinical appearance [127]. Emerging tools such as AI-based models, biomarkers, and molecular signatures are promising but need validation with further studies to establish their clinical utility [128].

Biomarkers are studied for the early detection of malignant transformation of OLP. The importance of MMP-9 and IL-13 in this context remains unclear, as studies have not consistently validated their role as predictive biomarkers. Genetic mutations, such as polymorphisms in codon 72 of the TP53 gene, have been associated with dysplastic changes [129]. OSCC has been compared with OLP and showed overexpression of the long noncoding RNA ANRIL, denoting potential as a prognostic marker [130]. CA1, TNNT3, and SYNM proteins have also been associated with malignant progression of OLP [125, 131]. However, more robust studies considering the clinical variability of LPO are needed to validate these biomarkers.

Conclusions

Oral lichen planus is a chronic immune-mediated disease that, when symptomatic, greatly diminishes the patient’s quality of life. Although there is no cure for OLP, various therapies aim to alleviate its symptoms. The mechanisms initiating and sustaining the immune response against oral keratinocytes remain undetermined and are widely debated. Current evidence suggests that OLP results from a complex interplay of microbial, environmental, and genetic factors. Further research involving large population samples that account for variations in age, sex, ethnicity, and disease severity is required to substantiate existing hypotheses. In vitro and animal studies are also necessary as they may offer valuable insights into the etiopathogenesis of OLP. Understanding the complex interactions between immune and inflammatory cells within the lesion microenvironment is crucial for identifying accurate diagnostic biomarkers and new therapeutic targets that could reduce reliance on corticosteroid therapy. Given that OLP is considered a potentially malignant disorder, patients should be informed of the risk of malignant transformation and adhere to periodic follow-up protocols for early detection of OSCC.

Author Contributions

All authors contributed to the study conceptualization and methodology. Material preparation and writing - original draft were performed by G.B.M.M. and T.L.G. Writing - review & editing, supervision and project administration were performed by R.M.M. and C.C.D. All authors read and approved the final manuscript.

Funding

Not applicable.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Ethics Approval and Consent to Participate

Not applicable.

Competing Interests

The authors declare no competing interests.