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Čēma, I.; Kakar, J.; Dzudzilo, M.; Murovska, M. Currently Existing Pathogenesis of Oral Lichen Planus. Encyclopedia. Available online: (accessed on 14 June 2024).
Čēma I, Kakar J, Dzudzilo M, Murovska M. Currently Existing Pathogenesis of Oral Lichen Planus. Encyclopedia. Available at: Accessed June 14, 2024.
Čēma, Ingrīda, Jagriti Kakar, Madara Dzudzilo, Modra Murovska. "Currently Existing Pathogenesis of Oral Lichen Planus" Encyclopedia, (accessed June 14, 2024).
Čēma, I., Kakar, J., Dzudzilo, M., & Murovska, M. (2023, June 10). Currently Existing Pathogenesis of Oral Lichen Planus. In Encyclopedia.
Čēma, Ingrīda, et al. "Currently Existing Pathogenesis of Oral Lichen Planus." Encyclopedia. Web. 10 June, 2023.
Currently Existing Pathogenesis of Oral Lichen Planus

Lichen ruber planus (LP) is a chronic, autoimmune, inflammatory mucocutaneus disease that influences the hair, skin, and nails, as well as the genital, oesophageal, laryngeal, conjunctival, and oral mucosa. Mostly, it is isolated only in the oral cavity without involving the skin or other mucous membranes. Oral lichen planus (OLP) is considered a T cell-mediated chronic inflammatory process activated by an unknown antigen, making basal keratinocytes vulnerable to a cytotoxic cell mediated immune response.

oral lichen planus chronic inflammation dendritic cells immune cells pathogenesis

1. Introduction

The aetiology of OLP is unspecified, but an attempt has been made to identify and summarize the possible etiological factors [1]. Possible provocative factors are mentioned several systemic diseases, like hypertension, with chronic inflammation related to other cardiovascular risk factors: dyslipidemia, metabolic syndrome, thyroid and liver dysfunction, diabetes mellitus, kidney disease, celiac disease, and genetic susceptibility to cancer [2][3][4]. De Porras-Carrique et al. [5] stated that the current data regarding autoimmune diseases such as Sjogren’s syndrome, lupus erythematosus, and rheumatic conditions, dermatological diseases, fibromyalgia and gastrointestinal disorders do not allow conclude whether these diseases are really associated with OLP. Studies on the pathogenesis of OLP may be significantly influenced by Th17 cells and the IL17A polymorphism [5], but connections between 14 functional gene polymorphisms indicate that susceptibility to OLP might be linked to the TNFR2 +587 gene polymorphism [6]. There are studies on the role of vitamin and mineral (nutritional) deficiencies in the development of OLP, suggesting that the severity of OLP may be related to the presence of abnormally high blood homocysteine levels as well as deficiencies in Hb, iron, folic acid, and vitamin B12 [7]. Studies have shown that vitamin D receptor (VDR) variants could affect susceptibility to OLP, making VDR gene polymorphisms possible candidate susceptibility regions for the condition [8]. Wang et al. [9] clarified through meta-analysis that the profile of oxidative stress and antioxidant state markers in OLP patients has been elucidated, revealing heterogeneity among the studies and underscoring the necessity for additional research on oxidative stress and antioxidant systems in both saliva and blood. In recent years, there have been several studies and review articles analyzing the pathogenesis of OLP from a microbiological standpoint, considering the potential for a microbial etiology of the disease [10][11][12]. Conflicting studies exist on H. pylori involvement: no statistically significant correlation was found between the presence of the bacteria and OLP [13]. On the other hand, another study has shown a significant correlation between H. pylori infection and the pathogenesis of erosive OLP [14]. Many studies demonstrate that the influence of psychological factors (depression, anxiety, and stress) has not lost its relevance in OLP development, as proved by [15][16][17].
Payera et al. [18] expressed the opinion that various external agents, particularly viruses, as well as internal agents such as stress and heat shock protein (HSP) antigen expression, may contribute to the pathogenesis of the condition, whether associated or not, and can trigger OLP. Over the past 10 years, researchers have re-engaged in studies on the potential involvement of viruses in the pathogenesis of OLP [19][20][21][22].
Until now, the hepatitis-C virus (HCV) has been the most studied virus that is connected with the aetiology of OLP. There are a lot of studies devoted to the question of the hepatitis C virus link with LP [23][24][25]. It is established that in different geographical locations, the influence of environmental and genetic factors is also different. Studies show that the development of the disease is determined not by the direct effect of the virus but by the host’s immune system responding to the presence of the virus particles. This means that the pathogenic pathways involved are not entirely clear [26].

2. Pathogenesis

The exact pathogenesis of OLP remains unclear, although it is currently understood to be a chronic inflammatory process mediated by T cells. This process is initiated by an antigen or antigens that transform basal keratinocytes, rendering them vulnerable to cytotoxic immune responses from cells [27]. It has been established that OLP involves both innate and adaptive immune mechanisms [28][29]. The trigger factor can be an unknown endogenous or exogenous antigen. The first cells involved in antigen recognition are keratinocytes, which can perceive small molecular elements expressed by microorganisms known as pathogen-associated molecular patterns (PAMPs). Typical PAMPs are bacterial lipopolysaccharides (LPS), endotoxins, and viral-derived nucleic acids, which are identified by pattern-recognition receptors (PRRs) [27][30]. On the keratinocyte surface are located PRRs, to which belong toll-like receptors (TLRs), C-type lectin receptors, cytoplasmatic nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), and retinoic-acid-inducible gene I (RIG-I)-like receptors [31]. Keratinocytes have the capability to produce various pro-inflammatory cytokines and chemokines, such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-α [32], which promote the recruitment of immune cells such as neutrophils and T lymphocytes to the infection site. PRRs are recognized as endogenous factors, which are substances that are released due to damage to cells or tissues and are named danger-associated molecular patterns (DAMPs) [33]. TLRs are also expressed on the membranes of leucocytes, macrophages, dendritic cells, natural killer cells, T cells, and B cells and located on intracellular vesicles. In the literature review of Osorio-Osorno et al. [29], the authors focused on the interrelationship between toll-like receptors (TLRs) and OLP, with a focus on the molecular behavior of oral keratinocytes following the activation of TLR signals. Therefore, it can be assumed that if a foreign protein molecule acts as an antigen by reaching the physical barrier of the oral mucosa and coming into contact with oral keratinocytes, it will be recognized by TLRs and the immune cells will become activated. In the pathogenesis of OLP, both antigen-specific and non-specific mechanisms may be involved [34][35]. In the case of an antigen-specific mechanism, an antigen-peptide-loaded MHC I complex, located on basal keratinocytes, activates antigen-specific cytotoxic CD8+ T cells (CTL) with the following apoptosis of antigen-specific keratinocytes. This process is accompanied by the release by activated CD8+ T cells of cytokines such as granzymes, perforins, tumor necrosis factor alpha (TNF-a), Fas ligand (FAS-L), INF-gamma, IL-1, and IL-17 from other cells. This all promotes further inflammation [34][35]. The secretion of several pro-inflammatory cytokines activates epithelial Langerhans cells (LCs), also known as antigen-presenting cells (APCs), and the TLRs-dependent activation is required to induce dendritic cell maturation and migration to regional lymph nodes and naive T cell activation [36].
From APCs or an active T helper cell, requires co-stimulation on CD4+ T and CD8+ T cells located T cell receptor (TCR) complex activation. The TCR recognizes the antigen and the relevant antigen-presenting MHC complex [37]. The specific adaptive immune response is controlled by the T follicular helper (Tfh), cytotoxic T lymphocytes (CTLs), T cell subtypes Th1, Th2, T17, and regulatory T cell (Treg), which are distinguished by the types of cytokines they secrete [38]. According to Jin et al. [38], TLRs are also involved in T cell development and give a signal to reprogram Treg cells into helper cells [38]. T cell subtypes Th1 and Th2 participate in the CD8+ T lymphocytes activation, thus helping the apoptosis of the keratinocytes [39].
Since all these processes activate TLRs, then through DAMPs or PAMPs, other keratinocytes may also be affected [40]. The inflammatory infiltrate consists mainly of cytotoxic CD+ T cells and is maintained by the released chemokines, which promote and sustain monocytes and polymorphonuclear cells attraction to the lamina propria and subsequent maintenance of inflammation [41]. It is noted that Th17 cells also play a pivotal role in the immune system, working on adaptative and innate responses [42].
All these mentioned processes are accompanied by mast cell degradation and matrix metalloproteinase (MMP) stimulation, the main reactions in the non-specific mechanisms in OLP pathogenesis [35]. CD4+ T lymphocytes clonally expand and maintain a pro-inflammatory state by releasing cytokines such as INF-γ and IL-2, leading to the activation and degranulation of mast cells. The number of mast cells in OLP is significantly increased, and the following degranulation releases TNF α, which upregulates endothelial cell adhesion molecule expression for lymphocyte adhesion and extravasation [43].
The major product of mast cells is chymases, which, through direct or indirect activation of T cells, secrete and activate matrix metalloproteinases 9 (MMP-9) and damage the epithelial basement membrane [35][41][43]. The chronic nature of the process creates and promotes further accumulation of T cells in the superficial lamina propria, the arrival of immune cells in the epithelia, and the apoptosis of keratinocytes [34][35]. The degradation of basement membrane structural proteins by mast-cell-derived chymase and tryptase is a crucial step in the pathogenesis of OLP. This enzymatic breakdown can cause disruptions in the epithelial basement membrane, leading to the infiltration of cytotoxic CD8+ T lymphocytes into the epithelial layer through breaks in type IV collagen created by tryptase [44].


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