Review

Oral lichen planus: an update on its pathogenesis

Patr
cia A. Nogueira, MD, Sueli Carneiro, MD, PhD, and Marcia Ramos-e-Silva, MD, PhD

Sector of Dermatology, School of Medicine, Abstract

Federal University of Rio de Janeiro, Rio de Oral lichen planus (OLP) is a common T cell-mediated mucocutaneous disease of
Janeiro, RJ, Brazil
unknown etiology. A great number of factors have been suggested as relevant to the
Correspondence
etiology of this disease. In this article, the authors assemble recent knowledge about the
Marcia Ramos-e-Silva, MD, PHD pathogenesis of OLP, discuss some proposed hypotheses, and compare OLP with oral
Sector of Dermatology lichenoid lesions.
School of Medicine
Federal University of Rio de Janeiro
Rua Dona Mariana 149/C-32
Rio de Janeiro 22280-020
RJ
Brazil
Email: ramos.e.silva@dermato.med.br

Funding: None.
Conflicts of interest: None.

the hypotheses proposed for the pathogenesis of OLP and

Introduction
Lichen planus (LP) is an inflammatory disease of
unknown etiology that affects mainly the skin and oral
mucosa. Other mucous membranes, such as those of the
genitalia, esophagus, and conjunctiva, as well as skin
appendage areas such as the scalp and nails may also be
affected.1 The disease presents clinically as erythematous
violaceous, polygonal, shiny, non-confluent, and symmet-
rical papules, on the surface of which are whitish streaks
known as Wickham striae.2 Oral LP (OLP) lesions usually
show a painful red center with erosions and ulcerations,
and a less painful or painless radiating white form with
papular or reticular patches over the buccal mucosa and,
to a lesser extent, the lips, tongue, and palate.3
Some lesions that are clinically and histologically simi-
lar to those of OLP are referred to as oral lichenoid
lesions (OLL). These comprise a group of lesions with
different etiologies that refer to the use of systemic medi-
cation or dental restorative materials and the consump-
tion of food and flavoring agents.35 The average age at
the time of diagnosis is 4045 years for the cutaneous
form and 5060 years for the oral disease in both OLP
and OLL.4,6,7 Although their pathogenic mechanisms and
triggering factors remain unknown,1,8 both LP and OLP
are considered to represent autoimmune diseases medi-
ated by T cells.9 In this review, we will describe some of
will discuss these in comparison with the pathogenesis of
OLL.
Etiology
The antigens that trigger the inflammatory immune
response in oral lichenoid disease (OLD), both OLP and
OLL, remain unknown1,8,9 but may include autoantigens8
or exogenous antigens, such as hepatitis C virus (HCV),
use of restorative dental materials, and/or use of
drugs.8,1012
Countless factors have been proposed as relevant to the
etiology of the lesions, including genetic history, dental
materials, drugs, infectious agents such as bacteria and
viruses, autoimmunity, associations with other autoim-
mune diseases, immunodeficiency, food, allergies, stress,
habits, trauma, diabetes and hypertension, malignant
neoplasms, and intestinal diseases.13,14
Viruses that are suspected of having an association with
OLP can be divided into two groups. The first group
includes viruses for which associations have been anecdot-
ally suggested, such as varicella zoster virus, EpsteinBarr
virus, cytomegalovirus, herpes virus, human papillomavi-
rus (HPV), and human immunodeficiency virus (HIV). The
second group includes viruses for which an association
with LP has been documented, such as HCV.8 1005

2015 The International Society of Dermatology International Journal of Dermatology 2015, 54, 10051010
1006 Review Pathogenesis of oral lichen planus
The relationship between HCV and OLP remains con-
troversial.15 Several studies suggest that the relationship
between the two diseases may be the result of genetic,
environmental, geographic, and other factors.1620 The
association seems to be stronger in Japanese and Mediter-
ranean populations, probably as a result of higher preva-
lences of HCV infection in these groups.21 Hepatitis C
virus RNA was detected in biopsies of the oral mucosa of
patients with hepatitis C, regardless of whether they were
or were not bearers of OLP.22,23 This finding suggests
that HCV is not sufficient by itself as a causative agent in
the development of OLP and that host factors play an
important role in the pathogenesis of HCV associated
with OLP.24 A study performed in Italian patients with
OLP and HCV showed a statistically significantly higher
frequency of human leukocyte antigen (HLA)-DR6 in
HCV patients compared with patients without HCV
infection, suggesting that HCV-positive patients with
HLA-DR6 are more prone to develop OLP lesions.24,25 It
is estimated that patients with hepatitis C are twice as
likely to develop LP than the general population.26
Figueiredo et al.24 observed the rate of HCV infection to
be six times higher among patients with OLP and the rate
of OLP to be eight times higher in patients with HCV
than in the general population.
Pathogenesis
Innumerable data suggest that immunological mecha-
nisms, particularly cellular immunity, are crucial in the
pathogenesis of OLP. Epidermotropic autoreactive
T cells, which are major histocompatibility complex
(MHC)-specific, produce a picture that is histopathologi-
cally indistinguishable from that of LP when injected into
the footpads of syngeneic mice; patients with chronic
graft-versus-host disease may develop oral and cutaneous
lesions that are clinically and histologically similar to
those of LP. Therapies that suppress cell-mediated immu-
nity, such as cyclosporine and etretinate, reduce lympho-
cytic infiltrate and induce clinical improvement.17
The various mechanisms hypothesized to be involved in
immunopathogenesis are: (i) an immune response mediated
by antigen-specific cells; (ii) an autoimmune response; (iii)
humoral immunity; and (iv) nonspecific mechanisms.13
Immune response mediated by antigen-specific cells
The human normal epidermis has a low percentage of
lymphocytes, generally in the basal membrane.27,28 The
lymphocytic infiltrate in lesions of LP consists mainly of
T cells, including CD4+ and CD8+ lymphocytes,17 that
migrate to the epithelium either by random antigen match
during routine surveillance or in a process mediated by
cytokines.29
International Journal of Dermatology 2015, 54, 10051010
Nogueira, Carneiro, and Ramos-e-Silva
The degeneration of basal keratinocytes observed in LP
is attributed to cytotoxic CD8+ T lymphocytes,1 which
represent the main component of the infiltrate located
within the epidermis and adjacent to damaged keratino-
cytes.1 As the disease progresses, a gradual accumulation
of CD8+ T lymphocytes occurs.17,30,31
The main event in the pathogenesis seems to be the
increased production of cytokines that induce recruitment
of Langerhans cells and clonal expansion of cytotoxic
cells.11,32,33
Activation of T cells
Cytotoxic lesional CD8+ T cells can be activated by
keratinocyte basal antigen associated with class I MHC,8
which releases many cytokines such as interleukin-2 (IL-
2), tumor necrosis factor (TNF), and interferon-a (IFN-a),
which induce not only the expression of HLA-DR in
basal keratinocytes17,34,35 but also the activation of den-
dritic cells, including Langerhans cells,17,36,37 thereby
attracting more lymphocytes.17
Lichen planus lesions present increased numbers of
helper CD4+ T cells and Langerhans cells.38 In these
lesions, helper CD4+ T cells can be activated by antigens
associated with class II MHC, present in Langerhans cells
and keratinocytes. Interleukin-12, produced by Langer-
hans cells and keratinocytes expressing class II MHC,
induces the secretion of IL-2 and IFN-c by helper CD4+
T cells.8 Most of the lymphocytes present in the lamina
propria are helper CD4+ T cells that activate CD8+
T cells through interaction with the RCA (regulators of
complement) receptor (RCA R) with RCA expressed in
CD8+ cells and in the secretion of IL-2 and IFN-c.13
Interferon-c induces keratinocytes to produce lympho-
toxin-a and TNF-a and to increase class II MHC, thereby
increasing the interaction with helper T cells.39 In addi-
tion, it increases the expression of intercellular adhesion
molecule 1 (ICAM-1) and vascular cell adhesion mole-
cule 1 (VCAM-1) by keratinocytes, Langerhans cells, and
other dendritic cells, facilitating lymphocyte adhesion to
keratinocytes, which determines the death of the keratino-
cyte by apoptosis.17,39
Apoptosis of basal keratinocytes
The possible mechanisms that induce keratinocyte apop-
tosis by CD8+ T cells are: (i) TNF-a secreted by T cells,
binding to TNF-a1 receptor on the surface of keratino-
cytes; (ii) expression of CD95L (Fas ligand) on the surface
of T cells, binding to CD95 (Fas) on the surface of kerati-
nocytes; and (iii) entry through the pores of the
membrane induced by perforin in granzyme B keratino-
cytes, secreted by T cells.8,13,39
Apoptosis may also be triggered by the release of mole-
cules such as perforin and granzyme B. In 2011, Lage
2015 The International Society of Dermatology
Nogueira, Carneiro, and Ramos-e-Silva
et al.40 confirmed the increased expression of granzyme B
and perforin in oral LP lesions in comparison with cuta-
neous LP lesions and considered this increase to be
related to the clinical behavior of the disease. All of these
mechanisms activate the caspase cascade, resulting in the
apoptosis of keratinocytes.13
Autoimmune response
The role of autoimmunity in the pathogenesis of the dis-
ease is supported by many autoimmune features of OLP,
including the diseases chronicity, onset in adulthood,
female preference, and associations with other autoim-
mune diseases, as well as the decreased immunosuppres-
sive activity in patients with OLP and the presence of
autocytotoxic T cells in OLP lesions.13
Deficiency of transforming growth factor-a1 (TGF-a1)
may predispose to autoimmune lymphocytic inflamma-
tion, and the administration of TGF-a1 may be therapeu-
tic in autoimmune diseases in which T cells play an
important role. In this context, the chronicity of OLP
may in part reflect a defect in the immunosuppressive
pathway of TGF-a1 involving: (i) an insufficient number
of TGF-secretor a1-Th3-regulator T cells; (ii) blocking of
TGF-a1 secretion; (iii) dysfunctional secretion of TGF-a1;
(iv) defective or insufficient expression of TGF-a1 recep-
tors; or (v) defective intracellular signaling of TGF-a1
receptors.32
In 2014, Shen et al.41 demonstrated the increased
expression of Foxp3 and IL-17 in LP lesions including
oral and cutaneous variants. The expression of Foxp3 in
oral LP was higher than that in cutaneous LP, a finding
that may reflect the difference in clinical behavior
between the two variants of the disease.
Humoral immunity
Autoantibodies have been identified in OLP patients.42,43
Anti-smooth muscle antibody (SMA) occurs at a signifi-
cantly higher frequency in patients with OLP than in
healthy control subjects.42 In the erosive form of OLP,
the concentrations of circulating antibodies against de-
smoglein 1 and 3 are significantly increased in compari-
son with those in healthy controls.44
Nonspecific mechanisms
Some of the T cells in OLP lymphocyte infiltrates are
unspecific. They can be attracted and retained within
OLP lesions by various mechanisms associated with the
pre-existing inflammation.
Epithelial basal membrane
A fine and complex membrane the basal membrane
separates the epidermis from the dermis.45 This plays an
important role in the mechanical support of adherence of
2015 The International Society of Dermatology
Pathogenesis of oral lichen planus Review 1007
the epidermis to the dermis and in the regulation of
metabolite transportation between the dermis and epider-
mis, as well as serving as support for the migration of
keratinocytes during scarring and for inflammatory cells
during immune processes that affect the skin.27,28
Keratinocyte apoptosis by CD8+ cytotoxic T lympho-
cytes may result in disruption of the basal membrane in
OLP, which allows nonspecific T lymphocytes present in
the subepithelial area to migrate to the epithelium.13
Metalloproteinase matrix
The metalloproteinase matrix (MMP) involves a family of
endoproteinases with at least 20 members13,46 that
degrade protein components of the extracellular matrix.47
In OLP, activation of MMP-9 results in the disruption of
the basal membrane.13,32,46
Chemokines
Chemokines are proinflammatory cytokines. RANTES is
a member of the CC chemokine subfamily and is pro-
duced by various cells including activated T lymphocytes,
bronchial epithelial cells, synovial fibroblasts, oral kerati-
nocytes, and mast cells. Chemokines play a critical role in
OLP through the recruitment of lymphocytes, monocytes,
natural killer cells, eosinophils, basophils, and mast cells.
CCR1, CCR3, CCR4, CCR5, CCR9, and CCR10,
which are cell surface receptors for RANTES, have been
identified in LP, including the oral variant.32,46,48 RAN-
TES, secreted by OLP lesional T cells, can attract mast
cells that, by undergoing degranulation, release TNF-a
and chemokines that stimulate more RANTES secretion.
Such a cyclical mechanism may be the underlying cause
of the diseases chronicity.13,32,46
Mast cells
Mast cells originate in the bone marrow, are scarce, and
are located in the perivascular and periannexial dermis.28
Studies show an increase in the density of mast cells in
OLP, 60% of which have undergone degranulation.13,46
Vascular endothelial growth factor
Vascular endothelial growth factor (VEGF) is important
in the regulation of angiogenesis.49 Its expression can be
induced by several inflammatory mediators, including IL-
6, IL-8, and IL-1, is regulated by the concentration of
oxygen in the tissue and is stimulated by hypoxia.50 As
an autoimmune disease of inflammatory origin and
chronic progression, OLP meets all prerequisites for
hypoxia, which is essential to angiogenesis.51 An increase
in angiogenesis and in VEGF levels can therefore be
expected.52 Corroborating this information, Mardani
et al.49 found serum levels of VEGF to be significantly
elevated in patients with OLP.
International Journal of Dermatology 2015, 54, 10051010
1008 Review Pathogenesis of oral lichen planus
Dermal dendrocytes
Dermal dendrocytes are cells derived from bone marrow,
of which two types can be basically identified by immu-
nohistochemical studies: (i) XIIIa+ factor, also called type
I, and (ii) CD34+ or type II.5355 Cardoso et al.53 identi-
fied dermal dendrocytes in different tissue distributions,
predominantly dermal dendrocyte XIIIa+ factor in the
superficial dermis, and CD34+ cells in the deep dermis,
suggesting that dermal dendrocytes, especially of type I,
may play an important role in the pathogenesis of OLP
that is attributable to their ability to express ICAM-1 and
TNF-a.
Langerhans cells
Langerhans cells originate from CD34+ hematopoietic
precursors of the bone marrow.27 They are mobile and
dendritic and take part in the presentation of antigens in
immune induction.28,56 These cells produce greater
amounts of IFN-a to induce more apoptosis mediated by
cytotoxic cells via a cascade of caspase.11,32,33
Others
The lesions of OLP and OLL have similar clinical and
histopathological features. A retrospective descriptive-
analytic study of 232 patients with clinical and histopath-
ological diagnoses of OLP and OLL was performed in
2013 by Aminzadeh et al.57 A band-like inflammatory
infiltrate mainly composed of lymphocytes, saw-toothed
rete ridges, Max Joseph spaces, and an atrophic epithe-
lium was seen with significant frequency in OLP. Hyper-
keratosis and deep connective tissue infiltrate composed
of eosinophils, neutrophils, and plasma cells were seen in
OLL. Recently, mast cell counts and morphology have
been theorized to facilitate such a differentiation.4,58
Recent data suggest that OLL presents a greater per-
centage of malignant transformation than OLP, but the
potential of both remains controversial. Although the
association between cancer and OLP has been docu-
mented in scientific reports, there is no association
between squamous cell carcinoma and cutaneous LP.5961
Malignant transformation of OLP may be related to, or
dependent on, a series of molecular stimuli originating in
the inflammatory infiltrate. Some molecules and radicals
generated by inflammatory cells can act as mutagenic
agents for epithelial cells. In 2013, Venkatesiah et al.5
reported a morphometric study that showed similar
changes in parameters such as the nuclear area, cellular
area, and nuclear volume in OLP, OLL, and normal
mucosa. No difference was observed between OLP and
OLL, and hence these factors may serve as potential dis-
criminators between normal and premalignant LP and
lichenoid lesions. As both types of lesion may be similar
International Journal of Dermatology 2015, 54, 10051010
Nogueira, Carneiro, and Ramos-e-Silva
in their potential for transformation, any apparent
increase in nuclear or cellular areas or volumes, suggest-
ing a higher risk for malignant transformation and mor-
phometry, cannot be used to differentiate between them.
The authors concluded that OLP and OLL cannot be eas-
ily differentiated clinically, histopathologically, or mor-
phometrically, and suggested that comparisons among
various clinical and histological stages of OLP and OLL
with and without dysplasia might better elucidate the
behavior of these lesions.5
Cyclooxygenase-2 (COX-2) is an enzyme for inflamma-
tory processes and cellular proliferation, the overexpres-
sion of which may represent a marker for malignant
neoplasias, tumor growth, invasion and metastasis, angio-
genesis, and inhibition of apoptosis. Cort
es-Ramrez
et al.62 analyzed COX-2 expression in 44 samples from
different subtypes of OLD and demonstrated that differ-
ences in COX-2 expression in subtypes of OLD may dis-
tinguish cases with a higher premalignant potential.
The growth of keratinocytes is regulated by a closed
balance between bcl-2, which controls cell survival, and
p53, which controls cell death. In 2014, expression of
bcl-2 and COX-2 in OLP and OLL was semi-quantita-
tively analyzed in 65 cases of OLL (n = 34) and OLP
(n = 31) by Arreaza et al.,63 who found both to be more
commonly expressed in OLP than in OLL.
Epidermal growth factor receptor (EGFR) is an impor-
tant oral carcinogenesis biomarker and is overexpressed
in several oral potentially malignant disorders. In 2014,
Cort
es-Ramrez et al.64 analyzed EGFR expression in
their 44 OLD cases to look for differences between OLP
and OLL and to correlate them with the main clinical
and pathological features. They found high EGFR expres-
sion in all OLD samples.64 The type of clinical lesion did
not relate to EGFR expression; however, differences in
patterns of EGFR expression between histological groups
may be related to differences in biological profile and risk
for malignancy.
Conclusions
Oral LP appears to be mediated by a mechanism that is
antigen-specific, which activates cytotoxic T cells and
nonspecific mechanisms, such as mast cell degranulation
and MMP activation.
Given all of these possible reactions in OLP, it is likely
that the initiation, maintenance, and aggravation of OLP
reflect the interaction of several factors. Further, although
there is as yet no consensus, it is possible that OLP
lesions may be converted into malignant squamous
carcinoma, and this possibility should stimulate further
investigation into the potential malignant transformation
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Nogueira, Carneiro, and Ramos-e-Silva Pathogenesis of oral lichen planus Review 1009

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