Vol. 122 No.
1 July 2016
Etiology and pathogenesis of oral lichen planus: an overview
Zoya B. Kurago, DDS, PhD
Oral lichen planus is a noninfectious, chronic inflammatory condition that involves the oral mucosal stratified
squamous epithelium and the underlying lamina propria and may be accompanied by skin lesions. This overview describes
the current understanding of the immunopathologic mechanisms implicated in oral lichen planus. (Oral Surg Oral Med Oral
Pathol Oral Radiol 2016;122:72-80)
Oral lichen planus (OLP) is recognized as a noninfec-
tious, chronic inflammatory condition that involves the
oral mucosal stratified squamous epithelium and the
underlying lamina propria and may be accompanied by
skin lesions. The causes that initiate and/or perpetuate
OLP (with or without skin lesions) are, for the most part,
unknown. The prevailing theories revolve around dys-
regulated T-cell-mediated disorder to exogenous triggers
as opposed to a dysregulated response to autologous
keratinocyte antigens (autoimmune), and definitive data
necessary to resolve this dilemma, in particular, the
initiating triggers and the target antigens, are currently
missing. Common difficulties in the study of OLP are
related to the overlap between the features of OLP and
those of other oral mucosal conditions, the highly vari-
able application of diagnostic criteria, and the potential
coexistence of additional non-OLP inflammatory con-
ditions in the same patients. Nevertheless, the growing
database of information about this disorder suggests
certain immune response patterns. The accumulating
knowledge will eventually facilitate a more reliable
separation of this condition from other disorders that are
typically included on the differential diagnosis list.
In contrast to OLP, cutaneous LP is typically a self-
limiting condition (except for the hypertrophic form)
and usually resolves within 6 to 12 months,1 suggesting
that the underlying mechanisms in OLP and cutaneous
LP may be distinct. It is not clear yet whether the
mechanisms driving isolated OLP are different from
those driving OLP with cutaneous lesions. The focus
of this overview is on OLP.
A number of potential OLP triggers have been pro-
posed, mainly (1) local and systemic inducers of cell-
mediated hypersensitivity, (2) stress, (3) autoimmune
Associate Professor, Departments of Oral Health and Diagnostic
Sciences and Oral Biology, Augusta University Dental College of
Georgia; Department of Pathology, Augusta University Medical
College of Georgia; Augusta University Cancer Center, Augusta, GA,
USA.
Received for publication Aug 25, 2015; returned for revision Mar 2,
2016; accepted for publication Mar 9, 2016.
Ó 2016 Elsevier Inc. All rights reserved.
2212-4403/$ - see front matter
http://dx.doi.org/10.1016/j.oooo.2016.03.011
72
response to epithelial antigens versus a dysregulated
response to external antigens, and (4) viral infections.
Hypersensitivity reactions generally align with
lichenoid mucositis, an umbrella term for OLP-like
mucositis in response to restorative and other mate-
rials (e.g., amalgam), reactions to drugs, and so on.
Hypersensitivity reactions usually resolve upon
removal of the trigger, and do not maintain a chronic
course, as is characteristic of OLP. Drugs may also be
implicated in exacerbations of pre-existing OLP, which
can create challenges in patient management.
Stress is thought to play a role in the pathogenesis of
OLP because anxiety and depression are reportedly
more common in patients with OLP in comparison with
normal controls,2 and OLP exacerbations correlate with
episodes of anxiety.3,4 However, a cause-and-effect
relationship between stress and the onset of OLP has
not been demonstrated. Moreover, studies show that
acute and chronic psychological stress can induce
pronounced changes in innate and adaptive immune
responses. These immune response changes are
predominantly mediated via neuroendocrine mediators
from the hypothalamicepituitaryeadrenal axis and the
sympatheticeadrenal axis (reviewed by Kemeny and
Schedlowski5). The implication of these studies is that
similar to other inflammatory conditions of various
causes, stress is more likely to play a secondary,
rather than a primary, role in OLP pathogenesis.
Autoimmune response to epithelial self-antigens
remains a possibility. A single study of cutaneous LP
reported evidence in support of autoimmunity by
Statement of Clinical Relevance
Oral lichen planus (OLP), a common inflammatory
disorder of unknown cause, can result in significant
morbidity. As studies investigate various aspects of
this condition, updates on the accumulating knowl-
edge are of value to clinicians who manage patients
with this disorder. This overview is focused on the
current understanding of OLP immunopathogenesis
in an effort to facilitate better management of pa-
tients with OLP.
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Fig. 1. Cells and molecules implicated in the pathogenesis of
OLP. The following hypothetical model of cell-mediated
immunopathogenesis combines data from OLP studies and
known immune system functions. An unidentified trigger
initiates cell/tissue damage and the immune response by
activating the resident myeloid DC (Langerhans cells and/or
stromal DC). Activated DC loaded with antigen undergo
maturation, produce cytokines and chemokines, and migrate
to regional lymph nodes to present the processed antigen to T
cells. Some mature DC remain in the mucosal lamina propria
and produce IL-12, IL-18 and TNF-alpha. The apparent lack
of B cells and antibodies in OLP suggests the absence of
soluble antigen. Mast cells in the damaged tissue release
granules with inflammatory mediators. Various resident cells
produce chemokines CCL5, CXCL9, CXCL10, which
particularly attract Th1 and cytotoxic T cells. The vascular
endothelial cells in the lamina propria also respond by pro-
ducing chemerin, which attracts plasmacytoid DC and NK
cells. Plasmacytoid DC interact with myeloid DC, T cells and
NK cells and secrete IFN-alpha. T cells and NK cells are
further activated by IL-12, IL18 and IFN-alpha to release IFN-
gamma and TNF-alpha, which in turn activates DC. Some
cytotoxic CD8þ T cells kill basal/parabasal keratinocytes
using perforin and granzyme, resulting in apoptotic (‘colloid’)
bodies. TNF-alpha activates anti-microbial responses and may
kill host cells. IFN-gamma stimulates the expression of MHC
class II on keratinocytes, which may facilitate their antigen-
dependent interaction with CD4þ T cells. How this interaction
affects the process is not clear. Equally unclear is what
REVIEW ARTICLE
Kurago 73
expanding in vitro T cells isolated from the skin lesions
of two patients, followed by testing the ability of these
T cells to kill autologous keratinocytes (cytotoxicity).6
Besides the lack of other convincing studies that
support the autoimmune mechanism, it is difficult to
reconcile autoimmunity with the typically self-limiting
course of cutaneous LP. As stated above, although the
immune response in OLP is dysregulated, none of the
reported studies to date has provided definitive evi-
dence for autoimmunity in OLP, that is, a response to
self-antigens. Current knowledge about immune system
cells and molecules participating in OLP pathogenesis
is summarized below.
Contributions of viral infections are discussed under
“OLP Associations with Microorganisms and Other
Systemic Disorders.”
OLP IMMUNOPATHOGENESIS
Investigations of immune system activities in OLP have
focused largely on erosive and reticular forms, some-
times comparing the two. Published reports include
evaluations of biopsy specimens, saliva, and blood.
Studies that have examined changes in the composition
of untreated OLP lesions over time are lacking; this is a
limitation, given the chronic waxing and waning course
of OLP. Following is a summary of published papers,
complemented by a diagram and a table of important
cells and soluble factors (Figure 1, Table I). A
hypothetical model of interactions implicated in OLP
pathogenesis is included in the legend to Figure 1.
Cells
T cells and NK cells. Established OLP lesions are
typically found to contain T cells with alpha-beta T-cell
receptors, including CD4þ (“helper”) and CD8þ (“cyto-
toxic”) T cells, both within the epithelium and lamina
propria infiltrates. Both cell subsets can be involved in a
type 1 immune response, where CD4þ T cells produce
Th1 factors, and CD8þ cytotoxic T cells kill host cells
and may contribute type 1 soluble factors. The vast
majority of oral mucosal and peripheral blood studies
show a dominant type 1 (Th1) cell-mediated immune
response. This response likely includes cell-mediated
cytotoxicity, as CD8þ T cells were often found at the
stimulates parakeratosis that presents clinically as white pla-
ques or striae. Erosive OLP, but not reticular OLP, is asso-
ciated with Th17 CD4þ T cells, a source of IL-17. Whether
IL-17 is an initiator or a consequence of the destruction that
results in mucosal ulceration, is not known. The lack of
myeloid or lymphoid suppressor cells in OLP likely also
contributes to the chronic and destructive inflammation. It is
unclear what a gut barrier-associated cytokine IL-22 or TLR
may be contributing to the OLP immunopathogenesis.
ORAL AND MAXILLOFACIAL PATHOLOGY OOOO
74 Kurago July 2016

Table I. Cells and soluble factors found in OLP OLP patients.11 Moreover, Th1 cells produce interferon-
Cells Functions in OLP
gamma (IFN-g), and IFN-g-positive cells were identified
in OLP.7 Natural killer (NK) cells also can produce
Myeloid dendritic cells (DC) Produce IL-12, TNF-a, (IL-18*)
Chemokines; interact with T cells IFN-g, and cells with NK cell markers (CD56
Plasmacytoid DC Produce IFN-a, chemokines; interact
dim
CD16þ) have been identified in OLP lesions.12 This
with T cells NK cell subset is known for cytotoxicity and the ability
Th1 T cells Produce IFN-g, TNF-a to produce TNF-a and IFN-g,13,14 but NK cell func-
Th17 T cells Produce IL-17
tions in OLP are not defined. Together, OLP-associated
Cytotoxic T cells Cytotoxicity; produce IFN-g*
NK cells Produce IFN-g*; cytotoxicity* IFN-g-positive cells could be Th1 cells and/or NK cells.
Mast cells Produce TNF-a, proteases, Another proinflammatory CD4þ T cell subset iden-
vasoactive mediators, MMPs, tified recently in OLP in high numbers is Th17,15 which
chemokine CCL5 is responsible for production of interleukin-17 (IL-17)
Soluble factors rather than IFN-g. Th17 T cells are important contrib-
Chemokines Likely effects utors to the defense against many bacterial and fungal
CCL5 Attract T cells, other leukocytes pathogens and to autoimmune conditions.16
CXCL9, CXCL10 Attract Th1 and cytotoxic T cells Not surprisingly, regulatory T cells (Treg), which are
Chemerin Attract NK cells well known for suppressing inflammation, were rare in
Cytokines Potential effects both erosive and nonerosive OLP lesions.15 As already
IL-12 Stimulate IFN-g expression (T cells, emphasized, the antigens to which either CD4þ or
NK cells) CD8þ T cells are responding in OLP are unknown.
IL-18 Complex effects depending on
Antigen-presenting cells. Professional antigen pre-
context; stimulate TNF-a and
IFN-g expression, T-cell and sentation to T cells leading to T-cell activation or
NK-cell cytotoxicity tolerance depends largely on dendritic cells (DC) and
IFN-a Stimulate MxA expression typically occurs in secondary lymphoid organs, such as
(keratinocytes, leukocytes) lymph nodes. Interestingly, studies have suggested that
IFN-g Keratinocyte apoptosis, MHC class II
DCeT-cell interactions leading to T-cell activation may
expression
TNF-a Antimicrobial activity, cell apoptosis be occurring on site within OLP lesions. The DC sub-
IL-17 (erosive OLP) Proinflammatory: antibacterial, sets characterized in OLP include mature and immature
antifungal, autoimmune conditions myeloid DC (both Langerhans cells and stromal DC)
IL-22 GI barrier maintenance and plasmacytoid DC.17 Mature DC, which are DC
Other factors Potential effects expressing all the molecules required for T-cell
MMPs Matrix degradation activation, were found mainly in the lamina propria in
Factors in saliva Potential effects clusters with each other and with T cells.17 Mature
IL-17 Marker of mucosal inflammation myeloid DC can produce the Th1 cytokine, IL-12.
Soluble TLR2 Not known However, plasmacytoid DC are the major producers
Soluble TLR4 Not known of IFN-a, another cytokine that stimulates a type 1
DC, dendritic cell; GI, gastrointestinal; IFN, interferon; IL, inter- immune response18 by inducing the expression of MxA
leukin; MHC, major histocompatibility complex; MMP, matrix met- and other genes.17,19 Consistent with IFN-a production,
alloproteinase; MxA, human myxovirus resistance protein 1; NK, epithelial and inflammatory cells in OLP lesions
natural killer; OLP, oral lichen planus; TNF, tumor necrosis factor;
TLR, toll-like receptor.
strongly expressed MxA.12,17 In the context of activated
*The stated activity has not been demonstrated in OLP but is likely mature plasmacytoid DC, IFN-a, and Th1 T cells, NK
based upon the known functions of the cells. cells are also likely to contribute to the type 1 response.
Macrophages also perform antigen presentation to
epithelial-connective tissue interface and sometimes T cells and are normal residents of the oral mucosa.
adjacent to apoptotic keratinocytes.7,8 Moreover, Their participation and contributions to OLP have not
cytotoxicity-related molecules perforin, Tia-1, and gran- been fully characterized.
zyme were all detected in the epithelium and the con- B lymphocytes, which, in addition to antibody pro-
nective tissue,9,10 which occurred much more often in duction, also perform antigen presentation, appear to
OLP than in cutaneous LP.9,10 Immune-mediated cell contribute little, if anything, in OLP,20 but a detailed
death can occur through several mechanisms. The spe- analysis of B cells in OLP has not been provided in
cific mechanism of cytotoxicity directed at keratinocytes the literature. Similarly, terminally differentiated
in OLP is still unclear. Other parameters indicating a Th1 B cells (plasma cells) and antibodies have not been
profile include the Th1 T cell regulator, transcription found to contribute to OLP.20
factor T-bet, which prevailed over Th2-related tran- Mast cells. Finally, activated mast cells have been
scription factor GATA-3 in peripheral blood T cells of described in OLP.21 Mast cells, normally associated
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with mucosal vasculature and nerves, may contribute
several soluble inflammatory mediators (Table I)21-23
and facilitate the migration of various inflammatory
cells from the bloodstream.
It is important to note that the characteristic
composition of the inflammatory infiltrate in OLP-
related ulcers and erosions and in the marginal
gingiva is distorted. This change in ulcers and erosions
is, at least partly, caused by surface breach and expo-
sure of the lamina propria to the oral microflora. Plaque
microflora likely contributes to the immune response in
the marginal gingiva. In these areas, other inflammatory
cells are present, particularly neutrophils, which
respond to microorganisms and necrosis. As a result,
the mechanisms operating in such lesions are more
complex, and the morphology of such lesions can
compromise the accuracy of the diagnosis. Incisional
biopsy samples that exclude erosions, ulcers, and
marginal gingiva are better for the histopathologic
diagnosis of OLP.
Soluble factors
Soluble factors include cytokines, growth factors, che-
moattractants, and enzymes. Both locally and in the
peripheral blood of OLP patients, the identified soluble
factors also indicate a type 1 immune response.7,24-27
Cytokines. Some of the cytokines have already been
mentioned earlier (IL-12, IFN-g, IFN-a). Tumor
necrosis factor-alpha (TNF-a) is another destructive
cytokine associated with type 1 responses, and it also
stimulates antimicrobial activities. Important producers
of TNF-a are T cells, NK cells, DC, and macrophages.
IL-12, IFN-g, and TNF-a are significantly elevated
over the prototypical Th2 cytokine IL-4,26,27 but
Th2-associated IL-10 and IL-13 would benefit from
additional analysis. IL-12 stimulates IFN-g production
and activates T-cell and NK-cell cytotoxicity. In addi-
tion to activating antimicrobial defenses, which are
particularly helpful against intracellular microorgan-
isms, IFN-g stimulates major histocompatibility com-
plex (MHC) class II expression. Consistent with this
effect, MHC class IIþ keratinocytes (which normally
express only MHC class I) have been described in
OLP.28 MHC class II expression can then permit a
direct antigen-specific interaction between keratino-
cytes and CD4þ T cells.29 Yet another cytokine
identified in OLP is IL-18,30,31 which can have
similar effects on cytotoxicity and IFN-g production to
those of IL-12. IL-18 may be produced by antigen
presenting cells and epithelial cells.32 The sources of
IL-18 in OLP have not been defined.
Only a few reports have suggested a dominant Th2
profile33 or a mixed Th1-Th2 profile,34 raising
questions about representative specimens (e.g.,
proximity to marginal gingiva), application of
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Kurago 75
diagnostic criteria (e.g., lichenoid mucositis vs OLP,
as hypersensitivities are often associated with Th2
responses), the simultaneous presence of other
inflammatory oral non-OLP conditions (e.g., peri-
odontal disease), and potential ethnic differences.
In recent studies, a proinflammatory Th17 cytokine
IL-17 was found to be significantly increased in the
erosive OLP lesions35 and saliva of patients with
erosive OLP, but not in those with reticular OLP.36
IL-17 is produced by Th17 T cells and several other
cell types. IL-17 is very important for clearance of
many bacterial and fungal pathogens and leads to
severe inflammation with marked tissue destruction.16
Based on known IL-17 activities, it may be a contrib-
utor to, and/or a consequence of, surface erosions and
ulcerations in OLP.
Other cytokines also identified in OLP are not
necessarily affiliated with a specific inflammatory profile
(e.g., IL-6). Yet another cytokine of interest that has
been described recently in OLP is IL-22.37 IL-22 can be
made by a subset of T cells and several other immune
system cells. The main function of IL-22 in the gut is to
stimulate epithelial proliferation to support and maintain
the gastrointestinal (GI) epithelial barrier. IL-22 also
facilitates barrier defense against bacterial pathogens by
stimulating the production of antimicrobial pep-
tides.38,39 IL-22 is implicated in multiple conditions with
dysregulated immune responses, including autoimmune
disorders.38,39 The sources and functions of IL-22 in
OLP are not known, and further studies are required.
As cytokines are critical factors in immune re-
sponses, the genetic regulation of their expression is
expected to affect susceptibility to, and severity of,
inflammatory diseases, such as OLP. Consistent with
this expectation, multiple studies have shown associa-
tions with certain sequence variations (functional
polymorphisms) in the regulatory regions of cytokine
genes implicated in OLP, particularly the Th1 cytokines
TNF-a,25,40-42 IFN-g,25,43,44 IL-12,45 and IL-18.31 A
positive correlation between certain polymorphisms
and the levels of cytokine production in OLP has
been shown for IL-18.31 The details of specific
polymorphisms vary somewhat with study populations.
Chemokines. Identified chemoattractants (chemo-
kines), the major function of which is to regulate cell
migration, also support a Th1 profile in OLP. In
contrast to myeloid DC and mast cells, as mentioned
above, a-b T cells, NK cells, and plasmacytoid DC are
not normal residents of the oral mucosa. Depending on
conditions, mucosal resident myeloid DC differentially
express either Th1-recruiting CXCL9, 10, and 11, or
Th2-recruiting chemokines.46 In OLP lesions
(including the epithelium) and in peripheral blood,
CXCL9, CXCL10, and several general inflammation-
associated chemokines have been identified.47
ORAL AND MAXILLOFACIAL PATHOLOGY
76 Kurago
Moreover, CD8þ T cells in OLP were found to express
the appropriate chemokine receptors CXCR3 and
CCR5 and produce their own CXCL10, possibly
leading to self-recruitment.48 In the vast majority of
OLP cases analyzed, NK cells in OLP lesions were
mainly in the lamina propria and, in contrast to
T cells, expressed ChemR23, a receptor for the
chemoattractant chemerin produced by the endothelial
cells of the mucosal vessels.12 Altogether, the
chemokine and chemokine receptor profiles in OLP
are consistent with a type 1 immune response.
During any inflammatory response, other factors are
induced as well. Among them are reactive oxygen
species that are important for antimicrobial activities
but also capable of inducing DNA damage. Some are
enzymes that contribute to matrix degradation (matrix
metalloproteinases), which facilitates cell migration and
removal of debris. Some are growth factors that regu-
late the proliferation and differentiation of cells. Such
factors are common in various inflammatory settings,
including OLP.
OLP immunopathogenesis and response to treat-
ment. Following are a few points regarding response to
treatment that speak to the immunopathogenesis of
OLP. The most widely used treatment for OLP is
immunosuppression with topical or systemic cortico-
steroids. Corticosteroids are effective because they
inhibit the activation of DC and T cells, secretion of
Th1 cytokines,49,50 as well as stimulate Th2 cytokine
IL-10 that also acts to interfere with Th1 cytokine
activities.51 However, not all OLP cases respond to
corticosteroids. Provided that the diagnosis of OLP is
accurate and no other complicating condition is
present, some patients with OLP may be resistant to
steroids. This phenomenon is also seen in other
noninfectious inflammatory conditions (inflammatory
bowel disease, rheumatoid arthritis, asthma, etc.).49,52
Resistance to steroids has a genetic basis, illustrated,
in part, by the wide variation in lymphocyte sensitivity
to steroids even in healthy individuals.52-54 With
functional polymorphisms in genes that encode
inflammatory mediators being responsible for disease
severity, additional polymorphisms in glucocorticoid
response pathways may further affect treatment options.
For example, a specific polymorphism in the regulatory
sequence of the TNF-a gene is well known for
imparting steroid resistance in several systemic in-
flammatory disorders.49
In cases of steroid resistance, calcineurin inhibitors
are often useful because they target T-cell activation
and proliferation directly. Other options include bi-
ologics, which can target individual cytokines or their
receptors.55 The best known target is TNF-a activity
(the cytokine or its receptor), although in OLP anti-
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July 2016
TNF-a biologics have not seen wide application.55
Studies comparing the effects of various treatments
for erosive OLP have been reviewed recently.56
OLP PATHOGENESIS AND POTENTIAL FOR
ORAL SQUAMOUS CELL CARCINOMA
There are numerous publications focused on OLP as a
possible precursor to squamous cell carcinoma (SCC),
some of which are listed here.26,57-63 So far, this question
remains unresolved for a variety of reasons, including
inconsistent application of diagnostic criteria, insufficient
documentation of all relevant information, incomplete
long-term follow-up, and lack of appropriate control
populations. These limitations most likely contribute to
the highly variable rates of oral SCC reported in patients
with OLP (0.4%e12.5%).26,57-63
For the purposes of this overview, the issue of
carcinogenesis in the context of OLP is of some rele-
vance because longstanding chronic inflammation in
some conditions is associated with increased risk of
cancer. For example, chronic noninfectious inflamma-
tory bowel diseases (IBD), that is, ulcerative colitis and
Crohn disease, are associated with risk of colorectal
adenocarcinoma. This risk increases over time,
depending on the population studied, from 1% or less at
10 years to much higher chances at 30 years.64
Although there is some overlap in the
immunopathologic mechanisms of IBD and OLP,
there are also significant differences between them,
between the oral mucosa and the intestinal mucosa,
and between the carcinoma types, so much remains to
be learned. One unifying feature is that certain aspects
of chronic inflammation at the mucosal surfaces
stimulate healing and repair and improve cell survival
while promoting proliferation, which make cells more
vulnerable to mutagenesis. Mutagenesis may be
induced by exogenous (e.g., chemical carcinogens) or
endogenous (e.g., reactive oxygen species) triggers.
How T-cell-mediated keratinocyte death in OLP
factors into the potential scenario is not clear.
Cytotoxicity aside, in OLP patients, it is theoretically
possible that certain genetic predispositions combined
with longstanding chronic activation of key
inflammation-related prosurvival factors make the
multistep process of initiation and progression of
carcinogenesis easier. In other words, the triggers of
mutagenesis (whether endogenous and/or exogenous)
in progenitor epithelial cells under such conditions are
less likely to kill the cells and more likely to lead to
malignant transformation. If this, indeed, is true in
OLP, then controlling inflammation should be impor-
tant for the prevention of chronic inflammation-related
carcinogenesis. With accumulating knowledge about
how various immunoregulatory drugs affect
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Volume 122, Number 1
inflammation and cancer risk, it will be possible to
make better decisions about management of patients
with chronic inflammatory conditions.
OLP ASSOCIATIONS WITH
MICROORGANISMS AND OTHER DISORDERS
Viral infections
A number of potential associations between specific
viral infections and OLP have been investigated,
including cytomegalovirus, herpes simplex virus-1,
human herpesvirus-6, Epstein-Barr virus, hepatitis B
virus, and human papillomavirus, without revealing
significant correlations.65 Currently, there is convincing
evidence that, at least in some geographic regions, OLP
is associated with hepatitis C virus (HCV) infection.
The HCVeOLP association is likely related to the
propensity for several other common extrahepatic
effects of HCV infection, such as cryoglobulinemia
and several autoimmune disorders.66 Analysis of eight
qualified studies revealed a significantly higher
probability of circulating anti-HCV antibodies or
HCV RNA in patients with OLP (with or without skin
lesions), with an overall odds ratio (OR) of 5.71 (95%
confidence interval [CI] 3.48e9.37).67 Similar results
were reported in Chinese studies68 (OR 5.4; 95% CI
3.5e8.3). Seropositivity for anti-HCV antibodies is
believed to represent an active infection, as 75% to 85%
of seropositive individuals have persistent chronic in-
fections. The same systematic review67 found
geographic regional differences: a strong HCVeOLP
association in Mediterranean populations (OR 6.63;
95% CI 4.68e9.40), in contrast to Northern European
studies (OR 2.14; 95% CI 0.59e7.69). Two studies
also supported the opposite: HCV patients are more
likely to develop OLP (OR 2.5; 95% CI 2.0e3.168
and OR 4.47; 95% CI 1.84e10.86,67 respectively).
HCVeOLP associations were also suggested in Japan
and the United States, but not in Ethiopia or Egypt,69
although some of the studies were quite small. There
is still ongoing debate regarding the impact of specific
HCV genotypes on the likelihood and strength of the
OLPeHCV association. The geographic variation in
the HCVeOLP association could be attributed to
population genetics, environmental factors, or even
HCV genotype, and so far, answers to these questions
have not been found.67,69
The mechanisms of OLP development in patients with
HCV are not clear. No effect of HCV genotype or viral
load on OLP prevalence was identified,70,71 and detec-
tion of HCV in OLP lesions is controversial. Moreover,
HCV lacks tropism for cells other than hepatocytes, as it
requires liver-specific miR122 for replication.72 The
immune response to HCV infection is mainly type 1,
that is, dominated by IFNs, TNF-a, and cytotoxicity
mediated by CD8þ T cells, with high levels of
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Kurago 77
circulating IFN-g and CXCL10,66 and there are several
extrahepatic complications of HCV associated with a
type 1 immune response. In this context, OLP lesions
fit the profile, but the relationship between OLP and
other extrahepatic HCV-associated disorders is unclear.
Bacteria
Apart from the studies on Helicobacter pylori, for which
no association with OLP has been found,65 bacterial
studies are in early stages. Microorganisms may be
triggers or could be responsible for sustaining or
exacerbating the chronic course of OLP. Significant
differences in bacteria were identified by 16S rRNA
sequencing in the saliva of patients with erosive OLP
versus patients with reticular OLP versus normal
controls.36 Of interest are observations that
Fusobacteria and Campylobacter were significantly
increased, whereas Porphyromonas were decreased in
saliva of patients with erosive OLP relative to normal
controls.36 Relevant to microbial colonization and OLP
pathogenesis are studies of toll-like receptors (TLRs), a
subset of pattern recognition receptors for microbial
molecules. TLR expression in saliva and in OLP biopsy
samples was reportedly different from those in normal
controls.73-77 Removal of plaque and calculus improved
the management of patients with gingival OLP,65 as did
the use of antimicrobial rinses (personal clinical
experience), suggesting that bacteria may contribute to
OLP-associated inflammation. Together, microbial and
pattern recognition receptor studies have the potential to
greatly improve our understanding of OLP, its subtypes,
and the relationship with other inflammatory disorders.
OLP AND OTHER SYSTEMIC DISORDERS
Ideally, multicenter studies with inclusion of relevant
controls are needed to obtain sufficient data for this type
of analysis. There are reports of association of OLP and
cutaneous LP with several autoimmune disorders (sys-
temic lupus erythematosus, Sjögren syndrome, and
others), which lack documentation of criteria used to
diagnose OLP. Unfortunately, careful studies of asso-
ciations between OLP and other noninfectious systemic
conditions that uniformly apply consistent diagnostic
criteria for OLP using both clinical and histopathologic
evaluations are rare. Without this approach, other ul-
cerative and red/white oral mucosal lesions can
complicate the results. Moreover, many studies do not
separate OLP from cutaneous LP.
With that said, several studies suggest a possible
association between OLP and thyroid disease. Among
thyroid disorders, Hashimoto thyroiditis (HT)78 and
hypothyroidism79 were identified. According to the
report of 15 cases in Italy,78 HT in OLP patients was
significantly more common (w14%) than HT-related
ORAL AND MAXILLOFACIAL PATHOLOGY
78 Kurago
hypothyroidism in the general population (w1%).
Further, HT preceded the onset of reticular OLP in 93%
of the study group. The diagnosis of OLP in all patients
was based on defined clinical and histopathologic
criteria.80 Another study79 of 152 OLP cases diagnosed
using the same criteria,80 patients with hypothyroidism
were approximately twofold more likely to present with
OLP compared with individuals without
hypothyroidism. The reticular form of OLP was the
most common type. There was no evidence in this
study that thyroxine treatment had an impact on the
oral lesions. The mechanisms that could explain the
described associations are not known.
Evidence for other OLP associations is difficult to
confirm for reasons stated earlier. This difficulty is
illustrated in reports that describe a possible link between
OLP and Good syndrome. Good syndrome is a rare
condition consisting of thymoma with an adult-onset
immunodeficiency, which is characterized by hypo-
gammaglobulinemia, low or absent B cells, and variable
defects in cell-mediated immunity that involves CD4þ
T cells.81 Thymoma without immunodeficiency is
associated with several autoimmune conditions,
including myasthenia gravis, pure red cell aplasia,
systemic lupus erythematosus, polymyositis.82 Because
of humoral and cell-mediated immunodeficiency,
patients with Good syndrome also have a variety of viral,
bacterial, and fungal infections of the upper respiratory,
gastrointestinal, and urinary tracts, as well as infections
of the skin, joints, bone, and the central nervous sys-
tem.82 Most reported cases of OLP associated with Good
syndrome83-85 are based on loose application of clinical
features only. In view of known coexistence of multiple
infections and autoimmune disorders in patients with
Good syndrome, oral mucositis from causes other than
OLP is a distinct possibility. Maehara et al. described
two cases of oral mucositis in the context of Good
syndrome and apparently found differences in several
immunologic parameters of the oral mucosal lesions
relative to those in seven OLP samples.86 An important
limitation of this study is that the clinical and
histopathologic criteria used for diagnosis were not
provided. Moreover, the photomicrographs depicting
examples of immunohistochemistry are of very low
resolution. Altogether, the link between OLP and Good
syndrome is not supported by the available evidence.
CONCLUSIONS
In summary, mucosal damage in erosive and reticular
OLP is largely caused by a type 1 immune response that
involves myeloid and plasmacytoid DC, CD4þ and
CD8þ T cells, NK cells, and mast cells, without
apparent contributions by B lymphocytes, plasma cells,
or antibodies. The dominant cytokines and chemokines
are consistent with a Th1 profile. In erosive OLP, Th17
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July 2016
profile appears to be another contributing factor. Patient
responses to treatment with corticosteroids and calci-
neurin inhibitors further support the role of T cells and
Th1 factors in OLP immunopathogenesis. Based on
available data summarized above, destruction of
keratinocytes in OLP could occur as a result of auto-
reactivity or as a bystander effect. There is a signifi-
cant association between OLP and HCV infection in
some geographic regions. The role of oral microflora in
OLP pathogenesis remains to be determined. How the
potential association between OLP and thyroid disor-
ders may factor into the immunopathogenesis of OLP is
not clear. To further advance our understanding of this
disorder, there is a need for more studies that use well-
documented OLP cases diagnosed with consistent
clinical and pathologic criteria and include appropriate
controls.
The author thanks Dr. Y.-S. Lisa Cheng, DDS, PhD, for her
valuable input.
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Reprint requests:
Zoya B. Kurago, DDS, PhD
Dental College of Georgia
Medical College of Georgia
Georgia Cancer Center
1430 JW Gilbert Dr.
Augusta, GA 30912
USA
ZKURAGO@gru.edu; zkurago@augusta.edu