Japanese Dental Science Review (2018) 54, 59—65

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Japanese Dental Science Review

journal homepage: www.elsevier.com/locate/jdsr

Review Article

Histological and immunological

characteristics of the junctional epithelium
Masanori Nakamura ∗

Department of Oral Anatomy and Developmental Biology, Showa University School of Dentistry, 1-5-8
Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

Received 6 June 2017; received in revised form 23 October 2017; accepted 14 November 2017

KEYWORDS Summary The continuity of epithelial tissue is collapsed by tooth eruption. The junctional
The junctional epithelium (JE) is attached to the tooth surface by hemidesmosomes, which constitutes the
epithelium; front-line defense against periodontal bacterial infection. JE constitutively expresses inter-
Intraepithelial cellular adhesion molecule-1 (ICAM-1), and neutrophils and lymphocytes penetrate into JE via
lymphocytes; interaction between ICAM-1 and LFA-1 expressed on the surface of these migrating cells. JE
ICAM-1; also expresses cytokines and chemokines. These functions of JE are maintained even in germ-
Cytokines; free condition. Therefore, the constitutive expression of adhesion molecules, cytokines, and
Chemokines; chemokines might be used not only for anti-pathogenic defense but also for maintaining the
Enamel organ physiological homeostasis of JE. In this review, we have mainly focused on the structural and
functional features of JE, and discussed the function of intraepithelial lymphocytes in JE as a
front-line anti-microbial defense barrier and regulator of JE hemostasis.
© 2017 The Author. Published by Elsevier Ltd. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

1. Introduction ............................................................................................................... 60
2. Structure of the JE ........................................................................................................ 61
3. Origin of the JE............................................................................................................61
4. Functional specificity of the JE ............................................................................................ 61
5. Role of commensal microflora ............................................................................................. 62
6. Intraepithelial cells in the JE .............................................................................................. 62

∗ Corresponding author.
E-mail address: masanaka@dent.showa-u.ac.jp

https://doi.org/10.1016/j.jdsr.2017.11.004
1882-7616/© 2017 The Author. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
60 M. Nakamura

7. The expected function of IELs in the JE....................................................................................63

8. Conclusion.................................................................................................................63
Conflicts of interest........................................................................................................63
Acknowledgment .......................................................................................................... 63
References ................................................................................................................ 63

1. Introduction

Epithelial tissues form junctional complexes to maintain

a continuous demarcation against the external environ-
ment and prevent the invasion of foreign substances inside
the living body. Tooth eruption collapses the continuity of
epithelial tissue in the oral cavity. Erupted teeth are sur-
rounded by the gingival epithelium, which is one of the most
specialized tissues of the body because the discontinuity of
the gingival epithelial sheath renders it susceptible to bac-
terial infection from dental plaques and periodontal disease
[1—3].
The gingival epithelium consists of the oral gingival
epithelium (OGE), oral sulcular epithelium (OSE), and junc-
tional epithelium (JE) (Fig. 1A, B). Among them, the JE
attaches to the tooth surface via hemidesmosomes, which
forms the front-line of defense against periodontal bacte-
rial infection [4,5]. In rodents, the JE is clearly distinguished
from OSE (Fig. 2). The JE originates from the enamel organ
and constructs the gingival epithelium along with OGE and
OSE, which are derived from the oral epithelium [6,7].
The OGE and OSE are keratinized squamous epithelial cells
with narrow intercellular space [8,9]. On the contrary, the
JE is non-keratinized epithelium and has wide intercellu-
lar space (Fig. 3A, B). In addition, many migrating cells
such as polymorphonuclear cells (PMNs) and lymphocytes are
located within JE [10—15] (Fig. 3A, B). The JE shows rapid
turnover, which might contribute to its defense against den-
tal plaque [16,17]. The structure of the gingival epithelium

Figure 2 Mouse gingiva. The JE is clearly distinguished from

OSE. Many migrating cells (arrows) are detected in the JE.
Bar = 50 ␮m.

Figure 3 Ultrastructure of the JE showing wide intercellular

Figure 1 Human gingiva. A: Inner gingival epithelium consists
space. Neutrophil (A) and lymphocyte are migrating within the
of OSE and JE. Bar = 250 ␮m. B: Higher magnification of the JE.
JE. Bars = 10 ␮m.
Bar = 100 ␮m.
Characteristics of the junctional epithelium 61

is maintained by the coordination of epithelial tissues of two

different origins. Therefore, the structure, origin, and func-
tion of the JE at the dento-gingival junction have been the
subject of interest and controversy.

2. Structure of the JE

JE is classified as non-keratinized stratified squamous

epithelium. Intercellular junctions formed in JE are rela-
tively loose and contain only few desmosomes, adherens
junctions, and gap junctions, which allow tissue exudate and
inflammatory cells to penetrate toward the gingival sulcus
[1,4,5,18—20].
JE has a true basement membrane towards the connec-
tive tissue of gingiva (called the external basal lamina, Figure 4 Immunohistichemical localization of ICAM-1 in the
EBL) and a simple ECM (called the internal basal lamina, JE of labial side (A) and intertooth area (B) of a germ-free-
IBL) against the enamel [21] (Fig. 3A, B). The EBL contains mouse. Intensive immunoreactions are detected at the JE. B:
structures that are identical to those of a typical basement The JE between the two molars. Endothelial cells beneath the
membrane, with the lamina lucida against the basal ker- JE also expressed ICAM-1. Bars = 80 ␮m.
atinocytes and the lamina densa towards the underlying
connective tissue. The protein composition of the IBL dif-
fers significantly from that of a typical basement membrane.
The IBL does not contain any typical basement membrane- and experimental animal gingiva [37—39]. The expression of
forming proteins such as laminin 111, laminin 511, type IV ICAM-1 is constitutively maintained even in the JE of germ-
and VII collagens, and perlecan [22]. The main cell adhe- free mouse [36].
sion protein identified so far in the IBL is laminin 332 Studies demonstrated that keratinocytic ICAM-1 expres-
[22—24]. Furthermore, reports show the presence of type sion in dermatological disease is localized precisely in the
VIII collagen and versican at the JE-tooth interface [25,26]. lymphocyte infiltration site of the epithelium. Keratinocytes
These proteins were not detected in other typical basement do not express ICAM-1 after recovery from disease [40—42].
membranes. These findings indicate the uniqueness of JE These results indicate that the expression of ICAM-1 is reg-
and provide important information regarding the biologi- ulated by pro-inflammatory cytokines such as interluekin-1
cal relationship between dental implants and the gingival (IL-1) and tumor necrosis factor-␣ (TNF-␣) [43—46]. There-
epithelium to establish the effective interface. fore, regulation of ICAM-1 expression and differences in
In general, epithelial cells form basement membranes for ICAM-1 levels in JE might be regulated not only by bacteria-
survival in cell culture systems [27—30]. However, detailed derived LPS, which stimulates macrophages to produce
studies regarding the protein composition of basement cytokines [46], but also by intrinsic factors. In fact, JE con-
membrane are lacking. Therefore, an extensive study of the stitutively express IL-1␤, which regulates the expression of
protein composition of epithelial cell basement membranes ICAM-1 in JE [36,47].
in culture might clarify the structure and function of the JE During tooth development, the inner enamel epithe-
basement membrane. lium differentiates into the secretary, transitional, mature,
and reduced stages of ameloblasts, and the stratum inter-
medium, adjacent to the secretary stage of ameloblasts,
3. Origin of the JE
differentiates into the papillary layer [48,49]. ICAM-1
expression is initiated during the formation of the papil-
The structure and the function of the JE are influenced by lary layer (Fig. 5A, B). However, all stages of ameloblasts do
the underlying connective tissue and by contact with a solid not express ICAM-1. The papillary layer adheres to the oral
substratum, such as enamel, dentin or cementum, the exact epithelial tissue during tooth eruption. These results indi-
mechanisms that lead to the formation and regeneration of cate that the JE might have originated from papillary layer
the JE remain unclear. Common notion posits that during cells and not the reduced ameloblasts. ICAM-1 expression
tooth development, the primary JE is formed by the fusion may be regulated by certain autocrine or paracrine factors
of the reduced enamel organ, which is replaced in time by a regulating cell death of ameloblasts at the transition stage.
secondary JE derived solely from cells of the OE [31—35]. Although IL-1␤ might be the key molecule for ICAM-1 expres-
The reduced enamel epithelium is composed of reduced sion [43—46], further studies are required to clarify the
ameloblasts and papillary cells located at the side of the mechanism of ICAM-1 expression during tooth development.
connective tissue. The histological analysis clearly distin-
guishes OSE from the JE. The function of JE is also entirely
different from OSE. Therefore, is might be reasonable that 4. Functional specificity of the JE
the JE is derived from the reduced enamel epithelium.
We previously demonstrated that the constitutive expres- The JE has several specific functions that differ from those of
sion of ICAM-1 in the gingival epithelium is restricted in the other oral epithelium. JE expresses defensive factors such as
JE of erupted molar teeth of mouse [36] (Fig. 4A, B). The ␤-defensins, secretory leukocyte protease inhibitor (SLPI),
expression of ICAM-1 in the JE was also reported in human and S100A8 against inflammation [50—52]. ␤-Defensins are
62 M. Nakamura

of the immune system and its appropriate functioning. An

interaction between commensal bacteria and the innate
defense system of the periodontal tissue has also been
reported [62]. Hayashi et al. observed the increased expres-
sion of SLPI in the JE compared to that in oral gingival
epithelium [50]. The expression of SLPI is regulated by a
cross-talk between epithelial cells and neutrophils. Thus,
Figure 5 Immunohistochemical localization of ICAM-1 during the constitutive expression of these factors and the migra-
the tooth development. A: ICAM-1 is not detected at the stratum tion of neutrophils in the JE might be induced by intrinsic
intermedium adjacent to the secretoru stage of ameloblasts and genetic regulation rather than by bacterial infection for the
expresses form the transition stage of ameloblasts at the pap- maintenance of the functional specificity of the JE.
illary layer. B: The papillary layer cells highly express ICAM-1 Histological examination indicated an increase in the
at the maturation and the reduced stages of ameloblasts. SI: JE area in conventional mice [47]. Immunohistochemistry
stratum intemedium, SA: secretory stage of ameloblast, TA: also indicated an increase in the number of PCNA-positive
transition stage of ameloblast, PL: papillary layer, MA: matu- epithelial cells within the JE upon bacterial infection
ration stage of ameloblast. Bars = 30 ␮m. [47]. Furthermore, the number of neutrophils and the
expression of chemokines (KC and MIP-2) in the junctional
epithelium are significantly higher in conventionalized mice
than in germ-free mice [47]. Tsukamoto et al. evaluated
small cationic peptides that contribute to innate host
the relationship between epithelial cell proliferation and
defense against bacterial challenge [50,52]. SLPI protects
inflammation in clinically healthy and inflamed human gin-
the intestinal epithelium from proteases secreted as part of
gival tissue and found that epithelial cell proliferation and
the inflammatory response and is associated with the main-
epithelial thickness were associated with gingival inflamma-
tenance of tissue integrity [53]. S100A8 and S100A9 form
tion [63]. Similarly, chemokines were induced by bacterial
a heterodimeric complex and constitute calprotectin, an
lipopolysaccharide [64,65]. Thus, commensal bacteria might
antimicrobial peptide [54].
be important for up-regulating the physiological barrier
The JE constitutively produces chemokines and
function of the JE.
cytokines, such as keratinocyte-derived chemokine (KC),
macrophage inflammatory protein-2 (MIP-2), and IL-1␤ in
conventional and germ-free mice [47]. KC and MIP-2 are 6. Intraepithelial cells in the JE
potent chemoattractants for neutrophils. The expression of
these chemokines is up-regulated by bacterial stimulation.
Intraepithelial cells (IELs) are lymphocytes located within
The JE also constitutively express follicular dendritic
the epithelial layer of mucosal tissues such as the gastroin-
cell-secreted protein (FDC-SP) and odontogenic ameloblast-
testinal and reproductive tract. IELs were localized in the
associated protein (ODAM) [55—57]. The genes encoding
middle layer of the JE as indicated by mucosa associated
FDC-SP and odontogenic ameloblast-associated protein
lymphoid tissue (MALT) [66]. IELs are characterized by the
appose at the gene cluster for secretory calcium-binding
presence of higher numbers of TCR␥␦+ lymphocytes than
phosphoproteins [58,59]. Secretory calcium-binding phos-
those in the systemic immune organs such as the spleen and
phoproteins interact with several bioactive molecules to
lymph nodes [67].
regulate cell adhesion, migration, proliferation, and tumori-
The vast majority of TCR␥␦+ IELs expresses CD8␣␣, but
genesis [60,61]. Furthermore, the gene encoding FDC-SP
a small proportion lacks CD8␣ and CD8␤, which is obvi-
lies adjacent to the cluster of genes encoding C—X—C
ously different from the TCR␥␦+ T cells located in lymphoid
chemokines [58]. These results suggest a close association
tissues, which show no CD8 expression [68,69]. The TCR
between the expression of pro-inflammatory cytokines and
repertoires of IELs in each mucosal tissue were restricted
chemokines and the expression of FDC-SP and odontogenic
by the in situ microbial colonizations in the tissue [70]. In
ameloblast-associated protein.
humans, the ␥␦ TCRs expressed by IELs predominantly use
Histological and immunohistological investigation indi-
the V␥1 gene and V␦1, whereas in mice, V␥5 T cells are
cates massive infiltration of lymphocyte function-associated
enriched in the intraepithelial tissues of the gut [71,72].
antigen-1 (LFA-1)-positive PMNs and lymphocytes in the JE
Non-classical molecules such as the thymus leukemia
[36,37]. The interaction of LFA-1 and ICAM-1 plays a key
antigen or the major histocompatibility complex (MHC) class
role in the migration of these cells in JE. Endothelial cells
I-like molecules are candidate ligands for TCR␥␦. TCR␥␦+ T
and fibroblasts underlying the JE also express ICAM-1, which
cells, including IELs, may be involved in a totally distinct
might provide a pathway for granulocytic and lymphocytic
type of host defense, whereas TCR␣␤-positive T cells, a
migration into JE.
major population in peripheral lymphoid organs, elicit the
MHC class II-restricted or MHC class I-restricted immune
5. Role of commensal microflora responses [73,74].
The TCR␥␦+ lymphocytes play an important role in the
All the factors mentioned above are up-regulated in con- defense mechanism as a front-line competent cell popula-
ventional conditions [47]. The commensal microflora plays tion. IELs are frequently exposed to a number of microbial
a critical role in the postnatal development of the system, antigens and might be cytotoxic against infected epithelial
as the physiological inflammatory response in the gut during cells [73,74]. IELs have also been suggested to be involved in
early postnatal ontogenesis is essential for the development graft-versus-host diseases and abrogation of oral tolerance
Characteristics of the junctional epithelium 63

always located under the OSE, while the tips of the JE are
guided to a position higher than the OSE by CsA treatment
(Fig. 6A, B). which indicate that the cytotoxic activity of IELs
expressing TCR␥␦ might be inhibited by CsA. These results
suggest that IELs in the JE regulate epithelial cell survival for
maintaining barrier function against bacterial stimulation
similar to that in the gastrointestinal tract. The inhibition of
rapid turnover of JE might decrease the survival activity and
the barrier function of JE, and permit the easy penetration
of bacterial LPS into the gingival connective tissue.

8. Conclusion

The JE is the only discontinuous epithelial tissue in the

Figure 6 The effect of cyclosporine A on the JE. Mice are body. The JE functions as a front-line barrier against for-
intraperioneally injected with cyclosporine A (25 mg/kg) for 21 eign antigens with structural and functional features such
days. A: Normal JE. The tip of the JE (arrow) is lower than the as adhesion to tooth surface via formation of basal lamina,
OSE. B: By cyclosporine A treatment, the JE elongated and the large intercellular space, expression of several cytokines
tip of the JE (arrow) reaches almost to the same level with the and chemokines, and the penetration of neutrophils and
OSE. Bars = 50 ␮m. lymphocytes to play as the front-line innate immune system
and to maintain the JE homeostasis. Further understand-
ing of the structure and function of the JE would provide
better understanding of systemic host defense system and
[75,76]. In contrast, IELs produce growth factors to regulate
specificity of the oral mucosal tissue.
the epithelial cell proliferation [77—79].
IELs in the JE express TCR␥␦ and CD3 in conventional
and germ-free mice [36,47]. The existence of TCR␥␦ T cells Conflicts of interest
in the JE was also reported in humans [80]. Furthermore,
TCR␣␤-expressing T cells and B cells could not be detected in
The author declare that no competing financial interests
the JE, whereas in other mucosal epithelial tissues, TCR␣␤-
exist.
positive T cells constituted the main population of IELs
[73,81]. These results suggest that the JE might be a spe-
cialized mucosal tissue in the body. The identification of TCR Acknowledgment
repertoires might be the next step for clarifying the exact
function and IEL antigens in JE. This study was partially supported by the Grants-in Aid for
Scientific Research (24592777, 15K11022) from the Ministry
7. The expected function of IELs in the JE of Education, Culture, Sports, Science and Technology of
Japan.
Previous studies from our and other laboratories indicated
that IELs in the duodenum and jejunum induced entero-
cyte apoptosis within 30 min after activation by anti-CD3␧
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