Article

Making sense of the epithelial barrier: What molecular biology and genetics tell us about the functions of oral mucosal and epidermal tissues

Department of Oral Biology, School of Dentistry, University of Washington, Seattle 98195-7132, USA.
Journal of dental education (Impact Factor: 0.97). 05/2002; 66(4):564-74.
Source: PubMed

ABSTRACT

The epidermis of skin and the oral mucosa are highly specialized stratified epithelia that function to protect the body from physical and chemical damage, infection, dehydration, and heat loss. To maintain this critical barrier, epithelial tissues undergo constant renewal and repair. Epithelial cells (keratinocytes) undergo a program of terminal differentiation, expressing a set of structural proteins, keratins, which assemble into filaments and function to maintain cell and tissue integrity. Two types of cell adhesion structures, desmosomes and hemidesmosomes, function to glue keratinocytes to one another and to the basement membrane, and connect the keratin cytoskeleton to the cell surface. Keratinizing epithelia such as the epidermis and oral gingiva that have to withstand severe physical and chemical forces produce a toughened structure, the cornified cell envelope. This envelope is a major component of the epithelial barrier at the tissue surface. This article summarizes our current understanding of the structure and function of these different cellular components and discusses various genetic and acquired diseases that alter tissue integrity and barrier function. We also highlight recent work demonstrating how loss or attenuation of certain proteases can lead to early onset periodontitis and tooth loss as well as other epithelial abnormalities.

Full-text

Available from: Richard Jurevic
564 Journal of Dental Education Volume 66, No. 4
Transfer of Advances in Sciences into Dental Education
Making Sense of the Epithelial Barrier:
What Molecular Biology and Genetics Tell
Us About the Functions of Oral Mucosal
and Epidermal Tissues
Richard B. Presland, Ph.D.; Richard J. Jurevic, D.D.S.
Abstract: The epidermis of skin and the oral mucosa are highly specialized stratified epithelia that function to protect the body
from physical and chemical damage, infection, dehydration, and heat loss. To maintain this critical barrier, epithelial tissues
undergo constant renewal and repair. Epithelial cells (keratinocytes) undergo a program of terminal differentiation, expressing a
set of structural proteins, keratins, which assemble into filaments and function to maintain cell and tissue integrity. Two types of
cell adhesion structures, desmosomes and hemidesmosomes, function to glue keratinocytes to one another and to the basement
membrane, and connect the keratin cytoskeleton to the cell surface. Keratinizing epithelia such as the epidermis and oral gingiva
that have to withstand severe physical and chemical forces produce a toughened structure, the cornified cell envelope. This
envelope is a major component of the epithelial barrier at the tissue surface. This article summarizes our current understanding of
the structure and function of these different cellular components and discusses various genetic and acquired diseases that alter
tissue integrity and barrier function. We also highlight recent work demonstrating how loss or attenuation of certain proteases can
lead to early onset periodontitis and tooth loss as well as other epithelial abnormalities.
Dr. Presland is Research Associate Professor in the Department of Oral Biology, School of Dentistry and the Division of
Dermatology, Department of Medicine; Dr. Jurevic is a graduate student in the Department of Oral Biology and the Division
of Oral Medicine, School of Dentistry, both at the University of Washington. Direct correspondence and requests for reprints
to Dr. Richard B. Presland, Department of Oral Biology, Box 357132, University of Washington, Seattle, WA 98195-7132;
206-685-3162 fax; rp@u.washington.edu.
Key words: oral mucosa, epidermis, keratin, epithelial barrier, genetic disease
Submitted for publication 1/3/02; accepted 2/6/02
Abbreviations used: CE, cornified envelope; IF, intermediate filament; EB, epidermolysis bullosa; PV, pemphigus vulgaris;
PF, pemphigus foliaceus; BMZ, basement membrane zone; kDa, kilodalton; SPRR, small proline-rich protein
E
pithelial tissues form a barrier between the
body and the environment. Depending on lo-
cation, they perform various functions, but
always serve to protect the internal tissues from en-
vironmental stresses, chemical damage, and bacte-
rial infection, whether the tissue is in the gut or on
the body surface. The stratified epithelia of the skin
and oral mucosa are examples of the toughest and
most protective epithelia. The evolution of these
structures and related appendages (for example,
feathers and scales in birds and reptiles, hair and nails
in mammals) played an important role in the coloni-
zation of land by vertebrates. Stratified epithelia such
as the epidermis and the gingival and hard palate tis-
sue of the oral cavity are examples of keratinized or
cornified epithelia (Figure 1). These tissues undergo
a program of terminal differentiation, and the result-
ing cornified (dead) cells or squames are filled with
keratin protein and lack nuclei and other organelles.
Surrounding each cornified cell is a cornified enve-
lope (CE) composed of crosslinked proteins and lip-
ids that replaces the plasma membrane and forms a
critical part of the epithelial barrier.
1,2
Stratified non-
keratinized epithelia include the buccal and soft pal-
ate tissue of the oral cavity, the esophagus, and
anogenital tract; these tissues do not have to with-
stand the same degree of mechanical trauma and are
non-keratinized (Figure 1). Simple epithelia such as
the epithelial cells that surround the liver and kidney
and line the gut are single layered or “non-stratified”
epithelia that have specialized secretory or absorp-
tive functions.
2,3
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April 2002 Journal of Dental Education 565
In the past decade there has been considerable
progress in our understanding of how epithelial tis-
sues are organized and function and how their for-
mation is choreographed during embryonic devel-
opment. Much of this knowledge is derived from the
study of both genetically inherited and acquired—
for example, autoimmune—diseases that affect the
development and function of epithelia. Modern mo-
lecular biology and genetic tools have also enabled
the function of individual genes to be examined us-
ing model organisms such as the mouse, fruit fly,
and worm through the use of gene disruption (knock-
out) and other genetic approaches. Using such mo-
lecular approaches, it has become clear that many of
the structural proteins produced by cornified epithe-
lia are essential for tissue integrity. In addition, many
regulatory molecules such as growth factors and tran-
scription factors are important for the normal devel-
opment and function of these tissues.
In this review we will focus on stratified epi-
thelia and discuss a number of different structural
proteins that both function to maintain cell and tis-
sue integrity and are required to form and maintain
the protective epithelial barrier. Further, we briefly
discuss some new findings that show the importance
of proteases and protein catabolism (turnover) in the
development and maintenance of epithelial tissues
in mammals.
Structural Proteins of
Stratified Epithelia and the
Dermal-Epidermal Junction
Keratins
Keratins are a family of related proteins that
are the predominant cytoskeletal proteins in all epi-
thelia. They are cytoplasmic proteins that belong to
the intermediate filament (IF) superfamily of struc-
tural proteins.
2,4
Keratins are divided into two fami-
lies (type I and type II) that differ in amino acid se-
quence and biochemical properties. They are
expressed in epithelial cells in pairs consisting of one
type I and one type II that self-assemble to form a
three-dimensional array of filaments that extend from
the nucleus to the cell membrane. These filaments
function as stress-bearing structures within epithe-
lial cells and are critical for the maintenance of cell
shape and viability. In the absence of a suitable kera-
tin partner, keratin protein molecules are unstable and
susceptible to degradation by protein degrading en-
zymes (proteases).
Keratin Expression Varies in a Tissue and
Cell Type-Specific Manner. In stratified squamous
epithelia such as the epidermis and oral mucosa,
keratins are frequently the most abundant cellular
proteins. Keratin filaments are attached to the cell
surface via specialized cell adhesion junctions termed
desmosomes that also function to glue cells to one
another (see the section on desmosomes below). Epi-
thelial tissues express different pairs of keratin pro-
teins depending on epithelial cell type and stage of
differentiation (Figure 1). Thus, most stratified epi-
thelia express the keratin pair keratin 5/keratin 14 (K5/
K14) in the proliferative basal layer that lies adjacent
to the basement membrane; this layer is normally the
only mitotic cell layer. Thus, stratified epithelial tis-
sues like the epidermis are continually being sloughed
from the surface and replaced by new cells derived
from the proliferative basal cell compartment where
the pluripotent stem cells are believed to reside.
5
The subsequent (suprabasal) cell layers are nor-
mally post-mitotic and undergo a program of differ-
entiation, expressing different pairs of keratin proteins;
hence, epidermal and gingival tissues express keratins
K1 and K10 in the spinous (prickle) layer, while non-
keratinizing tissues such as buccal and soft palate pro-
duce K4 and K13 in the suprabasal layers (Figure 1).
The junctional epithelium adjacent to the tooth sur-
face produces yet a different set of keratin proteins.
2
Additional keratins are also expressed in the upper
layers of these tissues, such as K2e in the epidermis,
and K6, K16, and K2p in the differentiating upper
layers of gingiva and hard palate tissues (Figure 1).
2
While the proliferation to differentiation switch
is normally carefully controlled and compartmental-
ized into the basal and suprabasal cell layers, respec-
tively, mitotic cells can occur in the differentiating
upper layers during normal repair processes such as
wound healing and in diseases such as cancer and
psoriasis.
6,7
During wound healing, cell proliferation
is stimulated by various inflammatory cytokines and
growth factors.
6
In oral cancer, as in many cancers, there is ab-
errant control over cell proliferation and an attenua-
tion of normal apoptosis (programmed cell death) as
a result of mutation or epigenetic silencing of one or
more genes.
8-12
A major impetus in cancer research
has been to critically assess the role and function of
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566 Journal of Dental Education Volume 66, No. 4
various genes (p53, p16, p21, bcl-2 family, etc.) in
the control of epithelial cell proliferation.
13
The epi-
thelial response to noxious stimuli (either chemical
or physical) is initially one of protection in the form
of increased keratin expression. What causes the con-
tinuum of progression through various stages of hy-
perkeratosis, dysplasia, and ultimately squamous cell
carcinoma is multifactorial and relates to location,
age, chronicity, viral or chemical interaction, and
genetic modification of specific genes.
9,10,14
The ad-
vent of molecular technologies has now enabled the
examination and classification of various epithelial
pathologic states based upon altered keratin expres-
sion patterns,
9
loss of heterozygosity in three chro-
mosome arms (3p, 9p, 17p),
10
abnormal DNA con-
tent (aneuploidy), and the associative role in cell
instability.
11,12
Yet with all these advances, the conun-
drum of systematic grading and staging precancer-
ous lesions and dysplasias is still dependent upon
inter-rater observation and careful correlation of clini-
cal and microscopic findings.
15
Mutations in Keratin Genes Cause Multiple
Epithelial Disorders. The evidence that the keratins
are critical for maintaining cell and tissue integrity
comes primarily from the study of human diseases
that result from mutations in keratin genes, and from
animal models in which similar mutations have been
genetically engineered.
2,4,16
A rule of thumb for hu-
man keratinopathies is that the disease phenotype
reflects the tissue and cell layers in which the par-
ticular keratin is expressed, although the severity of
phenotype can vary considerably between tissues.
Epidermolysis bullosa (EB) simplex is a well-stud-
ied blistering disease that results from mutations in
the genes encoding K5 and K14 which affects pri-
marily the epidermis, but also some other tissues such
as the oral mucosa in its more severe forms (Figure
1).
17
Oral manifestations involve occasional blister-
ing of mucosal tissues which usually heal without
scarring (Table 1).
18,19
This disease results from the
severe disruption of the keratin filament cytoskel-
eton in basal epithelial cells (where K5 and K14 are
expressed) and subsequent cytolysis. Most keratin
disorders are autosomal dominant; that is, only one
of the two gene copies (alleles) is mutated in affected
individuals. The cell and tissue manifestations are
believed to result from incorporation of the mutant
protein (~50 percent of the total, derived from ex-
Figure 1. Structure of keratinizing and non-keratinizing stratified epithelial tissues of skin and oral mucosa showing targets
for genetic disorders of keratinization. The cell layers of keratinizing epithelia (epidermis, gingiva, hard palate) and non-
keratinizing buccal epithelium are shown schematically. Basal epithelial cells express K5 and K14 in all regions, while K19 is
only expressed by basal cells of non-keratinizing epithelia. The suprabasal, differentiating layers of keratinizing epithelia express
K1 and K10 while keratinizing oral mucosal epithelia (gingiva, hard palate) also express K6 and K16. The upper layers express
an additional keratin: K2e (epidermis) or K2p (oral mucosa). The keratin diseases (keratinopathies) associated with mutations in
these keratin genes are shown. For further discussion of these diseases, see the text. IBS, Ichthyosis bullosa of Siemens; EHK,
epidermolytic hyperkeratosis; PC-1, Pachyonychia Congenita type I; EB simplex, epidermolysis bullosa simplex (adapted from
Presland and Dale
2
).
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April 2002 Journal of Dental Education 567
pression of the mutant keratin allele) into keratin fila-
ments, which either do not assemble correctly or are
fragile and prone to disruption. In many cases, these
diseases result from mutation of a single amino acid
residue in the central α-helical rod domain of the
protein in regions essential for normal assembly and
formation of keratin filaments.
4,17,20
Examples of other keratin diseases that affect
oral mucosal tissues include White Sponge Nevus
(Canon’s disease) and Pachyonychia Congenita type
I (PC-1, or Jadassohn-Lewandowsky type) that re-
sult from mutations in K4 or K13 and K6 or K16,
respectively (Figure 1). Oral symptoms include white
spongy plaques in the mouth (oral leukokeratosis),
with acanthosis and disruption (perinuclear aggre-
gation) of keratin filaments in the suprabasal lay-
ers.
2,17
Some of these disorders, such as Pachyony-
chia congenita, are sometimes referred to as
ectodermal dysplasias as they affect morphology and
function of multiple epithelial tissues (nails, palm
and sole skin, oral mucosa, and hair follicle in the
case of PC-1). Other keratin diseases that affect pri-
marily the suprabasal epidermal layers include
Epidermolytic Hyperkeratosis, a blistering disease
Table 1. Characteristics of the clinical variants of epidermolysis bullosa
1
EB variant
Simplex
Level of tissue separation
Intraepidermal
Mutated gene(s)
K5, K14
Major oral manifestations
3
Occasional oral blistering in
more severe forms (mainly
Dowling Meara) that heal
without scarring. Lesions
mostly commonly seen in
infancy and childhood.
Blistering of mucous
membranes; enamel
hypoplasia.
BP180 (collagen XVII,
BPAG2)
Basal keratinocyte/basement
membrane zone
Hemidesmosomal
GABEB
2
Basement membrane zone
EB-MD
2
Plectin Mostly affects skin and
muscle (late-onset muscular
dystrophy).
EB-PA
2
Integrins (α6, β4) Blistering of mucous
membranes; enamel
hypoplasia; associated with
pyloric or duodenal atresia.
Junctional Laminin 5 (genes encoding
all three protein chains)
Frequent mucosal blistering
erosions with occasional
scarring. Microstomia
commonly seen in the
generalized Herlitz form of
JEB. Enamel hypoplasia
common, which results in
high rate of dental caries.
Dystrophic Papillary dermis (anchoring
fibrils)
Collagen VII Recessive dystrophic forms
show most severe oral
scarring of all EB types, with
severe anklylogossia,
microstomia, and often loss
of lingual papilla and
associated structures.
Dominant DEB forms show
only occasional blistering
which heal without scarring.
1For references, see text.
2 GABEB, generalized atrophic benign EB; EB-MD, EB with late-onset muscular dystrophy; EB-PA, EB with pyloric atresia (stomach involvement).
3For more discussion of oral manifestations and references, see text.
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568 Journal of Dental Education Volume 66, No. 4
resulting from mutations in K1 and K10, and the more
benign skin disease Ichthyosis bullosa of Siemens
that results from mutations in the epidermal keratin
K2e (Figure 1).
2,4,17
Mouse models for some of these keratin disor-
ders have been developed by transgenic technology,
in which a mutant keratin gene is inserted into the
mouse germline and expressed in one or more epi-
thelia. For example, mouse models of epidermolysis
bullosa simplex (due to mutations in K5 and K14)
and epidermolytic hyperkeratosis (due to mutations
in K1 and K10) mimic many of the clinical symp-
toms.
21-23
These models have been useful for obtain-
ing a fuller understanding of the disease biology and
may be important for the future testing of disease
therapies. However, the poor survival of mutant mice
in the neonatal period is an impediment to the use of
such animal models in gene therapy studies.
Desmosomes and Desmosomal
Proteins
Desmosomes are cell adhesion complexes that
link epithelial cells to each other and attach keratin
filaments to the cell surface. Desmosomes are present
in all epithelia and in certain other specialized tis-
sues such as the myocardium. They consist of two
principal groups of proteins: the desmosomal
cadherins, the desmogleins and desmocollins, that
span the plasma membrane and a large group of pro-
teins that reside on the cytoplasmic face of the des-
mosome (comprising the structure visible in the elec-
tron microscope known as desmosomal plaque) that
function to link the desmosomal cadherin proteins
to the cytoplasmic keratin filaments (Figure 2).
2,24
These cytoplasmic plaque-associated proteins include
plakoglobin, the desmoplakins, the plakophilins,
envoplakin, and periplakin.
2,25
The desmosomal
cadherins, like the classical cadherins present in
adherens junctions, are believed to mediate cell ad-
hesion by calcium-dependent interactions between
their extracellular protein domains that glue cells to
each other. In addition to desmosomes, epithelial cells
also have adherens junctions that are composed of
the membrane-spanning proteins E-cadherin and P-
cadherin which are linked by a series of proteins to
the cytoplasmic actin cytoskeleton.
24,26
Genetic and Autoimmune Diseases That In-
volve Desmosomal Proteins. There are both acquired
(autoimmune) blistering diseases and rare inherited
genetic disorders that result in disruption of desmo-
some function. These diseases are characterized by
reduced cell-cell adhesion (acantholysis) and partial
or complete loss of attachment of keratin filaments
due to altered desmosome function. The pemphigus
diseases are autoimmune blistering diseases in which
separation of the suprabasal layers is found in con-
junction with circulating anti-desmoglein antibod-
ies. These antibodies bind to the cell surface of
keratinocytes and are diagnostic for the disorder by
direct immunofluorescence. The pemphigus diseases
used to be frequently debilitating or fatal, but now
can be treated with some success using corticoster-
oids. The two best studied forms of pemphigus are
pemphigus vulgaris (PV) and pemphigus foliaceus
(PF); both forms affect the epidermis, while pem-
phigus vulgaris involves erosions of other mucosal
epithelia, especially the oral cavity.
27-29
The differ-
ence in target tissues between the two diseases is due
to the major autoantigens involved: PV targets
desmoglein 3 which is expressed in many stratified
epithelia, whereas PF targets desmoglein 1 which is
found in epidermis but is poorly expressed in oral
epithelia.
30
Possibly the strongest evidence that the
desmogleins are the primary autoantigens in these
diseases is the passive transfer experiments in which
the desmoglein 1 (PF) and desmoglein 3 (PV) au-
toantibodies, purified from patient sera, were shown
to cause blistering when injected into newborn
mice.
27,28
However, despite a wealth of data the role
of desmoglein autoantibodies in the pathology of
these diseases is still a matter of considerable de-
bate. One aspect of this debate relates to the pres-
ence of autoantibodies in PV and PF patients to other
desmosomal and cell surface components, suggest-
ing that other antigens may play a role in disease
pathology.
31
However, the current consensus is that
desmoglein autoantibodies play a key role in the dis-
ease pathology of both PV and PF.
32,33
Linear IgA disease is another subepidermal
bullous disease that is characterized by a
pathomnemonic linear deposition of IgA at the base-
ment membrane zone (BMZ). IgA autoantibodies
appear to bind to the lamina lucida of the BMZ. The
autoantibodies are directed against the
hemidesmosomal transmembrane glycoprotein BP
180 (type XVII collagen), a 120 kDa filament an-
choring protein, LAD-1, and other antigens of 200
and 280 kDa.
34-37
The loss of adhesion and blistering
seen in epidermal and mucosal tissues is probably
the result of autoantiantibody-mediated disruption
Page 5
April 2002 Journal of Dental Education 569
of these proteins that are structural components of
the hemidesmosome and basement membrane.
38
In addition to autoimmune diseases, there have
been several reports of rare genetic skin fragility dis-
eases that affect the expression and function of
desmosomal proteins. These diseases primarily af-
fect the epidermis and associated appendages such
as hair and nails.
39-43
As with the keratin disorders, a
frequent finding is altered attachment of keratin fila-
ments to desmosomes, indicating altered function(s)
of the mutant protein in cell adhesion complexes.
Epidermolysis Bullosa Subtypes
Affecting Function of
Hemidesmosomes and Dermal-
Epidermal Junction
Other forms of EB involve fragility and blis-
tering of the skin and other epithelia at or below the
basement membrane zone (or dermal-epidermal junc-
tion). Non-keratin EB types have been classified into
three variants based on where the blistering occurs
in the skin and what gene(s) are involved (Figure 2;
Table 1). Hemidesmosomal forms involve mutations
in several components of the hemidesmosome, the
cell adhesion complex that anchors basal epithelial
cells and their associated keratin filaments to the
BMZ; junctional EB involves mutations in the three
genes encoding laminin 5, a component of the lamina
densa layer of the BMZ; and dystrophic EB involves
mutations of collagen VII, the major protein of an-
choring fibrils in papillary dermis (Figure 2; Table
1).
44,45
Oral involvement varies relative to disease
severity and can involve both hard and soft oral tis-
sues.
18,46-48
Patients having generalized recessive dys-
trophic EB exhibit the most severe involvement of
the oral tissues characterized by obliteration of the
vestibule, ankyloglossia, and microstomia. The pala-
tal rugae and lingual papilla tissues become severely
malformed with age due to blistering and scarring.
18,48
Oral involvement occurs in hemidesmosomal and
junctional EB diseases at a lower frequency, and the
blistering and tissue damage are generally less se-
vere than in dystrophic forms (Table 1).
18,46
However
in junctional EB there is always generalized enamel
hypoplasia associated with a high frequency of den-
tal caries.
49
In the hemidesmosomal forms there can
also be teeth and mucosal abnormalities including
enamel hypoplasia and an increased frequency of
caries.
50-52
The prevalence of dental caries is also sig-
nificantly higher in recessive dystrophic EB, while
little or no increase in caries frequency was observed
in dominant dystrophic and simplex EB types.
49
Proteins of the Cornified Cell
Envelope
The cornified envelope (CE) forms a tough coat
on stratified epithelial cells as they reach the sur-
face. It is 15 nm thick, and composed of cross-linked
proteins and lipids that are assembled during termi-
nal differentiation. This structure completely replaces
the plasma membrane in keratinizing epithelia. It is
an essential part of the epithelial barrier in the epi-
dermis and keratinizing oral epithelia. Thus, the stra-
tum corneum consists of cells with a proteinaceous
envelope that is crosslinked to the keratin cytoskel-
eton within the cells and to specialized lipids on the
outer surface. Researchers studying cornified epi-
thelia often refer to a “protein envelope” and a “lipid
envelope,” which are now recognized as both being
important parts of the permeability barrier of epi-
thelia (for reviews, see references 1, 2, 53, and 54).
All of the components of the protein envelope
are expressed in suprabasal cells of keratinizing epi-
thelia often in precursor or inactive forms; the pro-
teins are subsequently incorporated into the CE dur-
ing the process of keratinization as cells transit from
the granular to cornified layer (see Figure 1). This
process involves an orderly crosslinking into the CE
structure by Ca
2+
-dependent transglutaminase en-
zymes that catalyze the formation of covalent bonds
between lysine and glutamine residues of CE pro-
teins.
54
Transglutaminase 1 and 3 are expressed and
function in CE formation; other members of this en-
zyme family function in many other biological pro-
cesses such as catalyzing the formation of the fibrin
clot at sites of blood coagulation (factor XIII) and in
processes such as apoptosis (cell death) and wound
healing (transglutaminase 2 or tissue
transglutaminase).
There are many CE constituents; some are ex-
clusively produced in epithelia to be incorporated into
the CE, while others are better known for other func-
tions such as being desmosomal proteins (for ex-
ample, desmoplakin, envoplakin, plakoglobin,
desmogleins) or proteins associated with differen-
tiation and/or membrane/cytoskeletal functions (for
example, S100 calcium-binding proteins, annexins,
trichohyalin, filaggrin).
1,2
Examples of proteins that
seem to function exclusively as CE proteins include
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570 Journal of Dental Education Volume 66, No. 4
loricrin, the most abundant CE protein (65-85 per-
cent of total crosslinked protein), the small proline-
rich proteins (SPRRs), involucrin, and a new family
of CE components termed the LEPs (late envelope
proteins).
1,54,55
These proteins have a similar gene
organization and protein structure; that is, they are
rich in lysine and glutamine and hence good sub-
strates for transglutaminase-mediated crosslinking.
Interestingly, these genes are all located in a region
on human chromosome 1q21 termed the “epidermal
differentiation complex.”
56,57
Many of these CE pro-
teins are believed to have evolved from a single com-
mon ancestral gene that underwent extensive dupli-
cation and divergence during mammalian evolution.
58
Assembly of the cornified envelope has been
studied by a combination of sophisticated biochemi-
cal and microscopy methods both in vivo and using
keratinocytes grown in vitro. As discussed recently
by Kalinin et al.,
54
it appears that CE assembly is an
orderly process and that CE composition differs
among stratified epithelia depending on the physi-
cal demands placed on the tissue.
59
In most epithelia
studied, involucrin, periplakin, and envoplakin are
among the first substrates to be crosslinked, form-
ing a scaffold on which other proteins are subse-
quently added. At least in the epidermis, these early
CE proteins are covalently attached to the extracel-
lular lipids, mainly specialized ceramides, as well as
to one another by protein-protein crosslinks by the
action of transglutaminases. Subsequently, other pro-
teins such as the SPRRs and loricrin are added to
generate mature CEs. Keratins may also be attached
as well as other proteins that appear to be minor CE
components (for a detailed list, see references 1, 2,
and 54).
A modified or incomplete version of the CE
may form in the surface cells of noncornified oral
epithelia, based on the presence of several of the com-
ponent proteins including SPRRs and involucrin as
well as the crosslinking transglutaminase enzymes.
60-
62
However, the permeability properties of the bar-
rier formed in non-cornified oral epithelia differ sub-
stantially from those of the keratinized regions with
important implications for drug delivery.
63,64
Diseases Involving the Cornified Envelope.
Of the CE components that seem to function exclu-
sively in its formation, only one, loricrin, has been
associated with an epithelial disorder. Loricrin kera-
toderma is a rare skin disease characterized by
palmoplantar hyperkeratosis (thickening of the corni-
fied layers of palms and soles) with retention of nu-
clei (normally lost in the cornified layers), and con-
stricting bands encircling the digits of the hands and
feet. The mutations in the loricrin gene results in a
frame shift in the encoded mutant protein that leads
to its accumulation in cell nuclei rather than in
CEs.
65,66
Analysis of a transgenic mouse model of
loricrin keratoderma suggests that the disease pathol-
ogy is due not to the lack of loricrin in CEs, but rather
to a “gain-of-function” effect in which the mutant
Figure 2. Schematic showing the structure of basal epithelial cells and dermal-epidermal junction. Shown are the major
cytoskeletal and cell adhesion structures of epithelial cells and the basement membrane and the major protein components of
desmosomes and hemidesmosomes. The level of tissue separation in the different EB types are indicated next to the proteins
involved (for more details on the EB types, see Table 1 and text).
Page 7
April 2002 Journal of Dental Education 571
loricrin protein disrupts normal nuclear events that
are important for terminal differentiation of epider-
mal keratinocytes.
67
While such a model is attrac-
tive, exactly how the nuclear accumulation of this
CE protein disrupts normal terminal differentiation
and desquamation is yet to be determined.
Loss of epidermal transglutaminase 1 results
in neonatal lethality in mice due to excessive
transepidermal water loss.
68
In humans, mutations
in transglutaminase 1 result in the severe scaling skin
disorder lamellar ichthyosis, demonstrating the vital
role played by the CE in the epithelial barrier.
69,70
Proteases and Proteolysis:
Their Importance in
Epithelial Development and
Function
Proteases are enzymes that degrade other pro-
teins. They are essential for normal growth and de-
velopment and in combating disease. Proteases vary
greatly in their specificity, from the highly specific
caspases that cleave target proteins after aspartate
residues to digestive and lysosomal cathepsin pro-
teases that have a broader substrate specificity. Pap-
illon-Lèfevre syndrome is an autosomal recessive
disease characterized by early onset periodontitis and
palmoplantar hyperkeratosis that involves loss-of-
function mutations in the lysosomal cysteine protease
cathepsin C.
71-73
This enzyme is expressed and se-
creted by epithelial tissues (gingiva and palm and
sole epidermis) and by immune cells such as leuko-
cytes and macrophages.
72
It plays key roles in inflam-
mation by activating the proteases granzyme A and B
that are secreted by activated T-lymphocytes and func-
tion to kill lymphocytes or epithelial cells damaged
by infection or disease.
74
In Papillon-Lèfevre syndrome
there is an absence of cathepsin C activity associated
with premature loss of the primary and permanent
dentition and junctional epithelium, and alveolar bone
loss, as well as hyperkeratosis of some epidermal tis-
sues. Therefore, it appears that cathepsin C plays key
roles in regulating both inflammation and epithelial
morphogenesis. The loss of cathepsin C may mediate
destruction of the oral epithelium and tooth loss ei-
ther by impairing the ability of immune cells to re-
move plaque bacteria and/or by severely abrogating
the ability of cytotoxic T-lymphocytes and natural killer
T-cells to remove activated lymphocytes. Thus, this
pathway clearly plays a role in activation of immune
cells such as neutrophils and macrophages that remove
infected or damaged cells. It also may be important in
turning off these signals by destroying activated T-lym-
phocytes. In epidermal tissues (that is, palmoplantar
skin), cathepsin C may play a different role in differ-
entiation and barrier formation by processing and
modifying keratins or other proteins.
Cathepsin C mutations have also been reported
in a second related syndrome, Haim-Munk disease,
that occurs in a large Jewish kindred in India.
75
In this
disease, there was more severe epidermal involvement
and abnormalities in the fingers and nails.
In addition to the genetic disorders discussed
above, cathepsin C mutations have been reported in
one family with non-syndromic prepubertal periodon-
titis that exhibited similar oral findings to Papillon-
Lèfevre syndrome (periodontitis with tooth and alveo-
lar bone loss).
76
However, there was no epidermal
involvement in the individuals with this form of pre-
pubertal periodontitis. Cathepsin C mutations (or per-
haps even more common polymorphisms) could be a
genetic risk factor for periodontitis in addition to other
genes recently identified, such as IL-1α and IL-1β.
77
Another epithelial disorder that involves altered
proteolysis is X-linked hypohidrotic ectodermal dys-
plasia that results in the impaired formation of hair,
teeth, and sweat glands during fetal development.
This disease displays a significant mortality due to
hypothermia. The disease locus is ectodysplasin-A,
which encodes a protein that is a member of the tu-
mor necrosis factor (TNF) family of cytokines. This
protein, ectodysplasin-A, binds TNF-like receptors
at the cell membrane and appears to play important
roles in epithelial morphogenesis.
78,79
Recent studies
have shown that at least one ectodysplasin-A muta-
tion lies in a site recognized by the protease furin,
which normally cleaves this protein and facilitates
its export from the cell.
80
The disease mutation was
shown to prevent ectodysplasin-A processing by furin
resulting in a loss of function in epithelial tissues
such as hair, teeth, epidermis, and sweat glands where
both ectodysplasin-A and furin are expressed.
79,81
Conclusion
Epithelial tissues provide a barrier between an
organism and its environment and perform many
additional specialized functions depending on body
Page 8
572 Journal of Dental Education Volume 66, No. 4
site. In order to function correctly, stratified epithe-
lia such as the epidermis and oral mucosa have to
maintain tight cell-cell adhesion in the living cells
and retain the dead, keratinized squames as a protec-
tive sheath prior to being sloughed. Epithelial cell-
cell adhesion involves desmosomes that maintain
intercellular adhesion; hemidesmosomes, which
maintain keratinocyte-basement membrane adhesion
(Figure 2); and intercellular adherens junctions that
connect to the actin cytoskeleton in virtually all cell
types. In the epidermis and other keratinized epithe-
lia, a cornified cell envelope is variably assembled
in the last living layers that functions as a critical
part of the protective barrier that these tissues pro-
vide. This barrier provides protection from mechani-
cal and chemical stresses as well as being a selective
permeability barrier. The importance of both cell
adhesion junctions and the cornified envelope in
maintaining cell and tissue integrity and preventing
dessication is demonstrated by the large number of
genetic and autoimmune diseases that result from
altered expression or function of these structures.
Molecular biology and genetics are revolution-
izing all aspects of health care, including dentistry.
77,82
With the recent completion of the human genome
project and the identification of all 30,000-40,000
human genes,
83,84
the challenge now is to develop new
pharmaceutical and gene-based therapies that will
be used to treat (and hopefully one day cure) these
debilitating diseases. Drugs are being developed for
many diseases that specifically target disease genes,
for example, proteins involved in cancer pathology.
85
Another important goal of genetic medicine is to be
able to predict disease susceptibility based on the
genetic mutations and/or single nucleotide polymor-
phisms (SNPs) that each individual carries in his or
her DNA. Dental educators will need to incorporate
these subjects, including molecular biology, genet-
ics, and genomics, into core curriculums in order for
dentists to be appropriately trained for this “post-
genomic” world. This is a challenge that we can, and
must, face, in order to meet the health care needs of
the twenty-first century.
Acknowledgments
The work in the authors’ laboratories was sup-
ported by grants R29 AR45276 (to R.B. Presland)
and P01 AM 21557 (to B.A. Dale) from the National
Institutes of Health. R. Jurevic is supported by a
Dental Scientist Award (DSA K16 DE00161) from
the NIDCR of the National Institutes of Health. We
thank Dr. Beverly Dale for a critical reading of this
manuscript.
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  • Source
    • "The epidermis, composed of specialized epithelial cells called keratinocytes, protects the body from injury and invading pathogens (Presland and Jurevic, 2002). Therefore, damage to the epidermis must be promptly repaired to restore this essential barrier. "
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    • "Histological sections of healthy human skin confirm HYAL1 signal is prominent in the granular layer, whilst HA mostly surrounds basal and spinous keratinocytes. HYAL1 cannot be detected in oral mucosal epithelium (Figure 1f) which lacks a granular layer (Presland and Jurevic, 2002). HYAL1 activity is also clearly demonstrated using zymographic analysis of human epidermis extracts (Figure 1g). "
    [Show abstract] [Hide abstract] ABSTRACT: Abbreviations: HA, hyaluronan; HAS, hyaluronan synthase; HYAL, hyaluronidase; RHE, reconstructed human epidermis; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; TEER, trans-epithelial electric resistance; WT, wild-type
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    • "Desmosomal plaque is associated with different types of proteins including plakoglobin, the desmoplakins, the plakophilins, envoplakin, and periplakin. It provides adhesion by linking the desmosomal transmembrane cadherin proteins to the cytoplasmic keratin filaments [1,5]. Hemidesmosomes are specialized junctional complexes on the ventral surface of the basal keratinocytes that maintain the epithelial cell attachment to the underlying basement membrane. "
    [Show abstract] [Hide abstract] ABSTRACT: A group of autoimmune diseases is characterised by autoantibodies against epithelial adhesion structures and/or tissue-tropic lymphocytes driving inflammatory processes resulting in specific pathology at the mucosal surfaces and the skin. The most frequent site of mucosal involvement in autoimmune diseases is the oral cavity. Broadly, these diseases include conditions affecting the cell-cell adhesion causing intra-epithelial blistering and those where autoantibodies or infiltration lymphocytes cause a loss of cell-matrix adhesion or interface inflammation. Clinically, patients present with blistering, erosions and ulcers that may affect the skin as well as further mucosal surfaces of the eyes, nose and genitalia. While the autoimmune disease may be suspected based on clinical manifestations, demonstration of tissue-bound and circulating autoantibodies, or lymphocytic infiltrates, by various methods including histological examination, direct and indirect immunofluorescence microscopy, immunoblotting and quantitative immunoassay is a prerequisite for definitive diagnosis. Given the frequency of oral involvement and the fact that oral mucosa is the initially affected site in many cases, the informed practitioner should be well acquainted with diagnostic and therapeutic aspects of autoimmune dermatoses with oral involvement. This paper reviews the pathogenesis and clinical presentation of these conditions in the oral cavity with a specific emphasis on their differential diagnosis and current management approaches. Copyright © 2015. Published by Elsevier B.V.
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