EWA KAROLEWSKA, TOMASZ KONOPKA

Autoimmune Process Participation

in the Oral Pathologies
Udzia procesw autoimmunologicznych w patologiach jamy ustnej
Department of Oral Pathology, Wroclaw Medical University, Poland
Dent. Med. Probl. 2004, 41, 2, 267276
ISSN 1644387X
REVIEWS
Abstract
Autoimmune diseases are mostly chronic disorders with acute periods and remissions. This group of disorders con
sists of 70 entities and has a high prevalence, with 5% of worlds population affected. The aim of this paper was
to present basing on the contemporary literature the impact of autoimmune mechanisms on the diseases affecting
only oral cavity or in which oral cavity is one of many localizations. The localization and features of identified
autoantigens, the character of effector mechanisms in these diseases, suggested endo and exogenous factors lead
ing to the abolition of selftolerance were described. The issues were presented in respect to systemic lupus ery
thematosus, Sjgrens syndrome, pemphigus, pemphigoid, Behets disease, chronic ulcerative stomatitis and peri
odontitis. This knowledge has great importance in the diagnosis and therapy of these diseases (Dent. Med. Probl.
2004, 41, 2, 267276).
Key words: autoimmune disease, oral cavity, autoantigens, autoantibodies.
Streszczenie
Choroby autoimmunizacyjne maj najczciej przebieg przewleky, charakteryzuj si fazami zaostrze i remisji.
Do tej grupy schorze naley okoo 70 jednostek. Na choroby autoimmunizacyjne choruje okoo 5% wiatowej po
pulacji. Celem pracy byo przedstawienie na podstawie wspczesnego pimiennictwa wpywu mechanizmw au
toimmunizacyjnych na choroby wystpujce wycznie w jamie ustnej oraz tych, dla ktrych jama ustna jest tylko
jedn z wielu lokalizacji. Omwiono lokalizacje oraz cechy zidentyfikowanych autoantygenw, charakter mecha
nizmw efektorowych, sugerowane czynniki endo i egzogenne prowadzce do zniesienia autotolerancji. Zaga
dnienia te przedstawiono w odniesieniu do toczenia rumieniowatego ukadowego, zespou Sjgrena, pcherzycy,
pemfigoidu, zespou Beheta, przewlekego wrzodziejcego zapalenia jamy ustnej, a take zapale przyzbia. Wie
dza na temat schorze autoimmunizacyjnych ma znaczenie dla diagnostyki i terapii tych chorb (Dent. Med.
Probl. 2004, 41, 2, 267276).
Sowa kluczowe: choroby autoimmunizacyjne, jama ustna, autoantygeny, autoprzeciwciaa.
Autoimmunization is the effect of immune sys
tem on selfantigens, and develops in the situation
of overcoming selftolerance mechanisms protect
ing from not distinguishing self components of
body tissues from foreign antigens. In these
processes participate autoantigens, autoreactive
lymphocytes T (especially helpers CD4
+
), autore
active lymphocytes B and their products, autoanti
bodies [1]. Autoantigens can be found on the nor
mal organism cells, in their cytoplasm or can be
produced and excreted by them. Their epitopes are
recognized by lymphocytes T (with the MHC mol
ecule) and B. Autoantibodies after binding
autoantigens activate different immunological
mechanisms (complement, opsonization, antibody
dependent cellmediated cytotoxicity, deposition
of complexes) and can destroy tissues and organs
[1, 2]. Autoimmune diseases can be divided
according to their autoantigen localization on sys
temic or nonorgan specific (e.g. systemic lupus
erythematosus, scleroderma, Sjgrens syndrome)
and organ specific (e.g. Hashimotos disease,
aplastic anaemia, insulindependent diabetes melli
tus). They can also be divided depending on the
effector mechanisms of tissue destruction on those
dependent on the cellmediated immune defence
(Th1 cells activate cytotoxic lymphocytes,
macrophages and NK cells) and dependent on the
specific humoral defence [1]. The major role in the
course of systemic diseases usually plays the
immune complex deposition with all its conse
quences, in organspecific diseases dominates type
II hypersensitivity and cellmediated reactions.
Factors leading to failure of the selftolerance
maintenance can next be divided into endogenous:
genetic (MHC genes, complement components,
regulator genes mutation), hyperproduction of
cytokines (IL2, IL15, IL18), level of sexual hor
mones and apoptosis dysregulation (e.g. decreased
expression of Fas); exogenous: viral and bacterial
infections, which epitopes cause cross reactions
with host antigens (molecular mimicry), inflamma
tion, physical or thermal injury, drugs [1, 2].
Autoimmune diseases are mostly chronic dis
orders with acute periods and remission, which
often lead to permanent disability or death. This
group of disorders consists of 70 entities and has a
high prevalence, with 5% of worlds population
affected [1]. The aim of this work was, basing on
the contemporary literature, to present the impact
of autoimmune mechanisms on the diseases affect
ing only oral cavity or in which oral cavity is one
of many localizations. Their pathogenesis will be
presented with specific respect to the autoimmu
nization process, beginning with the most sys
temic, to oral cavityspecific pathologies. They
will be described in the following order: systemic
lupus erythematosus, Sjgrens syndrome, pem
phigus, pemphigoid, Behets disease, chronic
ulcerative stomatitis and periodontitis.
Systemic Lupus
Erythematosus
Systemic lupus erythematosus (SLE) is
a chronic autoimmune multiorgan disease, involv
ing skin and mucous membranes. Among 11 crite
ria of SLE introduced by American Rheuma
tological Association, two are mentioned, which
can be verified also by a dentist: oral ulceration
and a butterflylike facial erythema. The disease
manifests by autoantibodies production, circulat
ing immune complexes and periodic uncontrolled
activation of the complement. Among the identi
fied SLE autoantigens there are: double stranded
DNA, nuclear ribonucleoproteins (RNPs), Ro and
La in nucleolar and cytoplasmic ribonucleopro
teins, histones, protein p53 [3].
SLE affects mostly women in the reproductive
years, who between 2040 years of age develop
SLE 9 times more often then men [3, 4]. In the
remaining age range the female: male ratio is
reduced to 3 : 1 [4]. The female predominance in
this disorder indicates a potential role of hormonal
factors. SLE can also concern infants and develops
as a result of passive transfer of antibodies (main
ly Ro/SSA, often with La/SSB) from mother to
foetus [5]. Mother can suffer from SLE, Sjgrens
syndrome, or other connective tissue disease.
Attention draws the familiar coincidence of
this disease. It is known that statistically in 510%
of SLE patients close family will develop its
symptoms [6]. SLE patients more often have
HLADR2 (relative risk 5.8) [6].
Patients with SLE have recurrent vascular
changes in different organs (skin, kidneys, brain,
joints, lungs, serous membranes and alimentary
duct). Histopathological findings are not homoge
nous, they can be divided into 2 categories:
inflammatory and thrombotic [4]. Inflammatory
changes are associated with the complement acti
vation in the presence of immune complexes or
without their effect. Thrombotic lesions are usual
ly linked with the presence of circulating antiphos
pholipid antibodies. Immune complexes deposited
in the skin and internal organs initiate inflammato
ry processes, leading to tissue destruction and
release of new intracellular autoantigens and pro
duction of new complexes.
About 1% of SLE patients can have rarely
observed complement deficiency [7]. 98% of
patients with autosomal recessively inherited C1q
deficiency develop its symptoms [7]. Less spec
tacular is the association between C4, C1r/s defi
ciency and SLE. C2 deficiency contributes to the
development of lupustype disease in 1/3 of
patients.
Among environmental factors photosensitivity
especially to ultraviolet radiation (UV) plays the
major role in the development of skin lesions and
in the aggravation of systemic disease symptoms
of SLE. Many studies show the presence of apop
tosis dysregulation [8, 9]. In these conditions
extracellular or nuclear antigens can be the source
of autoantibodies formation. UV radiation in
healthy people causes changes in the DNAof spinous
and basal layer. In case when the mechanisms
responsible for DNA reparation fail, keratinocytes
get into the state of apoptosis, and the forming
apoptotic bodies are phagocytised, what prevents
from the organisms immune response. In lupus
predisposed subjects in the UV radiation leads to
apoptosis or its dysregulation in the epidermal and
skin cells [8, 9]. Extracellular presence of the
nucleus substance indicates the apoptosis dysregu
lation in its final phaze [8]. Immunoglobulins pre
sent in the dermalepidermal junction prove the
interaction between them and the fragments of
destroyed cells, which become epidermal autoanti
E. KAROLEWSKA, T. KONOPKA 268
gens. Phagocytosis of nuclear substance by
macrophages and its presentation to lymphocytes
CD4 enables the antinuclear antibody production.
As long as serum if free of circulating antinuclear
antibodies, process has a local character. With
their presence the disease is becoming systemic.
SLE is characterised by a dysfunction of sup
pressor lymphocytes, function and number defect
of NK cells and polyclonal B cell activation, lead
ing to autoantibodies and also nonspecific glob
ulins production [7, 10]. Such polyclonal activator
can be EpsteinBarr virus (EBV) [11]. The litera
ture presents a case of SLE development immedi
ately following the diagnosis of EBVinduced
infectious mononucleosis [12].
Among SLE clinical subgroups there is also
one induced by medications. The factors are most
often hydralazine, hydantoin, sulphonamids, pro
cainamide, dpenicyllamin, gold salts, hormonal
pills, isoniasid and chlorpromazine. Among clini
cal symptoms dominate skin lesions, joints pain
and serositis. The patients serum contain antihis
tone antibodies, there is lack of antibodies against
native DNA and normal complement concentra
tions are found [3].
Sjgrens Syndrome
Sjgrens syndrome (SS) may occur in the
context of other autoimmune diseases (rheumatoid
arthritis, SLE, scleroderma, mixed connective tis
sue disease) and is then described as secondary
Sjgrens syndrome (SSS). Prevalence of SS is
high, with about 0.83% of the population affect
ed, mostly females, which suffer 9 times more
often [1315]. It starts usually in the fourth and
fifth decade. The advantage of women in SS
development points to the potential role of hor
monal factor in the disease aetiopathogenesis.
A hypothesis has been drawn, which assumes the
participation of somatostatin (hypothalamic hor
mone which controls the secretion of soma
totropin) deficiency in the SS development [16]. It
is a multifunctional peptide, which reduces lym
phocyte activity, gastric and intestinal secretion,
activates hypothalamicpituitary axis and antin
flammatory action.
As for now a series of autoantigens have been
revealed, from which a part is used in the disease
diagnosis. Among them are nonorganspecific
autoantigens SSA/Ro, SSB/La and SS56, which
can also be associated with other autoimmune
disease [1315]. Antibodies against SSA/Ro,
SSB/La are detected in 4070% and 2540% of
patients respectively. Their titres show correlation
between disease symptoms and presence of extra
glandular symptoms [13]. Other autoantigens,
which are organspecific are fodrin, fodrin
and muscarine receptor M3 [13]. Their role in the
initiation and aggravation of SSS symptoms is not
clear, however antibodies directed against mus
carine receptor may participate in the loss of sali
vary function associated with this disease. Newly
detected autoantigen ICA69 is a protein of
unknown function that is expressed in neurons and
pancreatic B cells and in salivary and lacrimal
glands [17]. Often detected antibodies are:
rheumatoid factor, antinuclear antibodies against
histones and ssDNA and cryoglobulins [13].
The characteristic feature of SSS is the genetic
predisposition. The familiar presence and strong
relation with HLA DR3 antigens (relative risk 9.7)
can be observed [13]. Patients from different ethnic
groups show different HLAgene association. HLA
class II allele association has been reported to differ
among antiRo/SSApositive subjects according to
the presence or absence of coexisting antiLa/SSB.
Certain HLA haplotypes were associated with dif
ferent level of autoantibodies diversification in SS
patients. Stronger correlation was observed
between antiRo/SSA antibodies and DR3/DR2,
than that to the disease itself. Antibodies against
Ro/SSAand La/SSB showed relation with DR3 and
DQA1 antigens [13]. SS patients with alleles
DQ1/DQ2 have much more severe disease than
patients with in any other combination of HLADQ
alleles. The DR3DQ2 haplotype was proposed as a
possible marker of more active immune response in
Finnish SS patients [13].
Among exogenous factors, which can have
influence on the SSS development are viral infec
tions. Salivary glands are a place of latent viral
infections. Potential viral triggers include a num
ber of viruses: EBV, CMV, HTLV1, HHV6,
HCV, HIV [13]. Some immunoreactive regions
within La/SSB protein have similar sequences
with proteins of EBV, HHV6, HIV1. It seems
reasonable to suspect, that these viruses can pro
mote autoantibody production.
The other infectious factor potentially taking
part in the SSS etiopathogenesis is the role of
Helicobacter pylori infection. Despite conflicting
reports concerning participation of this bacteria in
SSS pathology, its eradication can improve clini
cal condition of the patients with SSS [13].
The pathognomic histological feature of sali
vary gland biopsies in the course of SS is the focal
infiltration of mononuclear lymphoid cells, replac
ing glandular epithelium. Immunohistologic
analysis shows that these infiltrations comprise
mainly of lymphocytes T (7080%) and B
(2025%), rarely of macrophages [13, 14]. The
majority of T cells are lymphocytes CD4
+
showing
Autoimmune Process Participation in the Oral Pathologies 269
activation features, with a CD4/CD8 ratio well
over two [14]. Lymphocytes T are activated, what
is expressed with HLADR and CD95 molecule
expression [18]. According to the present hypo
thesis, the destruction of tissues in SS is concerned
with the aggravation of apoptosis in the epithelia,
what helps autoantigen presentation activating
lymphocytes and cytotoxic effect of released by
their mediators. Research on the cytokine spec
trum produced by lymphocytes Th1 and Th2 show
increased value of cytokines from both groups in
the lymphocyte infiltration of glandular tissue,
with the predominance of secreted by Th1 cells
[18]. Polyclonal hyperactivity of lymphocytes B is
one of the most crucial etiopathological phenome
na in this syndrome. It manifests by hypergamma
globulinemia, presence of circulating immune
complexes and various organspecific and non
organspecific autoantibodies [19].
Pemphigus
Pemphigus is an autoimmune blistering dis
ease affecting skin and mucous membranes.
Intraepidermal and intraepithelial blisters appear
ing during its course are the effect of dissociation
of intercellular connections in epidermis and
epithelium. It is due to binding autoantibodies
directed against adhesive molecules in the intra
cellular spaces of epidermis or epithelium. These
molecules are called cadherinstransmembrane
adhesive molecules forming desmosomes, the
most important structures, which define ker
atinocyte cohesion [20].
There are many pemphigus subtypes, which
differ from each other with the clinical manifesta
tion, and so the depth of blister formation in the epi
dermis, what has the association with the type and
localization of antigen recognized by autoantibod
ies, course, prognosis and response to treatment.
Among pemphigus clinical subtypes there are two
major groups: pemphigus vulgaris (PV) with its
variant pemphigus vegetans and pemphigus foli
aceus (PF) comprising of pemphigus erythematosus
and pemphigus foliaceus. Apart from two major
groups there are also rare subtypes such as: pem
phigus herpetiformis, paraneoplastic pemphigus
(PNP), IgA pemphigus and pemphiguserythema
annularelike. Oral lesions occur mainly in the
course of pemphigus vulgaris and its variant pem
phigus vegetans, paraneoplastic pemphigus and in
20% of cases with pemphigus herpetiformis [21].
In the pemphigus etiopathogenesis great role
is ascribed to genetic predisposition (population
with HLADR4DQB living in the Mediterranean
basin and Israel) and exogenous factors such as
UV, burns, stress, viral infections, drugs or diet
[21, 22]. Probably the genetic predisposition can
be associated with the genes which code
immunoglobulins [21]. Diet rich of phenols
(mango, cachew nuts, mustard) and thiol groups
(onion, garlic, leek) can cause pemphigus aggra
vation and resistance to treatment [21, 22]. Also
some drugs with active thiol groups in the mole
cule such as Dpenicyllamin, captopril can aggra
vate its course or even induce pemphigus in
a healthy subjects [21, 22].
PV begins in the 2 or 3 decade. Because it
often begins with nonspecific oral erosions,
which precede for about 612 weeks skin lesions,
it is often diagnosed at late stage. The PV antibod
ies are directed against autoantigen desmoglein 3
(Dsg3) cadherin with 130 kD molecular weight,
which greatest expression is in the lower parts of
epithelium, however for PF it is Dsg1 (160 kD)
present in upper parts [20, 23]. Newly introduced
detecting methods showed that the serum of PV
patients reacts only with Dsg3 or with Dsg3 and
Dsg1, while serum from PF patients reacts only
with Dsg1 [22]. Some studies report cases of PVto
PF and vice versa exchange with the simultaneous
change of serum antibodies against Dsg3 to Dsg1
or Ds1 to Dsg3 [24, 25].
Pemphigus herpetiformis is atypical pemphi
gus described for the first time in 1975 by
Jaboska et al. [acc. 26]. It is characterized by the
presence of vesicles, blisters and papules in a her
petiform pattern, localized on the erythematous
basement. Skin lesions are accompanied by itch
ing and burning sensations, and in some cases also
erosions on mucous membranes are observed.
This disease is difficult in diagnosis because of the
atypical clinical symptoms. In immunofluores
cence examination IgG deposits are observed in
the epithelium and basement membrane, and in
some cases C3 complement depositions were
observed [26]. More frequent localization of IgG
in upper parts of epidermis confirms, that pemphi
gus herpetiformis is usually a variant of pemphi
gus foliaceus. Interesting is the fact that apart from
knowing the antigens, which are Dsg1 and 3, there
are totally different clinical symptoms. Probably
antibodies recognize epitopes which have less
important function in the intracellular adhesion,
that is why acantholysis is not observed [26]. They
are able to induce inflammatory process by acti
vating complement.
Paraneoplastic pemphigus (PNP) was separat
ed as an independent syndrome coinciding with
lymphoproliferative neoplasms. About 80% of
PNP cases are linked with only three neoplasms:
nonHodgkins lymphoma, chronic lymphocytic
leukemia and Castelmans disease [2731]. Other
E. KAROLEWSKA, T. KONOPKA 270
cases are less commonly associated with retroperio
toneal sarcomas, thymoma and Waldenstroms
disease [31, 32]. PNP is the most severe pemphi
gus subtype. It is characterized by suprabasal
acantholysis, dyskeratosis, basal layer vacuolar
changes and necrosis of keratinocytes [2831].
PNP mostly affects oral and genital mucous mem
branes [2834]. Clinical symptoms are resembling
severe pemphigus or erythema multiforme.
Additionally lichen planuslike skin lesions are
observed, which do not occur in other forms of
pemphigus [2831]. Autoantibodies directed
against proteins from the plakin family are present
in the nonstratified epithelia and therefore in the
course of PNP destruction of respiratory and intes
tine epithelium may be observed, in contrast to PV
[31, 33]. In PV antibodies react only with squa
mous epithelia. In PNP autoantibodies are directed
against different desmosomal components. They
are proteins, which belong to the plakin family:
desmoplakin I (250 kD) and desmoplakin II
(210 kD), which are intercellular components of
the desmosome, envoplakin (210 kD), protein
230 kD antigen pemphigoid bullous BPAG1
hemidesmosome constituent located completely
intracellularly, periplakin (190 kD) [20, 29, 31].
Plakins are cytoplasmic proteins lying along the
cellular membrane, linking keratinocytes and
desmogleins. Among antibodies found in PNP
attention has been drawn to those directed against
high molecular weight plakin, known also as
plectin or HD1 (466 kD) [29, 30]. Last research
studies show the presence of antibodies for Dsg3
and Dsg1, which expression is associated with the
aggravation of lesion on mucous membranes and
skin respectively [27, 2931]. Among closely not
identified antigens is transmembrane glycoprotein
170 kD [29, 34]. Antibodies directed against this
antigen alone are sufficient for the clinical expres
sion of PNP.
Pemphigoid
Pemphigoid is an autoimmune blistering disor
der characterized by subepidermal blisters on skin
and rarely by subepithelial blisters on oral mucous
membranes. The hallmark of this disease is the
presence of autoantibodies against hemidesmoso
mal proteins BP180 and BP230 [3538].
Antibodies against BP230 are present in 70% of
examined sera in pemphigoid patients, 55% of sera
show presence of antibodies against BP180, and
only 30% against both proteins [20]. The reaction
of these epitopes with autoantibodies leads to depo
sition of immunoglobulin deposits and or comple
ment constituents on the dermalepidermal junc
tion. Other autoantigen detected in a group of
patients with pemphigoid is plectin, a large protein
of 516 kD molecular weight with a wide tissue dis
tribution, which is also a cytoplasmic hemidesmo
somal constituent [39].
Pemphigoid autoantibodies belong to class
IgG4 and are directed against BP180, which uses
protein kinase C to lead the signal inside the cell.
These antibodies activate the release of IL6 and
IL8 from keratinocytes [36]. Pathogenicity of
IgG4 antibodies is still discussed. On one hand it
is believed that they have blocking features to
IgG1 which have proinflammatory features, on
the other hand this subpopulation has ability to
block the intracellular concentration of Ca
2+
ions
by IgG subclasses [36]. Antibodies IgG4 target
epitopes on both intra and extracellular domains
of BP180 [35].
Most of the patients with pemphigoid have
increased serum IgE antibodies and eosinophil
levels [40]. IgE are directed against intracellular
hemidesmosomal antigen BP230. Eosinophils are
the predominant cells of the lesional infiltrate.
They could play crucial role in the dermalepider
mal separation through the release of their cyto
toxic proteins granulations and enzymatic media
tors [40]. Probably Th2 and CD8
+
Tc2 lympho
cytes effects are responsible for the increased IgE
levels in patients, what was suggested in patients
with atopic dermatitis [4042]. The IgG4 skin
depositions correlate with the increase of IgE
serum level [40]. The association between IgE and
IgG4 was indicated on the molecular level [40].
The important part in this diseases can play Th2
lymphocytes, since they stimulate IgG1 and IgE
production by B lymphocytes [44]. The animal
model of pemphigoid was used to investigate neu
trophils, mast cells, macrophages and lymphocytes
contribution and their functional relationship in
the immunopathogenesis of this disease [44].
Obtained results revealed that mainly mac
rophages are responsible for the blister formation,
mast cells activate macrophages, which initiative
neutrophil recruitment.
Mucous membrane pemphigoid (MMP) is an
autoimmune blistering disease of ocular, oral and
genital mucous membranes. Apart from localiza
tion from the classical bullous pemphigoid it can
be distinguished by having the tendency to result
in fibrosis. In its course subepithelial blisters and
deposition of immunoglobulins and complement
along the basement membrane zone (BMZ) can be
observed. At the present it is suggested that MMP
is not a single entity, but a group of different sub
sets such as pure ocular cicatricial pemphigoid
(OCP) and pure oral pemphigoid (OP) [45]. Skin
lesions appear in about 30% MMP patients.
Autoimmune Process Participation in the Oral Pathologies 271
To date, a series of autoantigens were isolated,
which form hemidesmosomes or are a part of basal
cells. The hemidesmosome constituents are: trans
membrane protein collagenlike bullous pem
phigoid antigen 180 (BPAG2 or collagen XVII)
and plaque proteinantigen of bullous pemphigoid
230 (BPAG1) [35, 37, 38]. Other autoantigens can
be proteins which bind basal cells below the
hemidesmosomes. They are laminin 6 and chain
of laminin 5 (epiligrin), 4 integrin and type VII
collagen and mucosal antigen 168 kD [35, 37, 46].
Many studies show that in the MMP patho
genesis haplotype DBQ1*0301 is necessary [45,
47]. It may have a role in Tcell recognition of
basement membrane antigens, resulting in the pro
duction of antiBMZ IgG antibodies [48].
Serum of the minority of patients contains IgG
and IgA antibodies, which bind constituents of
dermalepidermal junction. This leads to comple
ment fixation, leukocyte infiltration with basal
cells keratinocytes detachment from BMZ. Their
pathogenic character is confirmed by correlation
of the reaction of circulation IgG and IgA
antibasement membrane antibodies with the
aggravation of disease symptoms [35, 48, 49].
Behets Disease
Behets disease (BD) is a multisystemic
inflammatory disorder with a chronic recurrent
course. Typical criteria are recurrent: oral aphthae,
recurrent genital ulcerations, eye lesions (iritis,
uveitis). Less characteristic manifestations include
arthritis, gastrointestinal disturbances, epididymi
tis, pulmonary changes, glomerulonephritis, endo
and pericarditis, changes in the central nervous
system (5052]. Disease is a chronic recurrent vas
culitis concerning small and medium vessels with
accompanying perivascular necrosis.
The etiology is presumed to be multifactorial.
It consists of genetic predisposition, immune sys
tem dysregulation and endothelial cell dysfunction.
For the specific genetic predisposition states
the atypical geographic distribution of disease and
its close association with the major histocompati
bility complex allele HLAB51 (HLAB5101
5106) (relative risk 6.3) [53, 54]. The geographic
distribution of disease encounters mainly countries
spanning from Mediterranean basin to Far East,
which lie between latitudes 30 and 45 north [53].
Geographic occurrence of HLAB51 among
healthy people covers the global disease distribu
tion. This connection suggests, that genetic risk
factors were propagated by migrant traders along
the Silk Road 2000 years ago, what lead to the
synonym of Silk Road disease [53]. More likely
explanation is that such distribution of genes was
associated with demographic movements across
Asia and the Beringia Landmass about 1013
thousands years ago [53]. Last studies concerning
genetic determination of BD show new association
between MHC loci, and also genes out of this
complex. They are allelic variants of within TNF
gene region and within the MHC class1polymor
phism i.e. allele MICA6 [53, 54]. The association
with the V factor gene mutation on first chromo
some (Leiden mutation) was also revealed, which
is associated with the retinal vascular occlusion
and with polymorphism of intracellular adhesion
molecule gene ICAM [53].
Among environmental factors Huluci Behet
himself postulated a viral (HSV1) trigger of for
this disease [53, 54]. Serum antibodies to HSV1
and circulating immune complexes with HSV1 are
both reported to be raised in patients [53, 54]. It is
possible that viral factor could be the trigger for
this disease, although there is still lack of evidence.
The immune background of BD is shown in
reports concerning the influence of heat shock pro
teins (HSP), alterations in the neutrophil and
macrophage activity, expression of numerous
cytokines secreted by lymphocytes Th1. The influ
ence of HSP65 on BS pathogenesis is confirmed
by: the increased concentrations of IgA against
HSP65, presence of antibodies to oral epithelial
antigens, crossreactivity between polyclonal anti
bodies to HSP and Streptococcus sanguis with oral
epithelium antigens [acc. 54]. HSP65 can induce
lymphocytes to accumulate in erosive lesions
and then to stimulate the local and systemic secre
tion of IFN and TNF [55]. Interaction of HSP
with T lymphocytes could also contribute to
hyperactivation of lymphocytes Th1 secreting IL2,
which increased serum titres could be observed in
diseases active periods [54]. In the erosion forma
tion participate neutrophils, which chemotaxis,
phagocytosis, oxygen and nonoxygen bactericidal
mechanism are clearly activated in this disease
[54]. Consecutively monocyte and macrophage
hyperactivity explains the increased levels of
proinflammatory cytokines (IL1, IL6, IL8,
TNF) in patients with active BD.
The specific IgM to endothelial cell mem
branebound antigen 44 kD can be responsible for
typical vascular lesions in the course of this dis
ease [54]. Biding of the circulating IgM complexes
to their endothelial receptor induces type III
immunological reaction, with epithelial cells
cytokine synthesis, what then stimulates the flow
and accumulation of inflammatory cells. Circ
ulating immune complexes together with the
enhanced neutrophil migration can be responsible
for systemic and mucosal lesions in BD. Increased
E. KAROLEWSKA, T. KONOPKA 272
levels of NK cell were observed in peripheral
blood of patients with active disease [55].
Additionally enhancement of coagulation and
thrombosis was noted [56].
Chronic Ulcerative
Stomatitis
Chronic ulcerative stomatitis (CUS) was
described as a new disease entity in 1990 by
Jaremko et al. [acc. 57]. This disease is character
ized by the presence of erosions and ulcerations
with healing difficulty, mainly appearing on the
tongue and desquamative gingivitis. Clinical fea
tures are similar to those of erosive lichen planus.
In about 14% of patients skin lesions characteris
tic for lichen planus are present. CUS mostly
affects women over 50 years of age, and respond
to treatment with hydroxychloroquine (in dosage
of 250 mg daily in 5 day therapeutic courses with
5 days intervals) [58].
The immunological marker of CUS is the
presence of serum high titres of antinuclear anti
bodies (SESANA) directed against the nuclear
antigens of basal and spinous layer of the epitheli
um [59]. They are detected in indirect immunoflu
orescence method using various stratified epithe
lial tissues e.g. monkey or guineapig oesophagus
as the antigen substrate [58, 59]. Depositions of
IgG in keratinocytes nuclei (granular pattern), not
detectable on conventional substrates for ANA,
which are Hep2 and mouses kidneys, are
observed in direct immunofluorescence of lesional
oral mucosa. In consecutive examinations using
immunoblotting technique in the sera of CUS
patients a molecule in the range of 70 kD from the
p53 family was discovered [60]. It was proved that
antibodies, which precipitated 70 kD protein were
the same autoantibodies, which were binding the
nuclei of epithelial cells. Autoantigen was named
CUS protein (CUSP) [61]. The analysis of cDNA
sequence for this protein revealed great homology
to p53 tumor suppressor and p73 putative tumor
suppressor genes and to p53like gene, KET vari
ant [57]. The p53like genes, p73 and the several
KET splicing variants probably have pathologic
significance [57]. It has not been established in
what way autoantibodies binding CUSP induce the
disease, however the association of these antigens
with CUSP is clear. It was noted that titres of the
antibodies against CUSP not always correlate with
the intensity of disease symptoms [57]. They were
not detected in sera of patients with other autoim
mune diseases (systemic lupus, dermatomyositis)
and typical oral pathologies (aphthous stomatitis,
lichen planus). CUSP is believed to be an essential
epithelial regeneration and developmental factor
and the presence of specific antibodies for this
protein is responsible for the problems with wound
and chronic ulceration healing.
Periodontitis
Periodontitis is not an autoimmune disease.
However, in its pathogenesis the influence of the
autoimmune process on the disease course can be
detected. Series of studies have pointed to collagen
type I as the main autoantigen in this disease
[6265]. Significantly higher levels in gingival
extracts compared to serum levels of class IgG and
IgA antibodies against collagen type I could be
detected, what was explained as local synthesis of
these antibodies in the active periodontal tissues
damage periods [62]. The main source of
immunoglobulins seem to be B CD5 cells, but at
the time of formation of inflammatory process of
periodontal tissues there is an exchange of classes
from natural antibodies IgM to IgG and IgA [65].
Anusaksathien et al. [62] examined the serum
level of class IgG antibodies directed against
12 autoantigens (DSDNA, SSDNA, human and
bull thyroglobulin, myoglobin, transferrin,
myosin, actin, human collagen type I, proteogly
can, cytochrom C and foetus antigen) in patients
with periodontitis. Increased titres of collagen I
were only observed. Other studies revealed that in
90% of sera and in all analysed samples of gingi
val cervicular fluid from patients with periodonti
tis IgG class antibodies against desmosomal pro
teins (desmoplakin 1 and 2) and glycoproteins
desmoglein 1, 2 and 3 were present [66]. It is sug
gested that some of the so far described autoanti
gens, for example collagen I and desmosomal pro
teins exposed or released from periodontal struc
tures (as a result of bacterial destruction) are the
factors influencing the polyclonal activation of
lymphocytes B and synthesis of specific for these
structures antibodies [6266]. These observations
indicate the secondary nature of autoimmune
processes induced by periodontal tissue destruc
tion. Autoantibodies can influence the apical
migration of junctional epithelium and periodontal
pocket formation and can counteract the reattach
ment of connective tissue to root surface in the
period of periodontal treatment. Govze and
Herzberg suggested, that periodontal diseases
have a multifactor model of autoimmune process
es [66]. They are initiated by polyclonal bacterial
activators, inducing expansion of autoreactive
lymphocytes B leading to class IgG antibody syn
thesis. Many pathogenic for periodontium bacteria
e.g. Porphyromonas gingivalis and Fusobacterium
Autoimmune Process Participation in the Oral Pathologies 273
nucleatum show the properties of polyclonal acti
vators of lymphocytes B. Along in the lasting
process lymphocyte B activation is supported by
autoantigen stimulation coming from destroyed
tissues e.g. collagen, desmosomes of junctional
epithelium. The research model showed the high
est production of antibodies against collagen,
when collagen I and bacterial polyclonal activators
were available in destroyed periodontal tissues
[63]. The influence of microorganisms could rely
on the adjuvant action, increasing the autoanti
body reaction to main autoantigens exposed in the
course of periodontal tissue destruction.
In patients with periodontitis serum concentra
tion of antibodies against neutrophils cytoplasm
(ANCA) [67] and against human and bacterial
heat shock proteins (HSP) were examined [68]. It
does not look as these epitopes had a greater sig
nificance in escalating and the clinical course of
periodontitis. Interesting are the observations,
which point to significantly increased serum titres
of anticardiolipin antibodies anti2glycoprotein
I in the course of generalized periodontitis (chron
ic or aggressive) [69]. Probably they cross react
with the chosen sequence of arggingipain pro
tease of Porphyromonas gingivalis. Postulated
pathogenicity of these autoantibodies is defined by
the activation of endothelial cells, inducement of
oxygenmediated injury due to their reactivity
with oxidized low density lipoproteins (LDL) or
interference with natural anticoagulants [69].
Induction of antiphospholipid antibodies forma
tion in generalized periodontitis can have serious
systemic implications as earlier described escalat
ed susceptibility to atherosclerosis and increased
probability of preterm lowbirthweight labour
dependent on the periodontal status.
E. KAROLEWSKA, T. KONOPKA 274
References
[1] WAKOWICZKALISKA A.: Zjawiska autoimmunologiczne. W: Immunologia. Red.: Gob J., Jakbisiak M.,
Lasek W., Wydawnictwo Naukowe PWN, Warszawa 2002, 424446.
[2] ROITT I.: Autoimmunizacja i choroby autoimmunizacyjne. W: Immunologia. Red.: Roitt I., Brostoff J., Male D.,
Wydawnictwo Medyczne Sotwiski Verlag, Brema 1996, 27.1 27.13.
[3] CHWALISKASADOWSKA H., JDRYKAGRAL A.: Tocze rumieniowaty ukadowy. Med. Dypl. 2002, 11, 8892.
[4] ABRAMSON S. B., BELMONT M.: SLE: Mechanisms of vascular injury. Hospital Practice 1998, 33, 107114.
[5] BASZCZYK M., ROSISKABORKOWSKA D., JARZBEKCHRZELSKA M., NIEURAWSKA G., KONCA I., JABOSKA S.:
Tocze rumieniowaty noworodkw. Przegl. Dermatol. 2000, 87, 207216.
[6] WONIACKA A., SYSAJDRZEJOWSKA A., TORZECKA J. D.: Systemic lupus erythematosus and concomitant disor
ders. Med. Sci. Monit. 1999, 5, 333340.
[7] STONE N. M., WILLIAMS A., WILKINSON J. D., BIRD G.: Systemic lupus erythematosus with C1q deficiency. Br.
J. Dermatol. 2000, 142, 521524.
[8] KARA Z., RUTKOWSKI R., ADAMSKI Z.: Tocze rumieniowaty: nowe moliwoci diagnostyczne? Post. Dermatol.
2000, 17, 261266.
[9] BAIMA B., STICHERLING M.: Apoptosis in different cutaneous manifestations of lupus erythematosus. Br.
J. Dermatol. 2001, 144, 958966.
[10] DACZAKPAZDROWSKA A., PROKOP J.: Znaczenie komrek ukadu immunologicznego w patogenezie i terapii
tocznia rumieniowatego. Post. Dermatol. 1999, 16, 231244.
[11] KANG I., QUAN T., NOLASCO H., PARK S.H., HONG M. S., CROUCH J., PAMER E. G., HOWE J. G., CRAFT J.:
Defective control of latent EpsteinBarr virus infection in systemic lupus erythematosus. J. Immunol. 2004, 172,
12871294.
[12] VERDOLINI R., BUGATTI L., GIANGIACOMI M., NICOLINI M., FILOSA G., CERIO R.: Systemic lupus erythematosus
induced by EpsteinBarr virus infection. Br. J. Dermatol. 2002, 146, 877881.
[13] JONSSON R., MOEN K., VESTRHEIM D., SZODORAY P.: Current issues in Sjgrens syndrome. Oral Dis. 2002, 8,
130140.
[14] POKRZYWICKAGAJEK I.: Zesp Sjgrena. Przegl. Dermatol. 2001, 88, 207213.
[15] KRAJKALAUER J., LASS P., KOSEDA M., CZUSZYSKA Z., KOZOWSKI J., CACKOWSKALASS A.: Zesp Sjgrena.
Kontaktol. Opt. Okul. 2001, 2, 7682.
[16] BACCAGLINI L., PILLEMER S. R., BAUM B. J.: Sjgrens syndrome: a possible pathogenetic mechanism involving
somatostatin. Oral Dis. 2000, 6, 264266.
[17] WINER S., ASTSATUROV I., CHEUNG R., TSUI H., SONG A., GAEDIGK R., WINER D., SAMPSON A., MCKERLIE C.,
BOOKMAN A., DOSCH H.M.: Primary Sjgrens syndrome and deficiency of ICA69. Lancet 2002, 360,
10631069.
[18] MITSIAS D. I., TZIOUFAS A. G., VEIOPOULOU C., ZINTZARAZ E., TASSIOS I. K., MOUTSOPOULUS H. M., THYPHRONITIS G.:
The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjgrens syn
drome. Clin. Exp. Immunol. 2002, 128, 562568.
[19] DIMITRIOU I. D., KAPSOGEORGOU E. K., MOUTSOPOULUS H. M., MANOUSSAKIS M. N.: CD40 on salivary gland
epithelial cells: high constitutive expression by cultured cells from Sjgrens syndrome patients indicating their
intrinsic activation. Clin. Exp. Immunol. 2002, 127, 386392.
[20] DACZAKPADROWSKA A., UCZKOWSKA M., PROKOP J., ABA R.: Zastosowanie biologii molekularnej w bada
niach nad autoimmunologicznymi chorobami pcherzowymi skry. Dermatol. Klin. Zab. 2000, 2, 149153.
[21] KOWALEWSKI C.: Nowe pogldy na etiopatogenez, diagnostyk i leczenie pcherzycy. Przegl. Dermatol. 2000,
85, 387395.
[22] SCULLY C., PAES DE MALMEIDA O., PORTER S. R., GILKES J. J. H.: Pemphigus vulgaris: manifestations and long
term management of 55 patients with oral lesions. Br. J. Dermatol. 1999, 140, 8489.
[23] BOWCZYCDMOCHOWSKA M., DMOCHOWSKI M.: Przeciwciaa IgG, IgG1 i IgG4 przeciwko desmogleinie 3 w suro
wicach na pcherzyc zwyk. Przegl. Dermatol. 2001, 88, 153156.
[24] TSUJI Y., KAWASHIMA T., YOKOTA K., TATEISH Y., TOMITA Y., MATSUMURA T., SHIMIZU H.: Clinical and serological
transition from pemphigus vulgaris to pemphigus foliaceus demonstrated by desmoglein ELISA system. Arch.
Dermatol. 2002, 138, 9596.
[25] KOMAI A., AMAGAI M., ISHII K., NIKISHAWA T., CHORZELSKI T., MATSUO I., HASHOMOTO T.: The clinical transition
between pemphigus foliaceus to pemphigus vulgaris correlates well with the changes in autoantibody profile
assessed by an enzymelinked immunosorbent assay. Br. J. Dermatol. 2001, 144, 11771182.
[26] NARBUTT J., TORZECKA J. D., WASZCZYKOWSKA E., SYSAJDRZEJOWSKA A.: Pcherzyca opryszczkowata trud
noci diagnostyczne. Przegl. Dermatol. 2000, 87, 397401.
[27] ANHALT G. J.: Paraneoplastic pemphigus: the role of tumors and drugs. Br. J. Dermatol. 2001, 144, 11021104.
[28] HSIAO C.J., HSU M. M.L., LEE J. Y.Y., CHEN W.C., HSIEH W. C.: Paraneoplastic pemphigus in association with
a retroperitoneal Castelmans disease presenting with a lichen planus pemphigoideslike eruption. A case report
and review of literature. Br. J. Dermatol. 2001, 144, 372376.
[29] ALLEN C. M., CAMISA C.: Paraneoplastic pemphigus: review of the literature. Oral Dis. 2000, 6, 208214.
[30] JABOSKA S., JARZBEKCHORZELSKA M., SYSAJDRZEJOWSKA A., MACIEJEWSKA B.: Paraneoplastyczna
pcherzyca. Przegl. Dermatol. 2001, 88, 103110.
[31] MIMOUNI D., ANHALT G. J., LAZAROWA Z., AHO S., KAZEROUNIAN S., KOUBA D. J., MASCARO JR., J. M., NOUSARI H. C.:
Paraneoplastic pemphigus in children and adolescents. Br. J. Dermatol. 2002, 147, 725732.
[32] MUSIAOWICZ D., HASHIMOTO T., JARZBEKCHORZELSKAM., SZCZNIAK N., KOACISKASTRASZ Z., JABOSKAS.:
Pcherzyca paraneoplastyczna towarzyszca misakowi wrzecionowatemu. Zoony zesp autoimmunologiczny
z przeciwciaami skierowanymi przeciw plakinom i desmogleinom. Przegl. Dermatol. 2000, 87, 139146.
[33] VAN DER WAAL R. I. F., PAS H. H., NOUSERI H. C., SCHULTEN E. A. J. M., JONKMAN M. F., NIEBOER C., STOOF T. J.,
STARINK T. M., ANHALT G. J.: Paraneoplastic pemphigus caused by an epitheilioid leiomyosarcoma and associat
ed with fatal respiratory failure. Oral Oncol. 2000, 36, 390393.
[34] BORRADORI L., LOMBARDI T., SAMSON J., GIRANDET C., SAURAT J., HGLI A.: AntiCD20 monoclonal antibody
(rituximab) for refractory erosive stomatitis secondary to CD20
+
follicular lymphomaassociated paraneoplastic
pemphigus. Arch. Dermatol. 2001, 137, 269272.
[35] SCHMIDT E., SKROBEK C., KROMMINGA A., HASHIMOTO T., MESSER G., BRCKER E.B., YANCEY K. B., ZILLIKENS D.:
Cicatricial pemphigoid: IgA and IgG autoantibodies target epitopes on both intra and extracellular domains of
bullous pemphigoid 180. Br. J. Dermatol. 2001, 145, 778783.
[36] DMOCHOWSKI M., BOWCZYCDMOCHOWSKA M.: Biece wiadomoci o patogenezie pemfigoidu pcherzowego.
Post. Dermatol. 2000, 17, 167174.
[37] LEVERCUS M., BHOL K., HIRAKO Y., PAS H., SITARU C., BAIER G., BRCKER E.B., JONKMAN M. F., AHMED A. R.,
ZILLIKENS D.: Cicatricial pemphigoid with circulating autoantibodies to 4 integrin, bullous pemphigoid 180 and
bullous pemphigoid 230. Br. J. Dermatol. 2001, 145, 9981004.
[38] CHRISTOPHORIDIS S., BDINGER L., BORRADORI L., HUNZIKER T., MERK H. F., HERLT M.: IgG, IgAand IgE autoan
tibodies against the ectodomain of BP180 in patients with bullous and cicatricial pemphigoid and linear IgA bul
lous dermatosis. Br. J. Dermatol. 2000, 143, 349355.
[39] LAFFITTE E., FAVRE B., FONTAO L., RIOU S., JAUNIN F., TAMM K., SAURAT J.H., BORRADORI L.: Plectin, an unusual
target antigen in bullous pemphigoid. Br. J. Dermatol. 2001, 144, 136138.
[40] DELAPORTE E., DUBOSTBRAMA A., GHOHESTANI R., NICOLAS J.F., NEYRINCK J.L., BERGOEND H., JANIN A.,
CAPRON M.: IgE autoantigens directed against the major bullous pemphigoid antigen in patients with severe form
of pemphigoid. J. Immunol. 1996, 157, 36423647.
[41] BOWCZYCDMOCHOWSKA M., DMOCHOWSKI M.: Badania charakteru zogw IgE w skrze chorych na pemfigoid
pcherzowy. Derm. Klin. Zab. 2000, 2, 115118.
[42] BIAYNICKIBIRULA R., JABOSKI ., BARAN W., KOODZIEJ T.: Najbardziej charakterystyczne rodzaje immunoglobu
lin i skadowych dopeniacza stwierdzane in vivo w pemfigoidzie pcherzowym. Derm. Klin. Zab. 2000, 2, 119122.
[43] BOWCZYCDMOCHOWSKA M., DMOCHOWSKI M.: Wykrycie ziarnistych zogw IgE w skrze waciwej, lecz nie li
nijnych zogw IgE wzdu poczenia skrnonaskrkowego, u niektrych chorych na pemfigoid pcherzowy.
Post. Derm. Alergol. 2001, 18, 177180.
[44] CHEN R., FAIRLEY J. A., ZHAO M.L., GUIDICE G. J., ZILLIKENS D., DIAZ L. A., LIU Z.: Macrophages, but not T and
B lymphocytes, are critical for subepidermal blister formation in experimental bullous pemphigoid: macrophage
mediated neutrofil infiltration depends on mast cell activation. J. Immunol. 2002, 169, 39873992.
[45] CARROZZO M., FASANO M. E., BROCCOLETTI R., CARBONE M., COZZANI E., RENDINE S., ROGGERO S., PARODI A.,
GANDOLFO S.: HLADQB1 alleles in Italian patients with mucous membrane pemphigoid predominantly affecting
the oral cavity. Br. J. Dermatol. 2001, 145, 805808.
[46] TABIUCHI K., TAKATA M., MATSUI C., FUSHIDA Y., UCHIYAMA K., MORI T., KAWARA S., YANCEY K. B., TAKEHARA K.:
Antiepiligrin (laminin 5) cicatricial pemphigoid associated with an underlying gastric carcinoma producing
laminin 5. Br. J. Dermatol. 1999, 140, 696700.
Autoimmune Process Participation in the Oral Pathologies 275
[47] SETTERFIELD J., THERON J., VAUGHAN R. W., WELSH K. I., MALLON E., WOJNAROWSKA F., CHALLACOMBE S. J.,
BLACK M. M.: Mucous membrane pemphigoid: HLADQB1*0301 is associated with all clinical sites of involve
ment and may be linked to antibasement membrane IgG production. Br. J. Dermatol. 2001, 145, 406414.
[48] SETTERFIELD J., SHIRLAW P.J., KERRMUIR M., NEILL S., BHOGAL B. S., MORGAN P., TILLING K., CHALLACOMBE S. J.,
BLACK M. M.: Mucous membrane pemphigoid: a dual circulating antibody response with IgG and IgA signifies
a more severe and persistent disease. Br. J. Dermatol., 1998, 138, 602610.
[49] SETTERFIELD J., SHIRLAW P. J., BHOGAL B. S., TILLING K., MALLON E., CHALLACOMBE S. J., BLACK M. M.:
Cicatricial pemphigoid: serial titres of circulating IgG and IgA antibasement membrane antibodies correlate with
disease activity. Br. J. Dermatol. 1999, 140, 645650.
[50] GRABSKI J., GRABSKI J. J. R.: Przyczynek do kliniki zespou Beheta. Pol. Tyg. Lek. 1990, 45, 520522.
[51] KUCHARZ E. J.: Choroba Beheta. Post. Nauk. Med. 1993, 6, 234237.
[52] WYSOCKA K., WONIAKOWSKA M., FERLASCHODNY E.: Choroba Beheta obserwacje 10 przypadkw. Reuma
tologia 1997, 35, 8995.
[53] VERITY D. H., WALLACE G. R., VAUGHAN R. W., STANFORD M. R.: Behets disease: from Hippocrates to the third
millennium. Br. J. Ophthalmol. 2003, 87, 11751183.
[54] ZOUBOULIS C. C., MAY T.: Pathogenesis of AdamantiadesBehets disease. Med. Microbiol. Immunol. 2003, 192,
149155.
[55] FREYSDOTTIR J., LAU S.H., FORTUNE F.: T cells in Behets disease (BD) and recurrent aphthous stomatitis
(RAS). Clin. Exper. Immunol. 1999, 118, 451457.
[56] KIRAZ S., ERTENLI ., ZYRK M. A., HAZNEDAROLU . C., ELIK ., ALGNERI M.: Pathological haemostasis
and prothrombotic state in Behets disease. Thromb. Res. 2002, 105, 125133.
[57] LEE L. A., WALSH P., PRATER C. A., SU L.J., MARCHBANK A., EGBERT T. B., DELLAVALLE R. P., TARGOFF I. N.,
KAUFMAN K. M., CHORZELSKI T. P., JABOSKA S.: Characterization of an autoantigen associated with chronic
ulcerative stomatitis: the CUSP autoantigen is a member of p53 family. J. Invest. Dermatol. 1999, 113, 146151.
[58] WRLE B., WOLLENBERG A., SCHALLER M., KUNZELMANN K.H., PLEWIG G., MEURER M.: Chronic ulcerative
stomatitis. Br. J. Dermatol. 1997, 137, 262265.
[59] SOLOMON L. W., AGUIRRE A., NEIDERS M., COSTALESSPINDLER A., JIVIDEN G. J.: Chronic ulcerative stomatitis:
clinical, histopathologic, and immunopathologic findings. Oral Surg. Oral Med. Oral Pathol. 2003, 96, 718726.
[60] PARODI A., COZZANI M., CACCIAPUOTI M., REBORA A.: Chronic ulcerative stomatitis: antibodies reacting with the
70kDa molecule react with epithelial nuclei. Br. J. Dermatol. 2000, 143, 671672.
[61] DELLAVALLE R. P., WALSH P., MARCHBANK A., GRAYSON T. E., SU LJ., PARKER E. R., DEGREGORI J., PENHEITER
K., ASZTERBAUM M., EPSTEIN E. H. JR., LEE L. A.: CUSP/p63 expression in basal cell carcinoma. Exp. Dermatol.
2002, 11, 203208.
[62] ANUSAKSATHIEN O., SINGH G., PETERS T., DOLBY A.: Immunity to selfantigens in periodontal disease.
J. Periodontol. 1992, 63, 194199.
[63] HAHN C.L., SCHENKEIN H., TEW J. G.: Polyclonal B cell activators and in vitro induction of autoantibody reac
tive with collagen. J. Periodontal Res. 1997, 32, 608613.
[64] HIRSCH H., TARKOWSKI A., MILLER E., GAY S., KOOPMAN W., MESTECKY J.: Autoimmunity to collagen in adult
periodontal disease. J. Oral Pathol. 1988, 17, 456459.
[65] SUGAWARA M., YAMASHITA K., YOSHIE H., HARA K.: Detection of, and anticollagen antibody produced by, CD5
positive B cells in inflammed gingival tissues. J. Periodontal Res. 1992, 27, 489498.
[66] GOVZE Y., HERZBERG M.: Serum and gingival cervicular fluid antidesmosomal antibodies in periodontitis.
J. Periodontol. 1993, 64, 603608.
[67] NOVO E., VIERA N.: Antineutrophil cytoplasmic antibodies: a missing link in the pathogenesis of periodontal dis
ease? J. Periodont. Res. 1996, 31, 365368.
[68] LOPATIN D., SHELBURNE C., VAN POPERIN N., KOWALSKI C., BAGRAMIAN R.: Humoral immunity to stress proteins
and periodontal disease. J. Periodontol. 1999, 70, 11851193.
[69] SCHENKEIN H., BERRY C., BURMEISTER J., BROOKS C., BARBOUR S., BEST A., TEW J.: Anticardiolipin antibodies
in sera from patients with periodontitis. J. Dent. Res. 2003, 82, 912922.
Address for correspondence:
Ewa Karolewska
Department of Oral Pathology Wroclaw Medical University
Kunicza 43/45
50138 Wrocaw
Poland
tel./fax: (+48 71) 342 42 16
email: oralpat@stom.am.wroc.pl
Received: 28.01.2004 Praca wpyna do Redakcji: 28.01.2004 r.
Revised: 23.02.2004 Po recenzji: 23.02.2004 r.
Accepted: 26.02.2004 Zaakceptowano do druku: 26.02.2004 r.
E. KAROLEWSKA, T. KONOPKA 276