ARTICLE
Auteur(s) : Fumio Kaneko1,
Noritaka Oyama1, Hirokatsu Yanagihori2, Emiko
Isogai3, Kenji Yokota4, Keiji
Oguma4
1Institute of Dermato-Immunology and -Allergy,
Southern TOHOKU Research Institute for Neuroscience, 7-115
Yatsuyamada, Koriyama, Fukushima, 963-8563
2Department of Dermatology, Fukushima Medical University
School of Medicine, Fukushima
3Department of Disease Control and Molecular
Epidemiology (Preventive Dentistry), Health Sciences University of
Hokkaido, Ishikari-Tobetsu, Hokkaido
4Department of Bacteriology, Okayama University Graduate
School of Medicine and Dentistry, Medical School, Okayama,
Japan
accepté le 14 Avril 2008
Behçet’s disease (BD) [1] or Adamantiades-Behçet’s disease [2]
is a chronic multisystemic inflammatory disorder characterized by
the recurrent involvement of muco-cutaneous (oral and genital
ulceration, erythema nodosum (EN)-like eruption, acne-like
eruption, etc.), ocular, vascular, digestive and/or nervous system
organs. Although the actual etiology of BD is still unclear, the
pathogenesis has become generally clearer by investigation of the
epidemiology, clinical manifestations and basic etiological
research based on the intrinsic genetic and extrinsic triggering
factors and the immunological findings [3-13]. The genetic
predisposition is included as one of the intrinsic factors, because
more than 60% of BD patients are associated with HLA-B51 [3-6]. As
one of the extrinsic triggering factors, an unhygienic oral
condition may be suspected, because periodontitis, decayed teeth,
chronic tonsillitis, etc. are frequently noted in the oral cavity
of BD patients [9, 10]. The proportion of Streptococcus sanguinis
(S. sanguinis), which was previously recognized as a species of the
genus Streptococcus named “S. sanguis” [11-13], was significantly
higher in the oral bacterial flora of BD patients than those of
healthy and disease controls (table 1).
The S. sanguis isolated from BD patients was different from
reference ATCC strains in DNA homology and sugar constituents.
Here, we call these clinical isolates S. sanguinis, although they
may include not only S. sanguinis but also S. oralis, because the
chemiluminescence of neutrophils obtained from BD patients was
increased in correlation with the proportion of S. sanguinis in the
oral flora. The strains isolated as S. sanguinis were serologically
different from various strain types from healthy controls, but the
DNA-DNA homology was shown as S. oralis and S. sanguinis-like
species [12, 13]. Then, S. sanguinis was identified as an uncommon
serotype KTH-1 (so-called BD113-20 strain) by its bacterial and
enzymatic properties [12, 13] Most patients tend to acquire delayed
type hypersensitivity against streptococci in their oral flora, and
as previously demonstrated, much stronger cutaneous reactions than
the general pathergy test when intracutaneous injections and/or
prickle tests were carried out using various killed bacteria and/or
their cell wall antigens, including streptococci, enterococci,
staphylococci, etc. (table 2) [9, 10,
14-16]. In vitro experiments, IL-6 and INF-γ were significantly
produced from PBMCs of BD patients in stimulation by KTH-1 antigens
[17]. The serum-antibody titers against streptococci were also
elevated in BD patients [18]. The 65kDa of a heat shock protein
(HSP-65) derived from oral bacteria, including S. sanguinis, can be
detected along with counterpart human HSP-60 which appears
reactively in the sera and lesions of BD patients. The peptides of
HSP-65 derived from the bacteria show considerable homology with
those of the human HSP-60 [19-21].
Although Sakane et al. [22] have reviewed the general clinical
manifestations and pathogenesis of BD, based on data since 1972
from the Research Committee for Behçet’s Disease organized by
Japanese Ministry of Health, Labour and Welfare, our Research
Committee, newly organized in 2001, revised the diagnostic criteria
established in 1987. In the new criteria, in 2003, we included
hypersensitivity skin reactions against streptococci in the
diagnosis as one of the references and the levels of disease
severity of BD patients, as introduced by Suzuki et al. [23].
Hence, we would mainly like to discuss the role of abnormally
hypersensitive immune reactions against oral streptococci as one of
the extrinsic triggering factors in connection with the intrinsic
factors in the pathogenesis of BD.
HLA genotyping of BD and streptococcal infection
HLA-B51 is supposed to be a highly associated genetic marker of BD
patients from many different ethnic groups, including European,
Mediterranean and Asian people [3, 5, 24, 25] and BD has several
unique epidemiological features which seem to go from Southern
Europe to Japan along “the old Silk Route” [3, 5, 6, 25]. Although
the HLA-B51 phenotype is important as an intrinsic factor for BD
patients, and HLA-B51-transgenic mice show enhanced neutrophil
function, because the HLA-B51 gene presents endogenous peptides to
CD8 T cells (cytotoxic T lymphocytes; CTLs), these mice do not
express BD symptoms [24]. The appearance of BD lesions is not
considered to be directly correlated with HLA-B51 in the
immunological background of patients, but it was recently found
that HLA-B51-restricted CTLs played some roles in BD pathogenesis
in correlation with the stressed target tissues expressing major
histocompatibility complex class I-related gene A (MICA) [26, 27].
When the transmembrane-MICA located nearly at the HLA-B51 gene is
preferentially expressed on epithelial and endothelial cells by
stress, they seem to be candidates for the HLA-B51-restricted CTLs
response [27]. These findings are based on the following; in
HLA-B51 positive BD patients in the acute phase, MICA-transmembrane
peptides derived from the amino acid sequence of MICA*009, which is
in strong linkage disequilibrium with HLA-B51 [28], were
significantly detected as targets of T cell responses. MICA
expression was lost after the BD-related symptoms disappeared and
the MICA-induced T cell response was also inhibited by anti-HLA
class I antibodies and by CD8 T cell depletion. MICA expressed on
the stressed epithelium and endothelium are considered to be the
ligand for activating natural killer (NK) cells with the NKG2D
molecule and CD8 T cells as CTLs [27]. BD lesional reactions might
be accelerated by inflammatory cytokines and chemokines secreted
from CTLs and NK cells [29, 30]. Regarding NK cell activation,
inhibitory CD34/NKG2A and activating CD94/NKG2C molecules are
alternatively expressed on NK,
CD4 +CD8 +T cells, indicating an
imbalance in cytotoxic activity in BD patients [31], although the
function of NK cells is supposed to be down-regulated in the active
stage and to be up-regulated in the remission stage of BD patients
[32].
It is considered that the HSP-65/60 derived from microorganisms
including S. sanguinis and from human tissues, which is detected in
the oral mucosal and skin lesions of BD patients [19, 20], also
becomes a stress-inducible factor in connection with MICA*009
expression. Generally, antigen presenting cells (APCs), which
produce IL-12 in correlation with Th1 type immune-reactions, are
thought to be activated in BD patients with HLA-B51 in the active
stage, as indicated by Yasuoka et al. [27]. However, we have
recently obtained interesting results that PBMCs from BD patients
without the HLA-B51 gene can be significantly stimulated by S.
sanguinis antigen in the expression of IL-12p40 mRNA and in the
increasing of protein levels in connection with IL-12p70
(70 kDa composed of p35 and p40 subunits), compared to those
of patients with HLA-B51 [33]. It has been suggested that the
antibacterial host response in T type immunity mediated by IL-12 is
much stronger in HLA-B51-negative BD patients, though the precise
findings will be discussed later again.
Table 1 Oral bacterial flora in BD patients, disease
controls and healthy controls. Subjects: 22 BD patients with oral
aphthous ulcerations (age-mean: 35.8) and 10 healthy controls and 8
disease controls including Vogt-Harada disease, sarcoidosis, herpes
simplex infection, etc. who were similarly aged to the BD patients.
Sampling: Supragingival plaque was taken from the lower first and
second premolars or first molar after clinical examinations. Cotton
swab specimens were obtained from the surface of the tongue dorsum
and buccal mucosa. Each sample was incubated on TYC agar with 5%
sucrose and Mitis-Salivarius agar for Streptococcus species at
37 °C for 2 days. For identification of streptococcus species,
API-STREP system and confirming tests were used and the total
viable count was calculated as percentage, as described by Isogai
et al. [13]. The proportion of S. sanguinis (S. sanguis) was
significantly higher in the oral bacterial flora of BD patients
than controls
|
Bacteria
|
% prominent flora (mean ± SE) of plaque from
|
|
Patients with BD (n = 22)
|
Healthy controls (n = 10)
|
Disease controls (n = 8)
|
|
Gram-positive bacteria
|
66.7 ± 3.6
|
69.0 ± 6.2
|
56.0 ± 6.2
|
|
Streptococcus
|
53.3±4.1 *
|
48.1 ± 4.6
|
39.0 ± 5.7
|
|
S. sanguis
|
26.7±3.7*,
|
9.4 ± 0.6
|
7.5 ± 2.3
|
|
S. salivarius
|
7.4 ± 1.4
|
6.6 ± 2.4
|
6.0 ± 1.9
|
|
S. mitis
|
14.9 ± 2.1 (**), ( *)
|
25.9 ± 4.5
|
24.0 ± 3.6
|
|
S. mutans
|
4.1 ± 1.1*,
|
0.2 ± 0.1
|
1.5 ± 0.6
|
|
Other streptococci
|
0.2 ± 0.1(*)
|
6.0 ± 2.5
|
< 0.1
|
|
Enterococcus
|
0.25 ± 0.11
|
0.01 ± 0.01
|
0.02 ± 0.01
|
|
Staphylococcus
|
0.26 ± 0.19
|
0.02 ± 0.01
|
< 0.001
|
|
Lactobacillus
|
1.6 ± 0.6
|
0.38 ± 0.02
|
0.19 ± 0.11
|
|
Eubacterium
|
0.36 ± 0.17
|
0.23 ± 0.28
|
0.17 ± 0.08
|
|
Gram-positive bacteria
|
33.2 ± 3.5
|
29.2 ± 7.1
|
44.0 ± 6.2
|
|
Bacteroides
|
16.5 ± 2.2*
|
6.4 ± 1.9
|
24.1 ± 5.1
|
- Black pigmented
- Bacteroides
|
3.1 ± 0.7**
|
0.9 ± 0.2
|
2.9 ± 1.4
|
|
Fusobacterium
|
2.6 ± 0.6( *)
|
1.9 ± 0.7
|
9.3 ± 3.8
|
|
Veillonella
|
3.3 ± 1.1
|
7.8 ± 3.1
|
3.1 ± 1.2
|
|
Enterobacteriaceae
|
< 0.001
|
ND
|
ND
|
|
Others
|
7.5 ± 1.1
|
6.8 ± 2.8
|
4.6 ± 1.3
|
|
Molds
|
0.15 ± 0.08
|
ND
|
< 0.01
|
Table 2 The skin tests by bacterial antigens and saline
for BD patients and healthy controls. Each 0.01 mL of the
bacterial antigens (bacteria vaccines: 1 × 109
org./mL. Hollister-Stier Lab., USA) was intracutaneously injected
in 84 BD patients and 10 healthy controls. The reaction was
observed at 15 min. and 48 hours after injection. The
erythematous skin reactions by streptococcal antigens were
significantly stronger than those by other antigens in BD patients
[9, 10]
|
Bacterial vaccines
|
Behçet’s syndrome
|
Normal controls
|
|
15 min
|
48 h
|
15 min
|
48 h
|
|
S. pyogenes
|
7 ± 8
|
41 ± 15
|
11 ± 11
|
8 ± 6
|
|
S. viridans
|
8 ± 7
|
46 ± 11
|
4 ± 4
|
2 ± 3
|
|
S. non-hemolyticus
|
7 ± 7
|
35 ± 14
|
5 ± 5
|
3 ± 4
|
|
S. faecalis
|
10 ± 8
|
40 ± 19
|
12 ± 11
|
0
|
|
Pneumococcus
|
16 ± 10
|
32 ± 14
|
8 ± 9
|
3 ± 4
|
|
E. coli
|
6 ± 7
|
16 ± 11
|
2 ± 1
|
1 ± 2
|
|
H. influenzae
|
11 ± 10
|
15 ± 15
|
9 ± 13
|
11 ± 12
|
|
Sta. aureus
|
8 ± 7
|
12 ± 13
|
3 ± 7
|
0 ± 1
|
|
Sta. epidemidis
|
5 ± 7
|
6 ± 7
|
2 ± 7
|
1 ± 2
|
|
Prot. vulgaris
|
10 ± 16
|
28 ± 13
|
6 ± 6
|
17 ± 4
|
|
Pseud. aeruginosa
|
1 ± 1
|
22 ± 11
|
2 ± 3
|
5 ± 0
|
|
SK-SD (50 U/mL)
|
|
9 ± 12
|
|
20 ± 9
|
|
Saline
|
|
2 ± 4
|
|
0 ± 1
|
Hypersensitivity against S. sanguinis
Generally, oral health is impaired in BD patients [9, 10, 12, 13],
which seems to be associated with disease severity [34]. It is not
clear that the predisposition of the patients is correlated with
streptococcal infection, but the uncommon oral S. sanguinis
serotypes are significantly increased in BD patients compared with
healthy and disease controls, as previously described [12, 13]. The
antibodies against S. sanguinis in sera from BD patients showed
cross reactivity with some synthetic peptides of HSP-65 derived
from S. sanguinis [35, 36]. The patients show strong delayed type
cutaneous hypersensitivity reactions against streptococcal antigens
in skin tests and sometimes BD symptoms were provoked by skin
injection of the antigens [9, 10, 14-16]. Because aphthous
ulceration can be also induced by a prick with streptococcal
antigens on the oral mucous membrane of a BD patient [10], the
appearance of aphthous ulceration is considered to be based on a
hypersensitive reaction against S. sanguinis, which may penetrate
traumatically into the oral membrane of BD patients. Isogai et al.
[36] demonstrated that symptoms mimicking BD appeared in germ-free
mice when S. sanguinis from BD patients was inoculated into their
oral tissue which was damaged by heat shock and/or mechanical
stress. This report suggests that immunization with S. sanguinis
through the oral membrane route elicits BD-like symptoms in the
animal model, as is seen in BD patients who carry S. sanguinis as
the pathogenic microorganism in their oral cavity. We tried to find
PCR targeting Bes-1 gene in BD lesions using 2 distinct primer sets
(peptides, 229-243 and 373-385) encoding S. sanguinis (serotype
KTH-1), which was prepared by Yoshikawa et al. [37]. Bes-1 DNA was
present in various muco-cutaneous lesions including oral and
genital ulcerations and EN-like lesions and the PCR-in situ
hybridization revealed that Bes-1 DNA was expressed in the
cytoplasm of inflammatory infiltrated monocytes adhering the
vascular walls in muco-cutaneous lesions (figure 1A and B) [38].
These infiltrated monocytes may express streptococcal antigens on
the cell membrane because they were detected by immunofluorescence
with anti-streptococcal antibodies, as previously reported (figure 2 A-C) [10,
15]. In contrast, we failed to detect the DNA of HSV-1, HSV-2,
cytomegalovirus, HHV-6 and HHV-7 in the lesions by PCR [39],
although HSV infection has been speculated as etiologically
important since the report of H. Behçet [1]. However, animal models
infected by HSV have been also demonstrated to mimic BD like
symptoms [40]. Interestingly, the amino acid sequence of the
peptides of Bes-1 (229-243 and 373-385) shows more than 60%
similarity to the human intraocular ganglion peptide, Brn-3b which
is a subfamily of POU (pit-Oct Unc) domain factors containing
Brn-3a and Brn-3c [41]. The peptide of Bes-1 (229-243) was also
found to be correlated with the peptide of HSP-60 (336-351) [35].
Recently it has been found that the peptide of Bes-1 (337-385)
stimulated the production of IFN-γ and IL-12 from PBMCs of BD
patients, although cellular proliferation was not observed [42].
These results suggest that Bes-1 derived from oral S. sanguinis
might be an inducer for the retinal and neural involvement possible
in BD patients.
HSP-65 derived from microorganisms and human HSP-60
HSPs, which scavenge denatured intracellular proteins, are supposed
to be induced by microorganisms and mammalian tissues under a
variety of stressful conditions [43] and they may be involved in
the pathogenesis of some autoimmune diseases [44]. In BD patients,
the serum levels of IgA antibodies to mycobacterial HSP-65, which
cross-reacts with selected strains of S. sanguinis, are increased
significantly [45, 46]. HSPs taken up by APCs are thought to
stimulate T cells directly, the monocytes expressing HSP-60 led T
cells to undergo apoptosis after IFN-γ production [47] and the
presence of HSP-60 was also detected in various lesions of BD
patients [46, 48, 49]. On the other hand, 4 peptides of HSP-65
(111-125, 154-172, 219-233 and 311-326) derived from S. sanguinis
were recognized as immuno-dominant agents for T cell and B cell
responses and they showed 50-80% homology to the counterpart human
HSP-60, as shown in figure 3 [20, 48-50]. The 4
peptides of HSP-65 were shown to significantly stimulate and
undergo CD4 and CD8 T cell apoptosis in PBMCs from BD patients and
HSP-60 also seemed to stimulate them [46, 47]. On the contrary, the
other two peptides of HSP-65 (21-35 and 401-415) corresponding to
the peptide of human HSP-60 (425-441), are reported not to
stimulate PBMCs from BD patients and healthy individuals (HIs)
[43]. The peptide of HSP-60 (336-351) was also identified to be
highly homologous to the T cell epitope [43, 45-52]. Whole HSP-60
is, however, suspected to increase vascular endothelial growth
factor (VEGF) which activates, impairs and proliferates vascular
endothelial cells [53] and which may lead to thrombophebitis and
vasculitis, by damaging endothelial cells in BD patients. Although
the term of “vasculitis” has been frequently used in BD lesions,
Jorrizo et al. [54] previously reported that the real vasculitis,
exhibiting “necrotizing vasculitis”, was rarely seen in the EN-like
eruptions of BD patients, and in most cases, the vascular reaction
is surrounded by monocytes and a few neutrophils, as we
demonstrated in figure
2B. This is so-called “lymphocytic vasculitis” seen
histologically, as recently described by other authors [55, 56]. It
is observed, however, that the serum levels of soluble(s) adhesion
molecules, such as s-selectins and s-intercellular adhesion
molecule-1, are elevated [57, 58] and also the expression of VEGF
is increased in the presence of HSP in the lesions of BD [59]. The
subcutaneous administration of HSP peptides to mice has been shown
to induce uveitis with vascular impairment [60].
On the other hand, it is of interest that the HSP-60 peptide
(336-351), linked to the recombinant cholera toxin B subunit
(rCTB), reduced the uveitis induced by whole HSP-60, although the
peptide without adjuvant is reported to induce uveitis in Lewis
strain rats [60, 61]. Recently, a therapeutic trial with the
peptide conjugated with rCTB was given orally to BD patients with
recurrent uveitis and successful results were obtained, as 5 of 8
patients had no relapse of the uveitis, no side-effects were
present and 2 of the remaining 3 patients had improved recurrent
oral ulceration, folliculitis, EN-like eruptions, and genital
ulcers [62]. In those patients with control of uveitis and
extra-articular manifestations, a lack of the peptide-specific CD4
T cell population, a decrease in expression of Th1 type cells
(CCR5, CXCR3) and a reduction of IFN-γ, TNF-α, CCR7 T cells and
co-stimulatory molecules (CD40 and CD28) were described in
comparison to BD patients with relapse of disease [62]. These
findings may suggest immuno-toleration in active BD patients. It is
hypothesized that CTLs play a role in BD pathogenesis by targeting
a self antigen selectively expressed in the affected tissues. In BD
patients with active disease, the endogenously generated MICA
transmembrane-peptide by autoreactive CTLs is present [27] and the
excessive inflammatory responses might be induced by extrinsic
factors correlated with S. sanguinis and other organisms, including
Helicobactor pylori, mycoplasma fermentas, etc. [63-65].
Neutrophilic hyperfunction and a cross-reactive autoimmune response
between microbial and human HSPs are proposed to be correlated with
the hyperreactivity against microorganisms, including S. sanguinis,
seen in BD patients [9, 10, 14-17]. These HSPs presented by APCs
can directly stimulate αβT and γδ T cells, which play important
roles in oral mucosal immunity as the first defense against
microorganisms. It is thought that Vγ9δ2+ T cells, a
major subset of γδ T cells in PBMCs, recognize antigens produced by
bacteria and that innate and adaptive immune responses are
influenced by secreting IFN-γ, towards a Th1 profile [20, 66, 67].
These γδ T cells seemed to be elevated in PBMCs and in the
muco-cutaneous lesions of BD patients [47, 66]. The second major
subset, γδ1+ T cell, is enriched in the mucosa and the
antigens are presented by APCs with stress-inducible MICA and MICB.
The γδ T cells, which highly express CD29 and CD69, produce IFN-γ
and TNF-α from stimulation by HSP-65/60 in the peripheral blood and
in the lesions of BD patients with active disease [20, 47, 66].
These activated APCs and γδ T cells might activate αβ T cells by
their secretion of sIL-2R, IFN-γ, TNF-α and also high levels of
other cytokines, IL-1α, IL-6, IL-8, IL-15, etc., which are detected
in the sera of BD patients [67-69]. In the active stage of BD
patients, IL-12 is also produced as a sign of an advanced Th1 type
reaction. The gene polymorphism in the promoter region regarding a
4 bp insertion within IL-12p40 was significantly higher in HLA-B51
negative BD patients than HLA-B51 positive patients and HIs. The
expression of IL-12p40 mRNA and protein levels in conjugation with
IL-12p70 induction were also significantly increased in PBMCs from
BD patients without HLA-B51 by stimulation with S. sanguinis
antigen, as previously described [33]. It has been recently found
that expression of IL-23, which is composed of a shared p40 subunit
of IL-12 and p19 subunit of IL-23, was also increased with IL-12 in
EN-like lesions of BD patients [70].
HSPs and BD pathogenesis
Although antibodies against the HSP peptides derived from bacteria
including S. sanguinis are found in sera of BD patients [35, 36],
HSP specific antibodies and T cells are considered to play a
complicated role in the pathogenesis of human autoimmune diseases
[71]. HSPs might trigger both innate and adaptive immune mechanisms
in BD. On the other hand, the therapeutic approaches involving HSP
immunomodulation may be available as “oral toleration” using the
peptide of HSP (336-351) linked to rCTB for BD patients with
advanced uveitis, as demonstrated by Stanford et al. [62]. Then, we
tried to analyze HSP-65 derived from S. sanguinis to find
homologous peptides to T cell epitopes of BD patients, and some
peptides were found to be highly homologous with T cell epitopes in
the correlation with human HSP-60, as indicated in figure 3. Attempts have
been made to find out how the newly synthesized homologous peptides
influence proinflammatory cytokine production from PBMCs of active
BD patients. The peptides, LO1 (249-264), IIIa (365-384), IIIb
(395-413), LO2 (480-499), LO3 (504-518) and UK (311-326),
corresponding to the peptide of human HSP-60 (336-351), were
applied to lead immuno-toleration for activated CTLs of BD patients
in vitro. PBMCs from 7 active BD patients and 5 HIs were incubated
with and without these peptides and 7 days after incubation IL-8,
IL-12, IFN-γ and TNF-α were measured and compared with those from
PBMCs of active BD patients incubated without the peptides as
controls. Although IL-12 and IL-8 were actively produced from PBMCs
in active BD patients, even though they were not stimulated, a
significant reduction of inflammatory cytokines was found by some
kinds of the peptides. The 5 peptides, LO1, LO2, LO3, IIIb and UK
significantly reduced IL-12 production and also LO1, IIIa and IIIb
significantly inhibited IL-8 production, except for LO2 and LO3
(figure 4A and
B). On the other hand, the cytokines from PBMCs of HIs were
significantly increased on stimulation by the peptides. In order to
understand the suppressive mechanisms of the cytokine production in
PBMCs from active BD patients, we tried to find the binding sites
of the peptides on monocytes by cDNA chips (Gene Chip; Human
Genome) using NOMO-1 cells (human macrophage cell line) activated
by S. sanguinis antigen and they were incubated with the peptides.
It was found that although the expression of IL-8, IL-16, IL-13R
and IL-17R was decreased after incubation with LO1 and UK,
respectively, LO2 did not decrease IL-8 production. CD58
(lymphocyte function-associated antigen-3) molecule and/or FK506
binding protein were highly expressed on the cell membrane by LO1
and UK [72]. It is considered that activated CTLs of BD patients
might lead to apoptosis and/or dysfunction of lymphoid cells by the
binding of LO1 and UK on the cell-receptors.
Toll-like receptor (TLR) expression in innate immunity
Regarding the recognition system for microorganism antigens in
humans, 10 members of the TLR family are supposed to act as innate
immune receptors by binding particular structures present on
bacteria, viruses, fungi, etc. [73]. Although, generally, TLRs are
weakly detectable in various human tissues with varying levels, the
TLR expression of the organs involved in immune responses and
exposed to the environment, is found to be significantly stronger
[74]. Our BD Research Group have already found the expressions of
TLR-2 (recognize: bacterial lipoprotein, zymosan,
lipopolysaccharide (LPS), lipoteicholic acid of microbial antigen,
etc.) and TLR-4 (LPS, HSP-65/60, etc.) on PBMCs and their presence
has also been recognized in intestinal lesions by immunohistology
(not yet published in the English literature) [75]. TLR-3 [ds RNA]
and TLR-6 (mycoplasma, staphylococci, etc.) are also reported to
have enhanced expression on the neutrophils and monocytes of BD
patients, when stimulated by HSP-60 and S. sanguinis antigens [76].
In oral ulcer lesions, expression of TLR-9 (unmethylated CpG DNA,
bacteria and virus) has recently been found [77]. These findings
suggest that the innate immune system contributes to the
acquisition of hypersensitivity against oral S. sanguinis as the
extrinsic factor in the pathogenesis of BD.
Complement system in innate immunity
It is generally accepted that the compliment system is accelerated
in relation to chemokine and neutrophilic activation [78, 79]. In
BD lesions, deposits of complement C3 with immunoglobulins are
frequently detectable by immunofluorescent techniques [15, 56].
With respect to the complement system of BD patients, the titer of
serum complement is generally high in the inactive stage but
decreases in the active stage, although levels of the
mannose-binding lectin (MBL) pathway of complement is reported to
be decreased [80]. The MBL pathway is considered to play an
important role in innate immunity. It is thought to be a C-type
serum lectin secreted by the liver, which binds to mannose and
N-acetyl-glucosamine oligosaccharides on the surfaces of yeast,
bacteria and viruses [81]. The reaction serves as the initiator of
the third pathway of the complement system, independently from
antibodies. Ficolin (FCN) is a soluble protein that binds to
carbohydrate on the microbial cells and 3 different types of FCN
are detected. FCN 1 and 2 genes are located in chromosome 9q34 and
the FCN 3 gene is assigned to chromosome 1. FCN 2 binds to
lipoteicholic acid on the cell wall constituent in all
Gram-positive bacteria and activate immune cells, to produce
proinflammatory cytokines [78, 82]. Recently, we have found that
novel FCN 2 gene single nucleotide polymorphisms (SNPs) were
identified in the promoter regions as well as in the exon regions.
The MBL genetic polymorphisms might be involved in immune responses
to streptococcus infections in BD patients, because a relationship
between MBL gene mutations and microbiological factors is suspected
in the lesional immune reaction of BD patients [83]. Although a
significant difference was not present in the genotype allele
frequencies of MBL gene SNPs between BD patients and HIs, the
allele frequencies of FCN2 gene SNPs were significantly recognized
in the promoter regions (-557 and -64 sites) among HLA-B51 positive
BD patients [84]. The findings suggest the possibility that the FCN
gene of the MBL pathway in the complement system contributes to
innate immununity in BD patients with the HLA-B51 haplotype.
How do the muco-cutaneous symptoms appear in BD patients?
BD symptoms are characterized by vascular involvements,
histologically showing swollen endothelial cells of the
micro-arteries, infiltrated by inflammatory monocytes and a few
neutrophils, a so-called “vascular reaction” seen in EN-like
eruptions (figure
2B) and other lesions [15, 54-56]. The strong
hypersensitivity reaction against S. sanguinis agents [9, 10,
14-17] which might be caused by APCs through the innate immune
mechanism, can be suspected as the extrinsic triggering factor in
the pathogenesis of BD. In the treatment by antibiotics for the
involvement of oral S. sanguinis, minocycline, which reduces not
only the growth of streptococci but also suppresses IL-1β and IL-6
production from inflamed T cells, was especially clinically
effective for aphthous ulceration, acne-like eruption and EN-like
lesions in BD patients [10]. Other studies also showed that
combination therapy, colchicine and benzathine penicillin, were
effective to suppress BD symptoms, compared to colchicine
monotherapy [85, 86]. Muncu et al. [86] and others [6-8] have
already reviewed the role of infectious agents in the pathogenesis
of BD, but we also dare to propose the hypothesis that after the
Bes-1 gene is taken into the cytoplasm of APCs (figure 1A and B) through
the TLRs in the oral cavity, the APCs, which are expressing the
streptococcal antigen as seen in figure 2C, produce HSP-65.
If these APCs are carried in the blood flow to the impaired and/or
MICA expressed endothelium of the vessels in correlation with
HSP-65/60, VEGF, adhesion molecules, etc., BD lesions might be
induced with “vascular reaction” and/or “lymphocytic vasculitis” as
the immunological reaction by the APCs expressing the S. sanguinis
antigen (figure
5).
Conclusion
The pathogenesis of BD was discussed, including aspects of the
intrinsic genetic factors and with oral bacteria antigens as one of
the extrinsic triggering factors. HLA-B51 restricted CTL was found
to target the MICA expressed organs by stress in correlation with
HSP-65/60 derived from oral bacteria, including S. sanguinis. The
immune responses which are based on a Th1 type reaction with
chemotaxis to the bacterial agents are considered to correlate with
various BD symptoms, histologically exhibiting “vascular reaction”
and/or “lymphocytic vasculitis”.
Acknowledgements
We deeply appreciate the valuable suggestions and helps by the
following members of the Japanese Research Committee for Behçet’s
Disease organized by the Ministry of Health, Labour and Welfare
since 2001. Drs. Shigeaki OHNO and Kazunori ONOE (Hokkaidou
University, Sapporo), Hidetoshi INOKO (Toukai University,
Sagamihara), Masataka KUWANA (Keio University, Tokyo), Noboru
SUZUKI (St. Marianna Medical University, Kawasaki), Yoshiaki
ISHIGATSUBO (Yokohama City University, Yokohama), Hidetoshi
KAWASHIMA (Saitama Redcross Hospital, Omiya), Keiji IWATSUKI
(Okayama University, Okayama), Koichiro NAKAMURA (Saitama Medical
University, Omiya), Tomoko OKADA, Hitoshi AKIBA and Hiroko
KOBAYASHI (Fukushima Medical University, Fukushima), Masae OTA
(Shinshu University, Matsumoto), Mariko NAITOU (Nagoya University,
Nagoya) and Yutaka INABA (Juntendou University, Tokyo).
We are deeply grieved by the loss of Professor Emeritus Yutaka
MIZUSHIMA (St. Marianna University Scholl of Medicine, Kawasaki)
who greatly contributed to the research development of Behçet’s
disease in Japan.
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