Behçet Syndrome

Behçet’s
Disease:
Autoinflammatory
features
Ahmet
Gül
Istanbul
University,
Istanbul
Faculty
of
Medicine,
Turkey
Outline
 
Clinical
picture
 
Characteristics
of
inflammatory
response
 
 
 
Autoinflammatory
features
Genetics
Controversial
issues
 
 
HLA
Class
I
association
  Antigen‐specific
/
adaptive
immune
responses
?
Efficacy
of
“T‐cell
specific”
treatments
Nothing
to
declare
relevant
to
this
presentation
Dr.
Hulusi
Behçet
 
3
patients
with
recurrent
 
 
 
 
Oral
aphthous
ulcers
Genital
ulcers
Uveitis
A
distinct
disease
 
 
Possible
viral
etiology
?
Role
of
focal
infection
?
Dermatologische
Wochenschrift
1937;
105:1152‐7
Behçet’s
Disease
 
34‐year‐old
female
 
 
 
 
Recurrent
attacks
of
oral
and
genital
aphthous
ulcers
for
7
years
Loss
of
appetite
and
fever
during
attacks
Eye
inflammation
during
severe
attacks
41‐year
old
male
 
 
 
Recurrent
attacks
of
oral
aphthous
ulcers,
genital
ulcers
and
eye
inflammation
with
loss
of
vision
Acne‐like
lesions
Fever
with
myalgias
Behçet’s
Disease
 
 
 
Multi‐system
disorder
Vasculitis
affecting
all
sizes
and
types
of
vessels
with
a
thrombotic
tendency
More
severe
disease
course
in
males
and
in
those
aged
<25
at
disease
onset
Behçet’s
Disease
 
Unknown
etiology
 
 
Enhanced
and
dysregulated
inflammatory
response
Complex
genetic
(multifactorial)
disease
Env
Gene-3
iron
men
t-1
Gene-1
Gene-2
Envir
onme
nt-2
Behçet’s
Disease
 
Recurrent
inflammatory
attacks
 
Usually
self
limited
and
heal
without
scarring
Behçet’s
Disease
 
Recurrent
inflammatory
attacks
 
Can
cause
permanent
tissue
damage
Behçet’s
Disease
 
Recurrent
inflammatory
attacks
 
Innate
immune
response
 
 
 
Increased
proinflammatory
cytokine
expression
Increased
superoxide
generation
Non‐specific
hyperreactivity
  Pathergy
phenomenon
Behçet’s
Disease
 
Increased
non‐specific
inflammatory
response
 
Pathergy
phenomenon
Skin
hyperreactivity
to
trauma
  Can
also
be
induced
in
  vessels
  oral
mucosa
  genital
mucosa
  joints
  etc.
 
Behçet’s
Disease
 
Recurrent
inflammatory
attacks
 
Innate
immune
response
 
 
 
 
Increased
proinflammatory
cytokine
expression
Increased
superoxide
generation
Non‐specific
hyperreactivity
  Pathergy
phenomenon
Adaptive
immune
response
?
 
 
Th1
type
polarization
Oligoclonal
T
cell
expansions
Behçet’s
Disease
 
Immune
reactivity
against
 
Self
antigens
 
 
 
 
 
 
 
 
HSP60
Other
hsp
proteins
(aB‐crystalline)
Alpha
enolase
Tropomyosin
Kinectin
Retinal
S,
IRBP,
UACA,
SBP
PINK1,
SWAP70
(by
SEREX,
Vural
et
al.
unpublished
data)
Microbial
antigens
 
 
 
Streptococcal
antigens
Herpes
simplex
virus
Gram
negative
bacteria,
Staphylococcus
aureus,
etc.
Behçet’s
Disease
 
Immune
reactivity
against
microbial
antigens
 
Adaptive
immune
response
and
cross‐reactivity
to
self
antigens
 
Between
microbial
and
self
hsp60
proteins?
 
 
Immune
reactivity
against
HSP60‐derived
peptides
(T
cell,
γδ
T
cell,
B
cell)
Uveitis
induced
by
HSP60‐derived
peptides
in
Lewis
rats
 
 
HSP60
336‐351
+
CFA
+
B.
Pertussis
Danger
signal
‐
activation
of
innate
immune
response
by
pathogen‐associated
molecular
patterns
 
LPS,
lipoteichoic
acid,
hsp,
etc.
Behçet’s
Disease
 
Overlapping
clinical
features
with
hereditary
autoinflammatory
disorders
Oral
aphthous
ulcers
HIDS,
TRAPS,
MWS
Genital
ulcers
HIDS
Arthritis
FMF,
TRAPS,
PAPA,
Blau,
MWS,
HIDS
Amyloidosis
All
Meningoencephalitis
FMF,
NOMID,
MWS
Uveitis
NOMID,
TRAPS,
Blau
Orchyepididymitis
FMF
Acne‐like
lesions
PAPA
Pathergy
reaction
PAPA
Behçet’s
Disease
 
Autoinflammatory
disorders
 
Seemingly
unprovoked
episodes
of
inflammation
 
Relative
lack
of
an
obvious
autoimmune
pathology
 
 
 
 
No
pathogenic
high‐titre
autoantibodies
No
antigen‐specific
T
cells
Genetic
defects
in
innate
immune
system
Behçet’s
disease
 
 
Complex
genetic
disorder
–
HLA
Class
I
association
Efficacy
of
“T
cell
specific”
treatments
(i.e.
Cyclosporin
A)
McGonagle & McDermott. PLoS Medicine 2006
Geographic
Distribution
 
Higher
frequency
of
HLA‐B51
in
healthy
populations
Verity
et
al.
Br
J
Ophthalmol
2003;
87:
1175‐83.
Behçet’s
Disease
and
HLA‐B51
Greek
Italian
Japanese
Mizuki
et
al.
Invest
Ophthalmol
Vis
Sci
2000;
41:
3702‐8
Behçet’s Disease and HLA-B51
 
Direct pathogenic role for HLA-B51 ?
 
Increased neutrophil activity
 
Transgenic mouse model (Takeno et al. A&R 1995)
 
Susceptibility to infection by certain microbes
 
Molecular mimicry
 
 
Cross reactivity
Presentation by HLA Class II molecules (Wildner et al. Eur J
Immunol 1997; Kurhan-Yavuz et al. Clin Exp Immunol 2000)
 
Interaction with NK cell KIR receptors (KIR3DL1)
Behçet’s
Disease
and
HLA‐B51
Presentation
of
BD‐specific
peptide(s)
 
 
 
No
B51‐restricted
CD8
response
Interaction
with
KIR3DL1
on
NK,
CD8
and
γδ
T
cells
?
Maenaka et al. J Immunol 2000; 165: 3260-7.
Behçet’s
Disease
and
KIR3DL1
 
Bw4
positive
(n
=
352)
 
 
 
Healthy
controls
=
153
Behçet’s
disease
=
199
Bw4
negative
(n
=
124)
 
 
Healthy
controls
=
82
Behçet’s
disease
=
42
χ2
for
trend
P
=
0.019
for
DL1/DL1
OR
=
1.7
(1.1‐2.6)
P
=
0.013
Duymaz‐Tozkır
J,
et
al.
(unpublished)
Behçet’s
Disease
and
KIR3DL1
 
B51
negative
(n
=
271)
 
 
Healthy
controls
=
180
Behçet’s
disease
=
91
for DL1/DL1 and Bw4 positives
OR = 2.1 (1.2-3.6)
P = 0.007
Duymaz‐Tozkır
J,
et
al.
(unpublished)
Distribution
of
KIR3DL1/DS1
Alleles
HLA‐Bw4
positive
patients
and
controls
*
*
HC
BD
HC
(n=127)
BD
(n=175)
OR
(95%
CI)
P
KIR3DL1*001
%39,4
%51,4
1,6
(1‐2,5)
0,038
KIR3DS1*013
%52
%33,7
0,47
(0,29‐0,75)
0,001
Duymaz‐Tozkır
J,
et
al.
(unpublished)
Distribution
of
KIR3DL1/DS1
Alleles
HLA‐B*51
negative
patients
and
controls
*
*
HC
BD
HC
(n=81)
BD
(n=48)
OR
(95%
CI)
P
KIR3DL1*001
%32,1
%64,6
3,8 (1,8-8,1)
0,0001
KIR3DS1*013
%60,5
%25
0,2 (0,09-0,5)
0,0001
Duymaz‐Tozkır
J,
et
al.
(unpublished)
Behçet’s
Disease
and
HLA‐B51
 
HLA‐Bw4
(B51)
+
peptide
and
KIR3DL1
interaction
  Strong
inhibitory
signal
 
 
 
Defective
clearence
/persistence
of
certain
antigens
?
Viral
etiology
?
Defective
inhibitory
signal
due
to
peptides
 
Changed
affinity
of
KIR3DL1
with
aminoacids
at
P7
and
P8
 
 
Disrupted
inhibitory
signal
Activation
of
NK,
CD8
or
γδ
T
cells
Behçet’s
Disease
and
HLA‐B51
 
Unfolded
protein
response
?
 
 
Slow
folding
HLA
Class
I
molecule
similar
to
HLA‐B27
HLA‐B27
transgenic
animal
models
suggest
ER
stress
and
unfolded
protein
response
as
a
possible
mechanism
Spliced
XBP‐1
transcripts
in
peripheral
blood
monocytes
Unspliced
Spliced
Karasneh et al. Arthritis Rheum 2005; 52: 1836-42
Karasneh et al. Arthritis Rheum 2005; 52: 1836-42
BD
and
Autoinflammatory
Disorders
 
Association
with
“autoinflammatory
genes”
?
 
MEFV
 
Increased
frequency
of
MEFV
mutations
 
 
Association
with
vascular
involvement
?
 
 
 
Atagündüz
et
al.
Clin
Exp
Rheumatol
2003;
21:
S35‐7
Rabinovich
et
al.
Scand
J
Rheumatol
2007;
36:
48‐52
Co‐incidental
BD
and
FMF
 
 
Touitou
et
al.
Human
Mutation
2000;
16:
271‐2
Japanese,
Matsuda
et
al.
Intern
Med
2006;
45:
799‐800
TNFRSF1A
 
Association
with
venous
thrombosis
(extracranial)
?
 
Amoura
et
al.
Arthritis
Rheum
2005;
52:
608‐11
Behçet’s
Disease
 
 
Not
a
single
gene
disorder
Genetic
polymorphisms
in
innate
immune
system?
 
 
 
Candidate
suscetibility
genes
in
the
linkage
area
?
Whole
genome
association
studies
?
Gene
expression
microarray
studies
Uric
Acid
and
Inflammasome
Proteins
 
Increased
skin
response
to
urate
in
Behçet’s
disease
 
 
Cakir
et
al.
Urate
crystal
test
in
Behcet's
syndrome.
Br
J
Rheumatol
1993;
32:
1112‐4.
Increased
inflammatory
response
to
uric
acid
in
Behçet’s
disease
 
Gogus
et
al.
Oxidative
burst
response
to
monosodium
urate
crystals
in
patients
with
Behcet's
syndrome.
Clin
Exp
Rheumatol
2005;
23
(4
Suppl
38):
S81‐5.
Behçet’s
Disease
 
Targeting
the
correct
inflammatory
pathways
?
 
 
 
 
 
 
 
 
Colchicine
Thalidomide
Corticosteroids
Azathioprine
Cyclosporin
A
Interferon
alpha
Anti‐TNF
?
Istanbul University
Istanbul Faculty of Medicine
Department of Internal Medicine
Division of Rheumatology
Ahmet Gül
Sevil Kamali
Murat İnanç
Lale Öcal
ARC Epidemiology Unit
University of Manchester
Ali Hajeer
Jumana Karasneh
Jane Worthington
Bill Ollier
Alan J Silman
Meral Koniçe
Orhan Aral
Fulya Cosan
Department of Physiology
Güher Saruhan Direskeneli
Aytül Uyar
Jülide Duymaz
Department of Ophthalmology
Ilknur Tugal Tutkun
DETAE, Department of Genetics
Duran Üstek
Neslihan Abaci
Aris Çakiris
Basar Oku
Ugur Özbek
Burçak Vural