Infections Role in Autoimmune Diseases

Infección y Autoinmunidad

Yehuda Shoenfeld, MD, FRCP
Jefe, Departamento de Medicina 'B' y Centro
Zabludowicz para Enfermedades Autoinmunes,
Centro Médico Sheba (Afiliado a la Universidad de
Tel-Aviv), y Titular de la Cátedra de Investigación
Laura Schwarz-Kipp en Enfermedades
Autoinmunes, Universidad de Tel-Aviv, Israel.

Yehuda Shoenfeld, MD,FRCP ( Hon.)

Mechanism of ARIDs;
Infections role
why SLE and why APS
Yehuda ShoenfeldMD ,FRCP
03 03 11
Bogota


Vaccines and
autoimmune diseases
Yehuda Shoenfeld MD ,FRCP


Infections
and autoimmunity
?friends or foes –
,Kivity S
,Agmon-Levin N
,Blank M
Shoenfeld Y
409:(8) 30 ;2009

The mosaic of
autoimmunity
Yehuda Shoenfeld MD,FRCP
1989

Genetic
,HLA)
Immune
(Genes Environmental
deficiency
.Infection,Vacc)
state
Drugs, UV
IgA def. Trg)
Hormonal (Smoking
( C‘ def., NK
Estrogen)
Testosterone prolactin
Vit. D( , Smell

The major pieces of the
Mosaic of Autoimmunity
Environmental:
 Infecting agents: viruses, bacteria, parasites
 Vit D. In all AIDs we have low Vit D levels.
 Drugs (e.g. idiopathic thrombocytopenia
purpura, myasthenia, SLE).
 Toxins (e.g. scleroderma).
 Cosmetics (e.g. silicone).
 UV light (e.g. SLE).
 Smoking (e.g. Goodpasture’s syndrome,RA,Thyr).
 Stress (e.g. SLE)
 Nutritional influence;Vit D (e.g. RA, SLE).

Geographical clustering of scleroderma in
south and west London.
Silman AJ, et al. Br J Rheumatol 1990 ;29:93-6

 Living in close proximity to an
air- port may be a marker for an
environmental hazard for
scleroderma although the
magnitude of any effect appears
to be very small.


Type-1 diabetes mellitus and multiple
sclerosis
Diabetes Mellitus type I Multiple sclerosis


Mycobacterium tuberculosis
infection precipitates SLE in
patients from endemic areas
Ghosh K et al
Rheum Int 2009; 29:1047-50
 In a cohort of 70 systemic lupus erythematosus patients
diagnosed over 2 years period, 14 patients were found to
have confirmed antecedent tuberculosis (20%) which was
40 times higher (p<0.001, 95%CI 36.2-48.6) than the
prevalence of tuberculosis in the local population.
 The prevalence of preceding Tubercular infection in SLE
patients which turned out to be 14/70 i.e. 40 times higher
than the population prevalence (95%CI 36.2-48.6 p<0.001)

,Reifen R, Blank M, Afek A
,Kopilowiz Y, Sklan D
,Gershwin ME, German B
.Yoshida S, Shoenfeld Y
Dietary polyunsaturated fatty acids
decrease
anti-dsDNA and
anti-cardiolipin antibodies
production in
idiotype induced
.mouse model of SLE
.Lupus 7, 192-197, 1998

,Reifen R. Amital H, Blank M, Sklan D
.Berkovich Z, Gershwin E, Shoenfeld Y
Diet and
Linseed Oil suppresses
Autoimmunity the antiB2GPI in
.experimental APS
.J Autoimmun 15: 381-385, 2000


Rheumatic
Fever


.SLE APS RA SyS etc


Most consistent associations between
infecting agents and autoimmune disease

n Epstein Barr Virus (MS, SLE, RA, Sjögren’s
syndrome)
n Cytomegalovirus (SLE, Atherosclerosis,
Diabetes mellitus, Systemic sclerosis, IBD)
n Helicobacter pylori (ITP, SSc, Crohn’s
disease, GBS)
n Chlamydia pneumoniae (Atherosclerosis,
MS)
n Parvovirus B19 (SSc?)
n E. coli (RA)
n P. mirabilis (RA)
n Yersinia enterocolitica (IBD)
n C.jejuni (GBS)

Mechanisms that could lead to autoimmune disease
upon exposure to infection
Molecular mimicry Bystander activation

Polyclonal Epitope spread
activation Autoimmune
Disease

Super-antigens Cryptic antigen


Infection and toll-like pathway


Hepatitis-C and
Autoimmune Diseases
1) Mixed cryoglobulinemia. 80
70
60
50
40

2) Ch. Active hepatitis.
30
20
10
0

C

RA
D
S

S

E

S

SS
ls

c
o

s
3) Polyarteritis nodosa.

us
ia

AP

AP

SL

s
PB
IB

M

SS
ve
ot
ro

ie
em

ig

im

a
nt

th
d-
ph

Gr
in
Co

sh

pa
2n
m
ul

yo
Ha
pe
ub

.M
gl

m
yo

fla
cr

In
4) Leukocytoclastic vasculitis. The prevalence of anti-HCVour cohort
:was 9.5% (116/1228) in
antibodies

5) Autoimmune thyroid disease.
6) Glomerulonephritis.
7) Polymyositis + anti-Jo-1 Ab.
8) Formation of autoantibodies and CIC
(A@R. 3: 437, 1995).

Soluble BAFF levels in HCV
Toubi et alJ Autoimmunity 2006;27;134-9

4
P = 0.001
BAFF (ng/ml)

3

2

1

0
Control HBV HCV SLE

The major pieces of the
Mosaic of Autoimmunity

Environmental:
Infecting agents: viruses, bacteria, parasites.


EBV genetics and autoimmune diseases

EBV
Autoimmune HLA-DR15
gene

Multiple sclerosis
Late EBV
Infection

EBV

Autoimmune HLA-DR3
gene

Late EBV Autoimmune
Infection thyroid disease


Influence of HLA-DR phenotype on the risk
of hepatitis C virus-associated mixed
cryoglobulinemia.
Cacoub P, et.al. Arthritis Rheum 2001 ;44:2118-24

 The presence of the DR11 phenotype is
associated with a significantly increased risk
for the development of type II MC in patients
with chronic HCV infection.
 In contrast, HLA-DR7 appears to protect
against the production of type II MC.

Frequency (%)
Po
ly
m
y

80
85
90
95
SL osi 100
S E tis
+
*
H yst
as e
hi m N APS
m ic o
*

ot Sc rm
o le a
Th ro l
yr sis
M oi
ul di
ti ti
In Pr pl s
f l im e
am ar S c SL
m y le E
a t Bi l ro
or ia si
y ry A s
Pe Bo Ci P
m w rrh S
ph el o
i g Di sis
G us se
ra V as
D ve ulg e
i a s'
be D a r
te ise is
s a
M M se
ix C el
l it
p>0.05

ed ry
C u
og s
*

ry lo
G o g bu R A
i a lo l in
nt b u m
Ce lin i a
ll em
Ar
EBV Nuclear Antigen (EBNA) IgG

th i a
ri
tis

Patients with systemic SLE have
abnormally elevated Epstein-Barr
virus load in blood
Moon UY, et al. Arthritis Res Ther. 2004; 6: R295-302

 Interestingly, the EBV burden in peripheral
blood mononuclear cells (PBMCs) was over
15-fold greater in SLE patients than in
healthy control individuals.
 EBV infection is abnormally regulated in SLE.


ELEVATED EBV ANTIBODIES
CORRELATED WITH CUTANEOUS
MANIFESTATIONS IN SLE PATIENTS
3.5 No manifestations
3.0 Manifestations

2.5 CUTANEOUS:
p=0.024 RASH,
2.0 PHOTOSENSITIVITY,
FIN 1.5 ALOPECIA,
MOUTH ULCERS,
SCLE
1.0 p=0.065
DLE
0.5

0.0
EBVIGM EBVEAG

EBV ANTIBODIES


anti-Ro and anti-La

Cutaneous Lupus

Sjögren Neonatal Lupus/CHB ( Hon.)
Yehuda Shoenfeld, MD,FRCP

ELEVATED EBV-VCA IGG TITERS
CORRELATED WITH JOINT
MANIFESTATIONS

FIN
No manifestations
8
Manifestations JOINTS
7
JOINT
p=0.003
6 TENDERNESS
5 JOINT
4 SWELLING
3 JACCOUD’S
2
ARTHROPATHY
1
0

EBV VIRAL CAPSID IGG

Yehuda Shoenfeld, MD,FRCP (& SLE
Zandman-Goddard G. EBV Hon.)

EBV infection associated with
cutaneous and joint involvement
 EBVEAG was significantly elevated
(p<0.024) and EBVIGM marginally
elevated (p< 0.065) in subjects with vs.
those without skin symptoms.
 EBVCAG was significantly elevated
(p<0.003) in subjects with vs. those
without joint involvement.


ELEVATED TITERS TO EBV EARLY
ANTIGEN IGG CORRELATED WITH
ANTI-RO AB

8

FIN 7
Negative
6
Positive
5
4
3
2
p=0.03
1 p=0.005 p=0.04

0
EAG-Ro CAG-ANA HM-RNP(*10)

AB to EBV AG- AB TO NUCLEAR COMPONENTS
Yehuda Shoenfeld, MD,FRCP (& SLE
Zandman-Goddard G. EBV Hon.)

EBV  anti-Ro skin involvement
Anti-Ro antibody and cutaneous vasculitis
in systemic lupus erythematosus.
Marcio Veronesi Fukuda , et al.
Clin Rheumatol 2009; 28: 301-304.
• Five hundred and nine consecutive patients
fulfilled the revised American College of
Rheumatology (ARA) criteria for the SLE.
• Anti-Ro antibody was associated to anti-La
antibody, female, and cutaneous vasculitis.
• In a multivariate analysis, patients with anti-Ro
antibody have 1.63 (95%) CI 1.07-2.50) more risk
to develop cutaneous vasculitis than patients
without this antibody.
Yehuda Shoenfeld, MD, FRCP.

EBNA-1 58-72 peptide immunized rabbits develop
Anti-Ro autoimmunity, lupus-like autoimmunity and
Clinical features of SLE
A EBNA-1 58-72 immunized rabbits B 3
Pre-imm une
2.5
Freund’s immunized rabbits 2
1.5
8
1

Absorbance
0.5
6
0
WBC

1 44 87 130 173 216 259 302 345 388 431 474 517
4
3
2.5
2
2
1.5
0
0 1 2 3 4 1
3 0.5
0
Creatinine

1 43 85 127 169 211 253 295 337 379 421 463 505
2
60kDa Ro Octapeptide Number
2.5
1 Pre-imm une
2
1.5
0 1
0 1 2 3 4
Absorbance

0.5
400
0
1 21 41 61 81 101 121 141 161 181 201 221
Platelets

300
2.5
2
200
1.5

100 1

0.5
0 0
0 1 2 3 4
1 21 41 61 81 101 121 141 161 181 201 221

Months post-immunization Sm B‘ Octapeptide Number

Helicobacter Pylori
 Infection rates vary in different parts
of the world, from 50% in the western
world to 90% in Asia and the far east.
 Most remain a-symptomatic, 10-15%
develop peptic ulcers, chronic
gastritis, autoimmune gastritis, or gastric
lymphoma (MALT).
 Also associated with atherosclerosis, ITP,
GBS and Systemic sclerosis
Suerbaum S. et al, Helicobacter pylori infection, N Engl J Med, 2002
Oshima T. et al, Association of Helicobacter pylori infection with systemic inflammation and endothelial
dysfunction in healthy male subjects.J Am Coll Cardiol, 2005
Showji Y. et al, Seroprevalence of Helicobacter pylori infection in patients with connective tissue
diseases.Microbiol Immunol, 1996
Franchini M. et al, Helicobacter pylori-associated immune thrombocytopenia. Platelets , 2006

0
10
20
30
40
50
60
70
80
90
100
No
W rm
eg al
en
er
's
G AP
ra
nu S
lo
G m
at
ian os
tC is

P<0.05
el
lA
rte
ri t
is
Sy
ste IB
m D
ic
Sc
P<0.05 P<0.001

P<0.01
ler
os
is

SL
E
SL
E
Cr +
yo AP
M gl S
i xe ob
d ul
ine
Cr
yo m
glo ia
bu
li n
G em
H. Pylori Prevalence Europe

ra ia
ve
s'
dis
ea
se
Po
l ym
yo
sit
is
Ha
sh
im
ot
o

PB
C

Helicobacter pylori
colonization is inversely
associated with childhood
asthma

The Journal of Infectious Diseases
2008;198:553-60

Disappearance of APS
after helicobacter pylori
eradication
The American Journal of Medicine 2001, 111: 163
Antonio Gasbarrini, Giovanni Gasbarini


Helicobacter Pylori
eradication therapy in
thrombocytopenic purpura

Ando T, et al. Helicobacter 2004;9:443–452

Platelet Response in ITP – Results

HP eradication responders

HP eradication nonresponders

HP not-eradicated patients

HP negative patients


Eradication of H. Pylori and
amelioration of autoimmunity

APS –Antonio Gasbarrini, Giovanni Gasbarini
Disappearance of APS after helicobacter pylori eradication
The American Journal of Medicine 2001, 111: 163
Sjogren – Gasbarrinin A, Franceschi F. Autoimmune disease
and Helicobactor pylori infection. Biomed Pharmacother 1999;
53:223-6.
RA – Zentilin P, Seriolo B, Dulbecco P et al. Eradication of
Helicobactor pylori may reduce disease severity in rheumatoid
arthritis. Aliment Pharmacol Ther 2002; 16:1291-9.


Implications for induction of
autoimmunity via activation of
B-1 cells by Helicobacter pylori
urease
Yamanishi S, et al. Infect Immun. 2006; 74: 248-56

 H. pylori urease predominantly stimulates the B-1-cell population
rather than B-2 cells, which produce antigen-specific conventional
antibodies among splenic B220(+) B cells.
 The production of various B-1-cell-related autoreactive antibodies
such as IgM-type rheumatoid factor, anti-single-stranded DNA
antibody, and anti-phosphatidyl choline antibody was observed when
the splenic B cells were stimulated with purified H. pylori urease in
vitro.
 H. pylori components, urease in particular, may be among the
environmental triggers that initiate various autoimmune diseases via
producing autoreactive antibodies through the activation of B-1 cells.


Rate of seropositivity,
Hepatitis B core IgG
 Lower prevalence

15%

10%

p<0.001 2.5%
10.7%
5%

0%

Controls (n=140) SLE (N-120)

Yehuda Shoenfeld, MD,FRCP ( 40
Berkun, SLE & Abs to infectious agents Hon.)

Hygiene and
autoimmunity
Improved hygiene in infancy and
the presence of rheumatoid
factor in adult life
Edwards CJ, Syddall HE,

Goswami P, et al.
Arthritis Rheum. 2004;

50: S356


SLE and malaria:
Another look at an old idea
Butcher GA, Clark IA.
Parasitol Today. 1990;6:259-61

 Where parasitic infections are common,
autoimmune diseases are rare.
 Malaria may exert a protective effect
against the autoimmune nephritis in
systemic lupus erythematosus.

Toxoplasma gondii
infection inhibits
the development of
lupus-like syndrome
in autoimmune
(New Zealand Black
x New Zealand
White) F1 mice.
Chen M, et al.

Int Immunol.
2004;16:937-46.


Parasitic worms and
inflammatory diseases

Zaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A. Parasite
Immunol. 2006; 28: 515-23


Therapeutic immunomodulators from
nematode parasites – clinical
impliactions/applications
Harnett W and Harnett MM
Expert reviews 2008; 10:1-13
 A “safe” species is Trichuris suis, which is similar to the human
whipworm T.trichiura, but can persist only for a limited period
in the human gastrointestinal tract following infection
 Human trials as a treatment for inflammatory bowel disease
 People suffering from inflammatory bowel disease have shown
improvement in symptoms following ingestion of embryonated
ova of this worm (Elliott DE et al. helminths as governors of
immunomediated inflammation. Int J Parasitol 2007;
37:457-64; Reddy A and Fried B. the use of Trichuris suis and
other helminths therapies to treat Crohn’s disease. Parasitol
Res 2007; 100:921-7)
 Crohn’s disease was treated with with 50 larvae
 Disease showed some improvement (Croese J et al. a proof of
concept study establishing necator americanus in Crohn’s
patients and reservoir donors. Gut 2006; 55:136-7)

Trichuris suis therapy in
Crohn’s disease
 Open label
 Worms were isolated from pigs colons
and cultured in vitro
 24 weeks: 29 CD patients returned every
three weeks to drink the ova suspended
in a commercial drink

Summers RW, Elliott DE, et al. Trichuris suis therapy in
Crohn’s disease. Gut 2005;54:87–90.


T Helper (CD4+ ) Subsets

Antigen

IL-4
Th0 Parasite
IL-12

Suicide FasL

Fas Th2
Th1 TRAIL
DR4 Anti-Inflammatory
Pro-Inflammatory
Cytokines Cytokines
IL-4
IFN-
IL-1
γ
0
IL-2
IL-1
LT
Th1 response 3
Cellular Immunity IL-5
Th2 response
DTH IL-6
Humoral Immunity
Acute Hypersensitivity MD,FRCP ( Hon.)
Yehuda Shoenfeld,

Results

No side effects or complications

Therapeutic immunomodulators
from nematode parasites
Harnett W and Harnett MM
Expert reviews 2008; 10:1-13

 ES-62 can inhibit components of a Th2 response,
such as IL-4 production
 Solely a Th2 polarizing agent was too simplistic (Diaz
A and Allen JE. Mapping immune response profiles:
the emerging scenario from helminth immunology.
Eur J Immunol 2007; 37:3319-26)
 Mimic the activity of ES-62 for use as drugs for
treating allergic and autoimmune diseases.

Phosphorylcholine - a common denominator for bacteriae,
fungi helminthes nematodes and apoptotic cells

♣Gram-positive bacteriae: Streptococcus
pneumoniae, Streptococcus spp. Clostridium spp.
Lactococcus spp. Bacillus spp
♣Gram negative bacteria: Haemophilus influenzae (Anti-PC Ab (Fab
♣Eukaryotic organisms: protozoa Leishmania
and Trypanosoma cruzi , a wide range of fungi, the
trematode Schistosoma mansoni , the tapeworm
Diphyllobothrium latum , several gastrointestinal
nematodes and all species of filarial nematode
(helminthes) (Wuchereria bancrofti, Brugia malayi and
Onchocerca volvulus).
PC
♣Apoptotic cells
Clinical features of Filarial nematode infection: elephantiasis,
chronic skin lesions and eye damage leading to blindness

Infections determine the type of autoimmune diseases-hypothesis

(Hypothesis)

HBC-
sAPS

CMV


Infections and autoimmunity
1. Infections can cause • The “burden of infections”
autoimmune diseases. through life induces
autoimmunity.
2. Infections can trigger an an
underlying immune • Infections during childhood
disregulation to overt affect autoimmunity in
autoimmune disease. adulthood.
3. Viruses, bacteria and • Vaccines may induce
parasites can determine autoimmunity depending on
which autoimmune disease the type of vaccine, the
will develop. adjuvant and the subject’s
genetic susceptibility.
4. Infections can alter the
clinical manifestations of • Infections can protect from
disease. some autoimmune disease
(i.e. the hygiene theory)
5. genetic susceptibility
determines autoimmune • Infectious agent can induce a
response to certain specific autoimmune disease,
infectious agents. and protect from another.

Five Jews change the
way we see the world:
Moses: ‘’the Law is everything.’’
Jesus: ‘’Love is everything.’’
Marx: ‘’Money is everything.’’
Freud: ‘’Sex is everything.’’
Einstein: ‘’Everything is relative.’’
The Mosaic of autoimmunity

Thank
!You


The prevalence of
helicobactor pylori in
obese subjects
Arslan E et al
Eur J of Intern Med 2009; 20:695-7
 Prevalence of H.pylori increased in subjects with
obesity. We considered that obesity can be a
risk factor for H.pylori infection. However,
further studies evaluating more subjects are
required.

Mycobacterium tuberculosis infection
precipitates SLE in patients from endemic areas
Ghosh K et al
Rheum Int 2009; 29:1047-50
 Classical model of experimental autoimmune diseases such as myobacteria
induced arthritis (Holoshitz J et al. arhtritis induced in rats by cloned T
lymphocytes responsive to myobacteria but not to collagen type II. J Clin
Invest 1984; 73:211-5. Van Eden U et al. arthritis induced by a T
lymphocyte clone that respondes to myobacterium tberculosis and the
cartilage proteoglycans. Proc Natl Acad SCI USA 1985; 82:5117-20.
Thomson SJ et al. modulation of pristane induced arthritis by myobacterial
antigens. Autoimmunity 1991; 11:35-43).
 Autoantibodies similar to that found in SLE patients have been regularly
detected (Pradhan VD et al. spetrum of anti-neutrophil cytoplasmic
antibodies in patients with pulmonary tuberculosis overlaps with that of
Wegner’s Granulomatous. Int J Med Sci 2004; 58:283-8. Shoenfeld Y et al.
Myobacterium and autoimmunity. Immunol Today 1988; 9:178-82.
Shoenfeld Y et al. immunolgic and genetic factors in autoimmune disease.
NEJM 1984; 311:1019-29).
 Monoclonal antibodies raised against M. tubersulosis can cross react with
DNA.
 Myobacterial infection could lead to anti-DNA antibodies without clinical
manifestation of SLE (Shoenfeld Y et al. Myobacterium and autoimmunity.
Immunol Today 1988; 9:178-82. Shoenfeld Y et al. immunolgic and genetic
factors in autoimmune disease. NEJM 1984; 311:1019-29.Shoenfeld Y et
al. monoclonal antituberculosis antibodies react with DNA and monoclonal
anti-DNA autoantibodies react with Myobacterium tuberculosis. Clin Exp
Immunol 1986; 66:255-61. Yehuda Shoenfeld, MD,FRCP ( Hon.)

Infections Role in Autoimmune Diseases

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