This document discusses Yehuda Shoenfeld, the head of the Department of Medicine 'B' and Center for Autoimmune Diseases at Sheba Medical Center in Israel. It provides information about Shoenfeld's background, positions, and areas of research focus, which include autoimmune diseases, autoantibodies, and the genetic and environmental factors involved in autoimmunity. The document presents Shoenfeld as a leading expert on the "mosaic of autoimmunity" and includes sections on the history and epidemiology of autoimmune diseases.
1. El Mosaico de la 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.)
2. Autoimmune diseases
The enemy from within
Yehuda Shoenfeld
MD FRCP
TAU 03 03 11
5. Paul Ehrlich (14.3.1854)
Virtuoso of test tube
Differential staining of
blood cells
Diagnosis of leukemia
(CLL vs CML)
Acid fast staining of TB
Anti-serum therapy of
diphtheria
Chemotherapy and
“Magic bullet” (Abs)
Salvarsan (compound 606)
for syphilis
Nobel Prize
“Horror autotoxicus”
Yehuda Shoenfeld, MD,FRCP ( Hon.)
6. History of
Autoimmunity
1945: Anti-red blood cell autoantibodies
and AIHA.
1950: Harrington -ITP plasma self
infusion induced severe
thrombocytopenia.
Still: Autoantibodies referred as
“factors”, SLE , RA-”connective
tissue”, “collagen” diseases.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
7. History of
Autoimmunity
1959: The first animal model of a
spontaneous AI disease:
NZB=AIHA.
(NZB/NZW) F1= SLE
(genetic basis for AI diseases)MD,FRCP ( Hon.)
Yehuda Shoenfeld,
9. Autoimmunity
1) Why Ms. X develops SLE at the age
of 30?
2) Why Mr. Y presents with
Goodpasture’s
Syndrome at the age of 50?
a) Why he and she?
b) Why the specific disease?
c) Why at that specific time?
Yehuda Shoenfeld, MD,FRCP ( Hon.)
30. AUTOANTIBODY EXPLOSION IN SLE
More than 100 Different Antibodies Found in SLE Patients
Y. Sherer,A. Gorstein,M. J. Fritzler Y. Shoenfeld; Sem A@R 2004
Yehuda Shoenfeld, MD,FRCP ( Hon.)
36. Message to Congress
to pay attention to
autoimmunity
According to AARDA,
approximately 50 million
Americans, 20 percent of the
population or one in five
people suffer from some 80
autoimmune diseases.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
37. Prevalence of
autoimmune
diseases
The seventh leading cause of death by
disease among females ages one to 14.
The fifth leading cause of death by
disease among females ages 15 to 44.
The seventh leading cause of death by
disease among females ages 45 to 65.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
38. Epidemiology of autoimmune diseases in
Denmark
Eaton WW et al. J Autoimmun. 2007; 29: 1-9
Table 1: Lifetime
prevalence of 31
autoimmune diseases
from two reviews and
among 5,472,032
persons in Denmark in
2001 per 1000
population
Yehuda Shoenfeld, MD,FRCP ( Hon.)
42. Witebsky-Rose (Koch) criteria for classical
autoimmune disease
Defining the autoantigen (e.g., AchR, gpllb, cadherin,
MBP).
Defining the autoantibody or autoreactive T cell (anti-
RBC anti-Tg, TSH).
Induction of the disease by active immunization of the
autoantigen with adjuvant (e.g. thyroiditis, collagen
arthritis, myasthenia).
Induction of the disease by passive transfer of the
autoantibody (or autoreactive T cell), e.g. ITP,
myasthenia, AIHA. Transfer of autoimmune disease from
the sick mother of the offspring, e.g. congenital
myasthenia, thyrotoxicosis, pemphigus, ITP.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
44. Autoantibodies- Anti P ribosomal
Causing behavioral changes
Novel aspects of the pathogenicity of
autoantibodies -psychiatric conditions.
Pathways; therapy; compound, peptides
Yehuda Shoenfeld, MD,FRCP ( Hon.)
45. Anti P ribosomal can induce
depression in an animal model.
Anti P Ribosomal Abs
Depression
Yehuda Shoenfeld, MD,FRCP ( Hon.)
46. Forced swimming test
Anti P rib. Ab Control mice
injected mice 350
300
control APS anti-P
Immobility time (sec)
250
200
150
100
50
0
Yehuda Shoenfeld, MD,FRCP ( Hon.)
first 120-sec last 240-sec total 360-sec
47. Autoantibodies in atrial
fibrillation: actor,
biomaker or bystander?
Baba A, Fu M. Autoimmunity . 2008; 41:470-2
At least three types of
autoantibody have been found
in AF: the anti-myosin heavy
chain autoantibody, the anti-M2
muscarinic receptor
autoantibody and the anti-heat
shock protein autoantibody.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
48. Autoimmunity
1) Why does Ms. X develop SLE at the
age of 30?
2) Why does Mr. Y present with
Goodpasture’s Syndrome at the age of
50?
a) Why he and she?
b) Why the specific disease?
c) Why at that specific time?
Yehuda Shoenfeld, MD,FRCP ( Hon.)
49. The major pieces of the
mosaic of autoimmunity
Cenetics:
Increased incidence of the disease in families.
Increased incidence of autoantibodies in first-degree
relatives of a patient.
Increased incidence of the disease in monozygotic
twins.
HLA studies – increased incidence of HLA-B8, DR2, DR3,
DR4 in some diseases. A protective effect, e.g. HLA
DR2 in type 1 diabetes.
Increased incidence of common idiotype of
autoantibodies in patients and first-degree relatives,
Gm-allotypes.
Complement component deficiencies.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
52. Triplets with SLE
Kamat SS, et al. Arthritis Rheum.
2003;48:3176-80.
The first case report of identical triplets who
developed systemic lupus erythematosus (SLE).
The children were diagnosed at ages 8, 9, and 11
years.
Each sibling manifested different clinical signs and
symptoms.
Findings of laboratory studies were similar,
including antinuclear antibodies, anti-native DNA,
and anti-double-stranded DNA, as well as low
levels of complement. Yehuda Shoenfeld, MD,FRCP ( Hon.)
53. HLA risk for SLE
A1, B8, DR3
is associated with
a 10 - fold increase
(Primary link with C4
null allele).
Yehuda Shoenfeld, MD,FRCP ( Hon.)
54. Evidence for a susceptibility
gene (SLEH1) on
chromosome 11q14 for
systemic lupus
erythematosus (SLE)
families with hemolytic
anemia
Kelly JA, et.al. Proc Natl Acad Sci
U S A 2002 ;99:11766-71
Yehuda Shoenfeld, MD,FRCP ( Hon.)
55. The major pieces of the
Mosaic of Autoimmunity
Defects in immune system:
IgA deficiency.
Complement component deficiencies
(e.g.C1q, C2, C4).
Qualitative and quantitative defects in T
suppressors (CD4+25+) ( Treg).
Defects in natural killer (NK) cells.
Defects in apoptosis (Fas) or
phagocytosis.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
56. Selective IgA deficiency in
children and adults with
systemic lupus
erythematosus
Cassidy JT et al. Lupus. 2007; 16: 647-50
12/77 SLE
Similar clinical
presentation
Yehuda Shoenfeld, MD,FRCP ( Hon.)
57. The major pieces of the
Mosaic of Autoimmunity
Sex and autoimmunity
Females have, on the average, higher Ig levels than males.
Females have an enhanced antibody production to both primary
and secondary Ag stimulation.
Females have a higher CMI response (e.g. homograft rejection).
Males are more prone to infections .
In male animals, it is easier to produce immune tolerance.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
58. Cutolo M et al. J Clin Ezndocrinol Metab 1996;81:820-827
Yehuda Shoenfeld, MD,FRCP ( Hon.)
59. Synovial tissue Macrophages stained for ER Cultured synovial Macrophages stained for ER
Synovial tissue Macrophages stained for AR Cultured synovial Macrophages stained for AR
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Cutolo M et al. J Clin Ezndocrinol Metab 1996;81:820-827
62. Beneficial effects of the anti-
oestrogen tamoxifen on systemic
lupus erythematosus of
(NZBxNZW)F1 female mice are
associated with specific reduction of
IgG3 autoantibodies.
Sthoeger ZM, Zinger H, Mozes E.
Ann Rheum Dis 2003 ;62:341-6
Yehuda Shoenfeld, MD,FRCP ( Hon.)
64. Hepatitis-C and
Autoimmune Diseases
1) Mixed cryoglobulinemia.
2) Ch. Active hepatitis.
3) Polyarteritis nodosa.
4) Leukocytoclastic vasculitis.
5) Autoimmune thyroid disease.
6) Glomerulonephritis.
7) Polymyositis + anti-Jo-1 Ab.
8) Formation of autoantibodies and CIC
(A@R. 3: 437, 1995).
Yehuda Shoenfeld, MD,FRCP ( Hon.)
65. The infectious origin of the antiphospholipid
syndrome (APS): induction of exp.APS by
passive transfer of anti-β 2GPI Abs induced
by common bacteria
1
Blank M, 1Krause I, 1Levy Y, 2Fridkin M,
Keller N and 1Y Shoenfeld
3
J Clin Invest 109;797-804,2002
Yehuda Shoenfeld, MD,FRCP ( Hon.)
67. 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
Yehuda Shoenfeld, MD,FRCP ( Hon.)
68. 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.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
69. Smoking and Goodpasture
Cigarette smoking and lung hemorrhage in
glomerulonephritis caused by autoantibodies to
glomerular basement membrane.
Lancet 1983 : 2 : 1390-3
Diffuse alveolar hemorrhage developed:
# 20% of non-smokers.
# 80% of smokers.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
70. Smoking increases peptidylarginine
deiminase 2 enzyme expression in
human lungs and increases
citrullination in BAL cells
Makrygiannakis D et al. Ann Rheum Dis. 2008; 67: 1488-92
Smoking enhances PAD2 expression in
the bronchial mucosal and alveolar
compartment, with consequent
generation of citrullinated proteins in
the latter.
Smoking is an environmental factor that
may lead to citrulline autoimmunity in
genetically susceptible subjects.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
71. Lipstick consumption and
systemic lupus
erythematosus: nothing to
gloss over
Kurien BT, Scofield RH.
Clin Rheumatol . 2008; 27: 1339-40
Yehuda Shoenfeld, MD,FRCP ( Hon.)
73. Multiple autoantibodies
in patients with silicone
breast implants
Bar-Meir E, Teuber SS, Lin HC, Alosacie I,
Goddard G, Terrybery J, Barka N, Shen
B, Peter JB, Blank M, Gershwin ME,
Shoenfeld Y.
J Autoimmunity 8: 267-277, 1995
Yehuda Shoenfeld, MD,FRCP ( Hon.)
74. Systemic lupus
erythematosus after
alpha-interferon therapy
for chronic hepatitis C :
a case report and review
of the literature
Fukuyama S, et al.
Am J Gastroenterol 2000 : 95: 310 - 2
Yehuda Shoenfeld, MD,FRCP ( Hon.)
75. Occupational risk factors for the
development of systemic lupus
erythematosus
Cooper GS, et al. J Rheumatol. 2004; 31: 1928-33
Associations were seen with self-reported
occupational exposure to mercury (OR 3.6, 95%
CI 1.3, 10.0), mixing pesticides for agricultural
work (OR 7.4, 95% CI 1.4, 40.0), and among
dental workers (OR 7.1, 95% CI 2.2, 23.4).
Yehuda Shoenfeld, MD,FRCP ( Hon.)
76. 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.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
77. ,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
Yehuda Shoenfeld, MD,FRCP ( Hon.)
78. The mosaic of
autoimmunity
Yehuda Shoenfeld MD
Genetic
,HLA)
Immune GM
Environmental
deficienccy Allotype
,infection)
state Idiotype
Drugs, UV
IgA def. Trg)
smoking
( C‘ def., NK Hormonal
Estrogen)
( Testosterone
Yehuda Shoenfeld, MD,FRCP ( Hon.)
79. The mosaic of autoimmunity.
A classical case of inhalation of a
polyclonal activating factor in a
genetically and hormonally
susceptible patient leading to
multiple autoimmune diseases.
Rahamim-Cohen D, Shoenfeld Y.
Isr Med Assoc J. 2001;3:381-2.
Yehuda Shoenfeld, MD,FRCP ( Hon.)
82. Galileo Galilei
Page 72 Opere Gallilei
Omnium rerum origo ipsa sui
immunis, donec res contraria
reperitur.
“Everything is
autoimmune until proven
otherwise”
Yehuda Shoenfeld, MD,FRCP ( Hon.)
87. Pet dogs owned by lupus patients are
at a higher risk of developing lupus
Chiou SH, et al. Lupus. 2004; 13: 442-9
Among 59 pet dogs owned by 37 SLE patients, 11 (18%)
were ANA positive, and three (5%) had SLE.
Of 187 pet dogs owned by non-SLE households, nine
(4.81%) were ANA positive, and none (0%) had SLE.
Pet dogs with human SLE contact were at a higher risk of
developing SLE.
A common environmental factor or zoonotic agent may be
involved in the development of human and canine SLE.
Yehuda Shoenfeld, MD,FRCP ( Hon.)