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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.)
Autoimmune diseases
  The enemy from within
      Yehuda Shoenfeld
              MD FRCP
                  TAU 03 03 11
Allergy and AID




             Yehuda Shoenfeld, MD,FRCP ( Hon.)
First Autoimmune Disease




            Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
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.)
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,
LE CELL-1948




      Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Anti- TSH-R




Yehuda Shoenfeld, MD,FRCP ( Hon.)
Exophthalmus




               Yehuda Shoenfeld, MD,FRCP ( Hon.)
Myxedema
Hypothyroidism




                 Yehuda Shoenfeld, MD,FRCP ( Hon.)
Anti- Desmoglein




Yehuda Shoenfeld, MD,FRCP ( Hon.)
Acantholysis -
            intraepidermal blister
      Pemphigus vulgaris (PV) –          Pemphigus foliaceous (PF) –blister
blister in suprabasal epidermal layers       in superficial epidermis




                                           Yehuda Shoenfeld, MD,FRCP ( Hon.)
Anti- Topoisomerase-I




         Correlation of serum
       anti-DNA topoisomerase
            I antibody levels
      with disease severity and
    activity in systemic sclerosis.
              Hu PQ, et.al.
. .Arthritis Rheum. 2003;48:1363-73




   Yehuda Shoenfeld, MD,FRCP ( Hon.)
Myasthenia Gravis
                    Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Vanda Lennon
with electric eel




                    Yehuda Shoenfeld, MD,FRCP ( Hon.)
Myasthenia Gravis – pre and post thymectomy




                      Yehuda Shoenfeld, MD,FRCP ( Hon.)
Polymyositis-Ovarian cancer


       Sjogren syndrome and
            lymphoma


     Paraneoplastic syndromes
      Small cell ca of the lung




Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Type-I Insulin-Dependent Diabetes Melitus – IDDM
  Organ specific, T-cell mediated autoimmune disease




                                Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
The original classification of autoimmune
         diseases into organ-specific and non-organ-
                           specific
         Simmonds MJ & Gough SCL. British Medical Bulletin. 2005; 71


Organ-specific                     Non-organ-specific
Hashimoto’s thyroiditis            Sjogren’s syndrome
Graves’ disease                    APECED
Pernicious anaemia                 Rheumatoid arthritis

Addison's disease                  Systemic lupus erythematosus
Myasthenia gravis
Type 1 diabetes
Multiple sclerosis

                                       Yehuda Shoenfeld, MD,FRCP ( Hon.)
Autoantibodies
        Predictive
           2005

Precede overt autoimmune disease
Predict specific clinical manifestation
Predict pregnancy loss.
                                      Yehuda Shoenfeld
                       Yehuda Shoenfeld, MD,FRCP ( Hon.)
Autoantibodies as Predictors Of Diseases

        Scofield RH. Lancet. 2004,8;363:1544-6 .
      Shoenfeld Y. Autoimmunity. 2004 (in press)
 RA: anti-ccp, IgM-RF-4.5y., NPV-75%, PPV-100%.
  Nielen MM, et.al. Arthritis Rheum, 2004;50:380-6
  Rantapaa-Dahlqvist S, et.al. Arthritis Rheum. 2003;48:2741-9.
 SLE: α DNA, 2.5-10y.

       α Ro,α Sm
  Arbuckle MR, et.al. N Engl J Med. 2003;349:1526-33
 PBC: α PDH-30y.

  Kisand KE. J Gastroenterol. 2001;36:248-54.
 Addison’s disease: α adrenal cortical and α 21 hydroxilase

 Ketchum CH, et.al.J Clin Endocrinol Metab. 1984;58:1166-70.
 Laureti S, et.al. J Clin Endocrinol Metab. 1998;83:3507-11.
 DM type I: α GAD, α Insulin, α IA-2A. Siblings, general. 99.5%

  specific, 50% PPV.
  Kupila A, et.al. Diabetologia. 2001;44:290-7.
                                    Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
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.)
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.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
PL Meroni   Yehuda Shoenfeld, MD,FRCP ( Hon.)
New congresses




        Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
New autoimmune
   diseases
  Endometriosis
 Duodenal ulcer
 Alopecia
  Psoriasis
  Autism
  Neuroleptic malignant
 Depression

 Schizophrenia
  Epilepsy (10% of 543 APS pts.) ( Hon.)
                 Yehuda Shoenfeld, MD,FRCP
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.)
Anti P ribosomal can induce
depression in an animal model.




           Anti P Ribosomal Abs




              Depression


                           Yehuda Shoenfeld, MD,FRCP ( Hon.)
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
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.)
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.)
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.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Marco Salvetti et al




Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
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.)
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.)
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.)
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.)
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.)
Cutolo M et al. J Clin Ezndocrinol Metab 1996;81:820-827




                                        Yehuda Shoenfeld, MD,FRCP ( Hon.)
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
monocytes

                          Estrogen
                          Receptors




            lymphocytes
                  Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
The major pieces of the
      Mosaic of Autoimmunity
    Environmental:
     Infecting agents: viruses, bacteria, parasites.
     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 (e.g. RA, SLE).

                                Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
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.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
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.)
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.)
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.)
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.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
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.)
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.)
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.)
,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.)
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.)
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.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
Systemic autoimmune diseases
Systemic diseases                    Reiter’s disease
                                     Reiter’
Systemic lupus erythematosus         Sneddons disease
Antiphospholipid syndrome            Autoimmune polyendocrinopathy, candidiasis-ectodermal
Rheumatoid arthritis                          dystropy
Juvenile Rheumatoid arthritis        Essential cryoglobulinemic vasculitis
Felty’s syndrome
Felty’                               Cutaneous leukocytoclastic angiitis
Large granular lymphocytosis (LGL)   Lyme disease
Sjogren’s syndrome
Sjogren’                             Rheumatic fever and heart disease
Systemic sclerosis (scleroderma)     Eosinophilic fasciitis
Crest syndrome                       Paroxysmal cold hemoglobinuria
Mixed connective tissue disease      Polymyalgia rheumatica
Polymyositis/ dermatomyositis        Fibromyalgia
Goodpasture’s Disease
Goodpasture’                         POEMS syndrome (polyneuropathy, organomegaly,
Wegener’s granulomatosis                      endocrinopathy, M-spot and skin changes)
Wegener’
                                     Relapsing polychondritis
Churg-Strauss syndrome
Henoch-Schonlein purpura             Autoimmune lymphoproliferative syndrome
                                     TINU syndrome (acute tubulointerstitial nephritis and
Microscopic polyangiatis
                                              uveitis)
Periarteritis nodosa
                                     Autoimmunity associated with immunodeficiency
Bechet’s syndrome
Bechet’
                                     Common variable immunodeficiency
Atherosclerosis
                                     TAP (transporter associated with antigen presentation)
Temporal (giant) cell arteritis               deficiency
Takayasu arteritis                   Omenn syndrome
Kawasaki disease                     HyperIgM syndrome
Ankylosing spondilitis               BTK agammaglobulinemia
                                     Human immunodeficiency virus
                                     Post bone-marrow-transplant

                                              Yehuda Shoenfeld, MD,FRCP ( Hon.)
Organ specific autoimmune diseases
Neurological                                     Dermatology                                            Reproductive
Myasthenia Gravis                                Pemphigus Vulgaris                                     Autoimmune premature ovarian failure
Congenital myasthenia gravis                     Pemphigus Foliaceus                                    Azoospermia
Multiple sclerosis                               Bullous phemphigoid/ Pemphigoid gestationis            Hypogonadism
Stiff-man syndrome                               Cicatrical pemphigoid                                  Male infertility associated with sperm
Tropical spastic paraparesis                     Dermatitis herpetiformis                                            autoantibodies
Rasmussen’s encephalitis
Rasmussen’                                       Epidermal bullosa acquisita                            Autoimmune orchitis
Acute motor axonal neuropathy                    Erythema multiforme                                    Premature ovarian failure
Acute sensory-motor axonal neuropathy            Herpes gestatonis                                      Autoimmune oophoritis
Dorsal root ganglion neuritis                    Vitiligo                                               Ocular
Acute pan-autonomic neuropathy                   Chronic urticaria                                      Uveitis
Brachial neuritis                                Discoid lupus                                          Retinitis
Acute necrotizing hemorrhagic lekoencephalitis   Alopecia universalis/Areata                            Sympathetic ophthalmia
Sporadic necrotizing myelopathy                  Psoriasis                                              Birdshot retinochoroidopathy
Paraneoplastic cerebellar degeneration           Hepatobiliary                                          Vogt-Koyanagi-Harada granulomatous uveitis
Guillain-Barre syndrome                          Autoimmune hepatitis                                   Retinal degeneration
Limbic encephalitis                              Primary biliary cirrhosis                              Lens-induced uveitis
Opsoclonus-myoclonus ataxia                      Chronic active hepatitis                               Optic neuritis
Sensory neuronitis                               Chronic active hepatitits/ Primary biliary cirrhosis   Vestibulocochlear
Autonomic neuropathy                                         overlap syndrome                           Autoimmune sensorineural hearing loss
Demyelinating neuropathy                         Primary sclerosing cholangitis                         Meniere’s disease
                                                                                                        Meniere’
AIDS-dementia complex.                           Hematopoeitic                                          Cardiac
Tourette’s syndrome
Tourette’                                        Autoimmune hemolytic anemia                            Autoimmune myocarditis
Miller-Fisher syndrome                           Idiopathic thrombocytopenic purpura                    Congenital heart block (neonatal lupus)
Alzheimer’s disease
Alzheimer’                                       Evans syndrome                                         Chagas’ disease
                                                                                                        Chagas’
Endocrine                                        Heparin-induced thrombocytopenia                       Adriamycin cardiotoxicity
Graves’ Disease
Graves’                                          Primary autoimmune neutropenia                         Dressler’s myocarditis syndrome
                                                                                                        Dressler’
Hashimoto’s thyroiditis
Hashimoto’                                       Autoimmune (primary) neutropenia of infancy            Respiratory
                                                                                                        Respiratory
Postpartum thyroiditis                           Autoimmune neutropenia following bone marrow           Bronchial asthma
                                                             transplant                                 Interstitial fibrosing lung disease
Focal thyroiditis
                                                 Acquired autoimmune hemophilia                         Nephrology
Juvenile thyroiditis
Idiopathic hypothyroidism                        Gastroenterlogy                                        Rapidly progressive glomerulonephritis
                                                 Autoimmune gastritis and pernicious anemia             Autoimmune tubulointerstitial nephritis
Type I (insulin dependent) diabetes mellitus
                                                 Coeliac disease
Addison’s disease
Addison’
Hypophysitis                                     Crohn’s disease
                                                 Crohn’
Autoimmune diabetes insipidus                    Ulcerative colitis
Hypoparathyroidism                               Sialadenitis
                                                                                      Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)

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27.futuro centros

  • 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
  • 3. Allergy and AID Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 4. First Autoimmune Disease Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 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,
  • 8. LE CELL-1948 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 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.)
  • 11. Anti- TSH-R Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 12. Exophthalmus Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 13. Myxedema Hypothyroidism Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 15. Acantholysis - intraepidermal blister Pemphigus vulgaris (PV) – Pemphigus foliaceous (PF) –blister blister in suprabasal epidermal layers in superficial epidermis Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 16. Anti- Topoisomerase-I Correlation of serum anti-DNA topoisomerase I antibody levels with disease severity and activity in systemic sclerosis. Hu PQ, et.al. . .Arthritis Rheum. 2003;48:1363-73 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 17. Myasthenia Gravis Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 20. Vanda Lennon with electric eel Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 21. Myasthenia Gravis – pre and post thymectomy Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 22. Polymyositis-Ovarian cancer Sjogren syndrome and lymphoma Paraneoplastic syndromes Small cell ca of the lung Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 24. Type-I Insulin-Dependent Diabetes Melitus – IDDM Organ specific, T-cell mediated autoimmune disease Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 26. The original classification of autoimmune diseases into organ-specific and non-organ- specific Simmonds MJ & Gough SCL. British Medical Bulletin. 2005; 71 Organ-specific Non-organ-specific Hashimoto’s thyroiditis Sjogren’s syndrome Graves’ disease APECED Pernicious anaemia Rheumatoid arthritis Addison's disease Systemic lupus erythematosus Myasthenia gravis Type 1 diabetes Multiple sclerosis Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 27. Autoantibodies Predictive 2005 Precede overt autoimmune disease Predict specific clinical manifestation Predict pregnancy loss. Yehuda Shoenfeld Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 28. Autoantibodies as Predictors Of Diseases Scofield RH. Lancet. 2004,8;363:1544-6 . Shoenfeld Y. Autoimmunity. 2004 (in press)  RA: anti-ccp, IgM-RF-4.5y., NPV-75%, PPV-100%. Nielen MM, et.al. Arthritis Rheum, 2004;50:380-6 Rantapaa-Dahlqvist S, et.al. Arthritis Rheum. 2003;48:2741-9.  SLE: α DNA, 2.5-10y. α Ro,α Sm Arbuckle MR, et.al. N Engl J Med. 2003;349:1526-33  PBC: α PDH-30y. Kisand KE. J Gastroenterol. 2001;36:248-54.  Addison’s disease: α adrenal cortical and α 21 hydroxilase Ketchum CH, et.al.J Clin Endocrinol Metab. 1984;58:1166-70. Laureti S, et.al. J Clin Endocrinol Metab. 1998;83:3507-11.  DM type I: α GAD, α Insulin, α IA-2A. Siblings, general. 99.5% specific, 50% PPV. Kupila A, et.al. Diabetologia. 2001;44:290-7. 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.)
  • 40. PL Meroni Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 41. New congresses 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.)
  • 43. New autoimmune diseases Endometriosis Duodenal ulcer Alopecia Psoriasis Autism Neuroleptic malignant Depression Schizophrenia Epilepsy (10% of 543 APS pts.) ( Hon.) Yehuda Shoenfeld, MD,FRCP
  • 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.)
  • 51. Marco Salvetti et al 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
  • 60. monocytes Estrogen Receptors lymphocytes Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 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.)
  • 63. The major pieces of the Mosaic of Autoimmunity Environmental:  Infecting agents: viruses, bacteria, parasites.  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 (e.g. RA, SLE). 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.)
  • 83.
  • 84. Systemic autoimmune diseases Systemic diseases Reiter’s disease Reiter’ Systemic lupus erythematosus Sneddons disease Antiphospholipid syndrome Autoimmune polyendocrinopathy, candidiasis-ectodermal Rheumatoid arthritis dystropy Juvenile Rheumatoid arthritis Essential cryoglobulinemic vasculitis Felty’s syndrome Felty’ Cutaneous leukocytoclastic angiitis Large granular lymphocytosis (LGL) Lyme disease Sjogren’s syndrome Sjogren’ Rheumatic fever and heart disease Systemic sclerosis (scleroderma) Eosinophilic fasciitis Crest syndrome Paroxysmal cold hemoglobinuria Mixed connective tissue disease Polymyalgia rheumatica Polymyositis/ dermatomyositis Fibromyalgia Goodpasture’s Disease Goodpasture’ POEMS syndrome (polyneuropathy, organomegaly, Wegener’s granulomatosis endocrinopathy, M-spot and skin changes) Wegener’ Relapsing polychondritis Churg-Strauss syndrome Henoch-Schonlein purpura Autoimmune lymphoproliferative syndrome TINU syndrome (acute tubulointerstitial nephritis and Microscopic polyangiatis uveitis) Periarteritis nodosa Autoimmunity associated with immunodeficiency Bechet’s syndrome Bechet’ Common variable immunodeficiency Atherosclerosis TAP (transporter associated with antigen presentation) Temporal (giant) cell arteritis deficiency Takayasu arteritis Omenn syndrome Kawasaki disease HyperIgM syndrome Ankylosing spondilitis BTK agammaglobulinemia Human immunodeficiency virus Post bone-marrow-transplant Yehuda Shoenfeld, MD,FRCP ( Hon.)
  • 85. Organ specific autoimmune diseases Neurological Dermatology Reproductive Myasthenia Gravis Pemphigus Vulgaris Autoimmune premature ovarian failure Congenital myasthenia gravis Pemphigus Foliaceus Azoospermia Multiple sclerosis Bullous phemphigoid/ Pemphigoid gestationis Hypogonadism Stiff-man syndrome Cicatrical pemphigoid Male infertility associated with sperm Tropical spastic paraparesis Dermatitis herpetiformis autoantibodies Rasmussen’s encephalitis Rasmussen’ Epidermal bullosa acquisita Autoimmune orchitis Acute motor axonal neuropathy Erythema multiforme Premature ovarian failure Acute sensory-motor axonal neuropathy Herpes gestatonis Autoimmune oophoritis Dorsal root ganglion neuritis Vitiligo Ocular Acute pan-autonomic neuropathy Chronic urticaria Uveitis Brachial neuritis Discoid lupus Retinitis Acute necrotizing hemorrhagic lekoencephalitis Alopecia universalis/Areata Sympathetic ophthalmia Sporadic necrotizing myelopathy Psoriasis Birdshot retinochoroidopathy Paraneoplastic cerebellar degeneration Hepatobiliary Vogt-Koyanagi-Harada granulomatous uveitis Guillain-Barre syndrome Autoimmune hepatitis Retinal degeneration Limbic encephalitis Primary biliary cirrhosis Lens-induced uveitis Opsoclonus-myoclonus ataxia Chronic active hepatitis Optic neuritis Sensory neuronitis Chronic active hepatitits/ Primary biliary cirrhosis Vestibulocochlear Autonomic neuropathy overlap syndrome Autoimmune sensorineural hearing loss Demyelinating neuropathy Primary sclerosing cholangitis Meniere’s disease Meniere’ AIDS-dementia complex. Hematopoeitic Cardiac Tourette’s syndrome Tourette’ Autoimmune hemolytic anemia Autoimmune myocarditis Miller-Fisher syndrome Idiopathic thrombocytopenic purpura Congenital heart block (neonatal lupus) Alzheimer’s disease Alzheimer’ Evans syndrome Chagas’ disease Chagas’ Endocrine Heparin-induced thrombocytopenia Adriamycin cardiotoxicity Graves’ Disease Graves’ Primary autoimmune neutropenia Dressler’s myocarditis syndrome Dressler’ Hashimoto’s thyroiditis Hashimoto’ Autoimmune (primary) neutropenia of infancy Respiratory Respiratory Postpartum thyroiditis Autoimmune neutropenia following bone marrow Bronchial asthma transplant Interstitial fibrosing lung disease Focal thyroiditis Acquired autoimmune hemophilia Nephrology Juvenile thyroiditis Idiopathic hypothyroidism Gastroenterlogy Rapidly progressive glomerulonephritis Autoimmune gastritis and pernicious anemia Autoimmune tubulointerstitial nephritis Type I (insulin dependent) diabetes mellitus Coeliac disease Addison’s disease Addison’ Hypophysitis Crohn’s disease Crohn’ Autoimmune diabetes insipidus Ulcerative colitis Hypoparathyroidism Sialadenitis 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.)