Programa 8:30 a.m. a 9:15 a.m.        El mosaico de la autoinmunidad                             Yehuda Shoenfeld, MD, ...
 El Mosaico de la AutoinmunidadYehuda Shoenfeld, MD, FRCPJefe, Departamento de Medicina B y CentroZabludowicz para Enferme...
Autoimmune diseases  The enemy from within      Yehuda Shoenfeld              MD FRCP                   TAU 03 03 11
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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        (...
History of  Autoimmunity1945: Anti-red blood cell autoantibodies      and AIHA.1950: Harrington -ITP plasma self          ...
History of     Autoimmunity1959: The first animal model of a      spontaneous AI disease:      NZB=AIHA.        (NZB/NZW)...
LE  CELL-1948       Yehuda Shoenfeld, MD,FRCP ( Hon.)
Autoimmunity1) Why Ms. X develops SLE at the age of 30?2)  Why Mr. Y presents with Goodpasture’s      Syndrome at the age ...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Anti- TSH-RYehuda Shoenfeld, MD,FRCP ( Hon.)
Exophthalmus               Yehuda Shoenfeld, MD,FRCP ( Hon.)
MyxedemaHypothyroidism                 Yehuda Shoenfeld, MD,FRCP ( Hon.)
Anti- DesmogleinYehuda Shoenfeld, MD,FRCP ( Hon.)
Acantholysis -             intraepidermal blister      Pemphigus vulgaris (PV) –          Pemphigus foliaceous (PF) –blist...
Anti- Topoisomerase-I          Correlation of serum        anti-DNA topoisomerase             I antibody levels       with...
Myasthenia Gravis                    Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Vanda Lennonwith 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...
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.)
The original classification of autoimmune          diseases into organ-specific and non-organ-                           s...
Autoantibodies        Predictive           2005Precede overt autoimmune diseasePredict specific clinical manifestationP...
Autoantibodies as Predictors Of Diseases                 Scofield RH. Lancet. 2004,8;363:1544-6 .               Shoenfeld ...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
AUTOANTIBODY EXPLOSION IN SLE More than 100 Different Antibodies Found in SLE PatientsY. Sherer,A. Gorstein,M. J. Fritzler...
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.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Message to Congress        to pay  attention  to           autoimmunity   According to AARDA,     approximately 50 millio...
Prevalence of         autoimmune           diseases   The seventh leading cause of death by     disease among females age...
Epidemiology of autoimmune diseases in                      Denmark               Eaton WW et al. J Autoimmun. 2007; 29: 1...
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, gpl...
New autoimmune        diseases                 Endometriosis                 Duodenal ulcer                 Alopecia      ...
Autoantibodies- Anti P ribosomal        Causing behavioral changesNovel aspects of the pathogenicity ofautoantibodies -ps...
Anti P ribosomal can induce depression in an animal model.           Anti P Ribosomal Abs              Depression         ...
Forced swimming test   Anti P rib. Ab                                     Control mice   injected mice                    ...
Autoantibodies in atrial           fibrillation: actor,     biomaker or bystander?      Baba A, Fu M. Autoimmunity . 2008;...
Autoimmunity1) Why does Ms. X develop SLE at the age of 30?2)  Why does Mr. Y present with Goodpasture’s Syndrome at the a...
The major   pieces of the      mosaic of autoimmunityCenetics:  Increased incidence of the disease in families.  Increas...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Marco Salvetti et alYehuda Shoenfeld, MD,FRCP ( Hon.)
Triplets with SLE           Kamat SS, et al. Arthritis Rheum.                      et al.                  2003;48:3176-80...
HLA risk for SLE          A1,  B8,  DR3          is associated  with          a 10 - fold increase      (Primary link with...
Evidence for a susceptibility      gene (SLEH1) on   chromosome 11q14 for       systemic lupus    erythematosus (SLE)   fa...
The major pieces of the       Mosaic of Autoimmunity Defects in immune system:       IgA deficiency.       Complement co...
Selective IgA deficiency in  children and adults with       systemic lupus       erythematosus     Cassidy JT et al. Lupus...
The major pieces of the         Mosaic of Autoimmunity    Sex and autoimmunity   Females have, on the average, higher Ig ...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Cutolo M et al. J Clin Ezndocrinol Metab 1996;81:820-827                                        Yehuda Shoenfeld, MD,FRCP ...
Synovial tissue Macrophages stained for ER       Cultured synovial Macrophages stained for ERSynovial tissue Macrophages s...
monocytes                          Estrogen                          Receptors            lymphocytes                  Yeh...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Beneficial effects of the anti- oestrogen tamoxifen on systemic       lupus erythematosus of    (NZBxNZW)F1 female mice ar...
The major pieces of the        Mosaic of Autoimmunity     Environmental:          Infecting agents: viruses, bacteria, pa...
Hepatitis-C and   Autoimmune Diseases1)  Mixed cryoglobulinemia.2)  Ch. Active hepatitis.3)  Polyarteritis nodosa.4)  Leuk...
The infectious origin of the antiphospholipid syndrome (APS): induction of exp.APS bypassive transfer of anti-β 2GPI Abs i...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
EBV genetics and autoimmune diseases                               EBVAutoimmune         HLA-DR15   gene                  ...
Influence of HLA-DR phenotype on the risk         of hepatitis C virus-associated mixed                   cryoglobulinemia...
Smoking and GoodpastureCigarette smoking and lung hemorrhage inglomerulonephritis caused by autoantibodies toglomerular ba...
Smoking increases peptidylarginine       deiminase 2 enzyme expression in          human lungs and increases           cit...
Lipstick consumption and       systemic lupus erythematosus: nothing to         gloss over             Kurien BT, Scofield...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Multiple autoantibodies  in patients with silicone      breast implants Bar-Meir E, Teuber SS, Lin HC, Alosacie I,    Godd...
Systemic lupus    erythematosus after alpha-interferon therapy  for chronic hepatitis C : a case report and review      of...
Occupational risk factors for the       development of systemic lupus               erythematosus     Cooper GS, et al. J ...
Geographical clustering of scleroderma in               south and west London.       Silman AJ, et al. Br J Rheumatol 1990...
 ,Reifen R, Blank M, Afek A                           ,Kopilowiz Y, Sklan D                         ,Gershwin ME, German B...
The mosaic of         autoimmunity        Yehuda Shoenfeld MD                  Genetic                   ,HLA)   Immune   ...
   The mosaic of autoimmunity.  A classical case of inhalation of a  polyclonal activating factor in a    genetically and ...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Galileo Galilei     Page 72 Opere GallileiOmnium rerum origo ipsa sui immunis, donec res contraria          reperitur.    ...
Systemic autoimmune  diseasesSystemic diseases                    Reiter’s disease                                     Rei...
Organ specific autoimmune diseases Neurological                                     Dermatology                           ...
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;...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
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1 shoenfeld

  1. 1.    Programa 8:30 a.m. a 9:15 a.m.    El mosaico de la autoinmunidad Yehuda Shoenfeld, MD, FRCP 9:15 a.m. a 10:00 a.m.  BAFF, Linfocitos B en autoinmunidad Pierre Youinou, MD, Dr.Sc.10:00 a.m. a 10:30 a.m. CAFE 10:30 a.m. a 11:00 a.m. Nefritis Lúpica Ricard Cervera, MD, PhD11:00 a.m. a 11:30 a.m. Embarazo y enfermedades autoinmunes  Claudio Galarza, MD, PhD (c).11:30 a.m. a 12:00 a.m. Glucocorticoides endógenos y exógenos Frank Buttgereit, MD12:00 a.m. a 12:30 a.m. Preguntas12:30 p.m. a 2:00 p.m. Almuerzo Yehuda Shoenfeld, MD,FRCP ( Hon.)
  2. 2.  El Mosaico de la AutoinmunidadYehuda Shoenfeld, MD, FRCPJefe, Departamento de Medicina B y CentroZabludowicz para Enfermedades Autoinmunes,Centro Médico Sheba (Afiliado a la Universidad deTel-Aviv), y Titular de la Cátedra de InvestigaciónLaura Schwarz-Kipp en EnfermedadesAutoinmunes, Universidad de Tel-Aviv, Israel. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  3. 3. Autoimmune diseases The enemy from within Yehuda Shoenfeld MD FRCP  TAU 03 03 11
  4. 4. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  5. 5. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  6. 6. Allergy and  AID Yehuda Shoenfeld, MD,FRCP ( Hon.)
  7. 7. First Autoimmune Disease Yehuda Shoenfeld, MD,FRCP ( Hon.)
  8. 8. 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.)
  9. 9. History of Autoimmunity1945: 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.)
  10. 10. History of Autoimmunity1959: 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,
  11. 11. LE  CELL-1948 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  12. 12. Autoimmunity1) 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.)
  13. 13. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  14. 14. Anti- TSH-RYehuda Shoenfeld, MD,FRCP ( Hon.)
  15. 15. Exophthalmus Yehuda Shoenfeld, MD,FRCP ( Hon.)
  16. 16. MyxedemaHypothyroidism Yehuda Shoenfeld, MD,FRCP ( Hon.)
  17. 17. Anti- DesmogleinYehuda Shoenfeld, MD,FRCP ( Hon.)
  18. 18. Acantholysis -  intraepidermal blister Pemphigus vulgaris (PV) – Pemphigus foliaceous (PF) –blisterblister in suprabasal epidermal layers in superficial epidermis Yehuda Shoenfeld, MD,FRCP ( Hon.)
  19. 19. 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.)
  20. 20. Myasthenia Gravis Yehuda Shoenfeld, MD,FRCP ( Hon.)
  21. 21. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  22. 22. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  23. 23. Vanda Lennonwith electric eel Yehuda Shoenfeld, MD,FRCP ( Hon.)
  24. 24. Myasthenia Gravis – pre and post thymectomy Yehuda Shoenfeld, MD,FRCP ( Hon.)
  25. 25. Polymyositis-Ovarian cancer  Sjogren syndrome and lymphoma Paraneoplastic syndromes Small cell ca of the lungYehuda Shoenfeld, MD,FRCP ( Hon.)
  26. 26. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  27. 27. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  28. 28. Type-I Insulin-Dependent Diabetes Melitus – IDDM Organ specific, T-cell mediated autoimmune disease Yehuda Shoenfeld, MD,FRCP ( Hon.)
  29. 29. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  30. 30. 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-specificHashimoto’s thyroiditis Sjogren’s syndrome Graves’ disease APECEDPernicious anaemia Rheumatoid arthritisAddisons disease Systemic lupus erythematosus Myasthenia gravisType 1 diabetes Multiple sclerosis Yehuda Shoenfeld, MD,FRCP ( Hon.)
  31. 31. Autoantibodies Predictive 2005Precede overt autoimmune diseasePredict specific clinical manifestationPredict pregnancy loss. Yehuda Shoenfeld Yehuda Shoenfeld, MD,FRCP ( Hon.)
  32. 32. 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.)
  33. 33. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  34. 34. AUTOANTIBODY EXPLOSION IN SLE More than 100 Different Antibodies Found in SLE PatientsY. Sherer,A. Gorstein,M. J. Fritzler Y. Shoenfeld; Sem A@R 2004 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  35. 35. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  36. 36. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  37. 37. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  38. 38. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  39. 39. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  40. 40. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  41. 41. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  42. 42. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  43. 43. 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.)
  44. 44. 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.)
  45. 45. Epidemiology of autoimmune diseases in Denmark Eaton WW et al. J Autoimmun. 2007; 29: 1-9Table 1: Lifetimeprevalence of 31autoimmune diseasesfrom two reviews andamong 5,472,032persons in Denmark in2001 per 1000population Yehuda Shoenfeld, MD,FRCP ( Hon.)
  46. 46. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  47. 47. PL Meroni Yehuda Shoenfeld, MD,FRCP ( Hon.)
  48. 48. New congresses Yehuda Shoenfeld, MD,FRCP ( Hon.)
  49. 49. 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.)
  50. 50. New autoimmune  diseases Endometriosis         Duodenal ulcer         Alopecia Psoriasis Autism Neuroleptic malignant                 Depression                                     Schizophrenia Epilepsy (10% of 543 APS pts.) ( Hon.) Yehuda Shoenfeld, MD,FRCP
  51. 51. Autoantibodies- Anti P ribosomal Causing behavioral changesNovel aspects of the pathogenicity ofautoantibodies -psychiatric conditions. Pathways; therapy; compound, peptides Yehuda Shoenfeld, MD,FRCP ( Hon.)
  52. 52. Anti P ribosomal can induce depression in an animal model. Anti P Ribosomal Abs Depression Yehuda Shoenfeld, MD,FRCP ( Hon.)
  53. 53. 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
  54. 54. 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.  ( Hon.) Yehuda Shoenfeld, MD,FRCP
  55. 55. Autoimmunity1) 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.)
  56. 56. The major   pieces of the  mosaic of autoimmunityCenetics:  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.)
  57. 57. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  58. 58. Marco Salvetti et alYehuda Shoenfeld, MD,FRCP ( Hon.)
  59. 59. Triplets with SLE Kamat SS, et al. Arthritis Rheum.   et al.  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.)
  60. 60. 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.)
  61. 61. 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.)
  62. 62. 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.)
  63. 63. 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.)
  64. 64. 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.)
  65. 65. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  66. 66. Cutolo M et al. J Clin Ezndocrinol Metab 1996;81:820-827 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  67. 67. Synovial tissue Macrophages stained for ER Cultured synovial Macrophages stained for ERSynovial 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
  68. 68. monocytes Estrogen Receptors lymphocytes Yehuda Shoenfeld, MD,FRCP ( Hon.)
  69. 69. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  70. 70. 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.)
  71. 71. 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.)
  72. 72. Hepatitis-C and  Autoimmune Diseases1)  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.)
  73. 73. The infectious origin of the antiphospholipid syndrome (APS): induction of exp.APS bypassive 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.)
  74. 74. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  75. 75. EBV genetics and autoimmune diseases EBVAutoimmune HLA-DR15 gene Multiple sclerosis Late EBV Infection EBVAutoimmune HLA-DR3 gene Late EBV Autoimmune Infection thyroid disease Yehuda Shoenfeld, MD,FRCP ( Hon.)
  76. 76. 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.)
  77. 77. Smoking and GoodpastureCigarette smoking and lung hemorrhage inglomerulonephritis caused by autoantibodies toglomerular basement membrane. Lancet 1983 : 2 : 1390-3Diffuse alveolar hemorrhage developed: # 20% of non-smokers. # 80% of smokers. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  78. 78. 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.)
  79. 79. 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.)
  80. 80. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  81. 81. 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.)
  82. 82. 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.)
  83. 83. 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.)
  84. 84. 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.)
  85. 85.  ,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.)
  86. 86. The mosaic of  autoimmunity Yehuda Shoenfeld MD Genetic ,HLA) Immune GM Environmental deficienccy Allotype ,infection) state Idiotype Drugs, UVIgA def. Trg) smoking( C‘ def., NK Hormonal Estrogen) ( Testosterone Yehuda Shoenfeld, MD,FRCP ( Hon.)
  87. 87.    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.)
  88. 88. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  89. 89. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  90. 90. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  91. 91. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  92. 92. Galileo Galilei Page 72 Opere GallileiOmnium rerum origo ipsa sui immunis, donec res contraria  reperitur. “Everything is autoimmune until proven  otherwise” Yehuda Shoenfeld, MD,FRCP ( Hon.)
  93. 93. Systemic autoimmune  diseasesSystemic diseases Reiter’s disease Reiter’Systemic lupus erythematosus Sneddons diseaseAntiphospholipid syndrome Autoimmune polyendocrinopathy, candidiasis-ectodermalRheumatoid arthritis dystropyJuvenile Rheumatoid arthritis Essential cryoglobulinemic vasculitisFelty’s syndromeFelty’ Cutaneous leukocytoclastic angiitisLarge granular lymphocytosis (LGL) Lyme diseaseSjogren’s syndromeSjogren’ Rheumatic fever and heart diseaseSystemic sclerosis (scleroderma) Eosinophilic fasciitisCrest syndrome Paroxysmal cold hemoglobinuriaMixed connective tissue disease Polymyalgia rheumaticaPolymyositis/ dermatomyositis FibromyalgiaGoodpasture’s DiseaseGoodpasture’ POEMS syndrome (polyneuropathy, organomegaly,Wegener’s granulomatosis endocrinopathy, M-spot and skin changes)Wegener’ Relapsing polychondritisChurg-Strauss syndromeHenoch-Schonlein purpura Autoimmune lymphoproliferative syndrome TINU syndrome (acute tubulointerstitial nephritis andMicroscopic polyangiatis uveitis)Periarteritis nodosa Autoimmunity associated with immunodeficiencyBechet’s syndromeBechet’ Common variable immunodeficiencyAtherosclerosis TAP (transporter associated with antigen presentation)Temporal (giant) cell arteritis deficiencyTakayasu arteritis Omenn syndromeKawasaki disease HyperIgM syndromeAnkylosing spondilitis BTK agammaglobulinemia Human immunodeficiency virus Post bone-marrow-transplant Yehuda Shoenfeld, MD,FRCP ( Hon.)
  94. 94. Organ specific autoimmune diseases Neurological Dermatology ReproductiveMyasthenia Gravis Pemphigus Vulgaris Autoimmune premature ovarian failureCongenital myasthenia gravis Pemphigus Foliaceus AzoospermiaMultiple sclerosis Bullous phemphigoid/ Pemphigoid gestationis HypogonadismStiff-man syndrome Cicatrical pemphigoid Male infertility associated with spermTropical spastic paraparesis Dermatitis herpetiformis autoantibodiesRasmussen’s encephalitisRasmussen’ Epidermal bullosa acquisita Autoimmune orchitisAcute motor axonal neuropathy Erythema multiforme Premature ovarian failureAcute sensory-motor axonal neuropathy Herpes gestatonis Autoimmune oophoritisDorsal root ganglion neuritis Vitiligo OcularAcute pan-autonomic neuropathy Chronic urticaria UveitisBrachial neuritis Discoid lupus RetinitisAcute necrotizing hemorrhagic lekoencephalitis Alopecia universalis/Areata Sympathetic ophthalmiaSporadic necrotizing myelopathy Psoriasis Birdshot retinochoroidopathyParaneoplastic cerebellar degeneration Hepatobiliary Vogt-Koyanagi-Harada granulomatous uveitisGuillain-Barre syndrome Autoimmune hepatitis Retinal degenerationLimbic encephalitis Primary biliary cirrhosis Lens-induced uveitisOpsoclonus-myoclonus ataxia Chronic active hepatitis Optic neuritisSensory neuronitis Chronic active hepatitits/ Primary biliary cirrhosis VestibulocochlearAutonomic neuropathy overlap syndrome Autoimmune sensorineural hearing lossDemyelinating neuropathy Primary sclerosing cholangitis Meniere’s disease Meniere’AIDS-dementia complex. Hematopoeitic CardiacTourette’s syndromeTourette’ Autoimmune hemolytic anemia Autoimmune myocarditisMiller-Fisher syndrome Idiopathic thrombocytopenic purpura Congenital heart block (neonatal lupus)Alzheimer’s diseaseAlzheimer’ Evans syndrome Chagas’ disease Chagas’Endocrine Heparin-induced thrombocytopenia Adriamycin cardiotoxicityGraves’ DiseaseGraves’ Primary autoimmune neutropenia Dressler’s myocarditis syndrome Dressler’Hashimoto’s thyroiditisHashimoto’ Autoimmune (primary) neutropenia of infancy Respiratory RespiratoryPostpartum thyroiditis Autoimmune neutropenia following bone marrow Bronchial asthma transplant Interstitial fibrosing lung diseaseFocal thyroiditis Acquired autoimmune hemophilia NephrologyJuvenile thyroiditisIdiopathic hypothyroidism Gastroenterlogy Rapidly progressive glomerulonephritis Autoimmune gastritis and pernicious anemia Autoimmune tubulointerstitial nephritisType I (insulin dependent) diabetes mellitus Coeliac diseaseAddison’s diseaseAddison’Hypophysitis Crohn’s disease Crohn’Autoimmune diabetes insipidus Ulcerative colitisHypoparathyroidism Sialadenitis Yehuda Shoenfeld, MD,FRCP ( Hon.)
  95. 95. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  96. 96. 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.)
  97. 97. Yehuda Shoenfeld, MD,FRCP ( Hon.)

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