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Infección y AutoinmunidadYehuda Shoenfeld, MD, FRCPJefe, Departamento de Medicina B y CentroZabludowicz para Enfermedades ...
Mechanism of ARIDs;  Infections rolewhy SLE and why APS  Yehuda ShoenfeldMD ,FRCP       03 03 11        Bogota            ...
Vaccines andautoimmune diseases  Yehuda Shoenfeld MD ,FRCP                Yehuda Shoenfeld, MD,FRCP ( Hon.)
Infectionsand autoimmunity?friends or foes –       ,Kivity S   ,Agmon-Levin N      ,Blank M     Shoenfeld Y  409:(8) 30 ;2...
The mosaic of       autoimmunity    Yehuda Shoenfeld MD,FRCP                                        1989                 G...
The major pieces of the      Mosaic of Autoimmunity    Environmental:     Infecting agents: viruses, bacteria, parasites...
Geographical clustering of scleroderma in              south and west London.       Silman AJ, et al. Br J Rheumatol 1990 ...
Type-1 diabetes mellitus and multiple              sclerosisDiabetes Mellitus type I   Multiple sclerosis                 ...
Mycobacterium tuberculosis       infection precipitates SLE in       patients from endemic areas                          ...
,Reifen R, Blank M, Afek A                        ,Kopilowiz Y, Sklan D                      ,Gershwin ME, German B       ...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Rheumatic                  FeverYehuda Shoenfeld, MD,FRCP ( Hon.)
.SLE APS RA SyS etc            Yehuda Shoenfeld, MD,FRCP ( Hon.)
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Most consistent associations betweeninfecting agents and autoimmune disease  n Epstein Barr Virus (MS, SLE, RA, Sjögren’s ...
Mechanisms that could lead to autoimmune disease          upon exposure to infection Molecular mimicry       Bystander act...
Infection and toll-like pathway                     Yehuda Shoenfeld, MD,FRCP ( Hon.)
Hepatitis-C and         Autoimmune Diseases1)   Mixed cryoglobulinemia.               80                                  ...
Soluble BAFF levels in HCV                   Toubi et alJ Autoimmunity 2006;27;134-9               4                      ...
The major pieces of theMosaic of Autoimmunity Environmental:Infecting agents: viruses, bacteria, parasites.               ...
EBV genetics and autoimmune diseases                               EBVAutoimmune         HLA-DR15   gene                  ...
Influence of HLA-DR phenotype on the risk        of hepatitis C virus-associated mixed                  cryoglobulinemia. ...
Frequency (%)                                                   Po                                                       l...
Patients with systemic SLE have       abnormally elevated Epstein-Barr               virus load in blood       Moon UY, et...
ELEVATED EBV ANTIBODIES           CORRELATED WITH CUTANEOUS          MANIFESTATIONS IN SLE PATIENTS    3.5   No manifestat...
anti-Ro and anti-La          Cutaneous LupusSjögren                     Neonatal Lupus/CHB ( Hon.)                        ...
ELEVATED EBV-VCA IGG TITERS        CORRELATED WITH JOINT           MANIFESTATIONSFIN       No manifestations8       Manife...
EBV infection associated with       cutaneous and joint involvement   EBVEAG was significantly elevated    (p<0.024) and ...
ELEVATED TITERS TO EBV EARLY      ANTIGEN IGG CORRELATED WITH               ANTI-RO AB      8FIN   7                      ...
EBV  anti-Ro skin involvement Anti-Ro antibody and cutaneous vasculitis in systemic lupus erythematosus.       Marcio Ver...
EBNA-1 58-72 peptide immunized rabbits developAnti-Ro autoimmunity, lupus-like autoimmunity and             Clinical featu...
Helicobacter Pylori    Infection rates vary in different parts     of the world, from 50% in the western     world to 90%...
0                                                                           10                                            ...
Helicobacter pylori colonization is inverselyassociated with childhood         asthmaThe Journal of Infectious Diseases   ...
Disappearance of APSafter helicobacter pylori       eradicationThe American Journal of Medicine 2001, 111: 163         Ant...
Helicobacter Pylori  eradication therapy inthrombocytopenic purpura Ando T, et al. Helicobacter 2004;9:443–452
Platelet Response in ITP – Results                             HP eradication responders                             HP er...
Eradication of H. Pylori and        amelioration of autoimmunityAPS –Antonio Gasbarrini, Giovanni GasbariniDisappearance ...
Implications for induction of     autoimmunity via activation of     B-1 cells by Helicobacter pylori                  ure...
Rate of seropositivity,          Hepatitis B core IgG   Lower prevalence                                                 ...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Hygiene and        autoimmunityImproved hygiene in infancy and  the presence of rheumatoid       factor in adult life     ...
SLE and malaria:    Another look at an old idea                 Butcher GA, Clark IA.            Parasitol Today. 1990;6:2...
Toxoplasma gondii   infection inhibits   the development of   lupus-like syndrome   in autoimmune   (New Zealand Black   x...
Parasitic worms and    inflammatory diseasesZaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A. Parasite              ...
Therapeutic immunomodulators from          nematode parasites – clinical           impliactions/applications              ...
Trichuris suis therapy in                Crohn’s disease   Open label   Worms were isolated from pigs colons    and cult...
T Helper (CD4+ ) Subsets                                Antigen                                             IL-4          ...
ResultsNo side effects or complications                                   Yehuda Shoenfeld, MD,FRCP ( Hon.)
Therapeutic immunomodulators        from nematode parasites                  Harnett W and Harnett MM                 Expe...
Yehuda Shoenfeld, MD,FRCP ( Hon.)
Phosphorylcholine - a common denominator for bacteriae,    fungi helminthes nematodes and apoptotic cells♣Gram-positive ba...
Infections determine the type of autoimmune diseases-hypothesis                         (Hypothesis)                      ...
Infections and autoimmunity1. Infections can cause           •   The “burden of infections”   autoimmune diseases.        ...
Five Jews change theway we see the world:Moses:    ‘’the Law is everything.’’Jesus:     ‘’Love is everything.’’Marx:     ‘...
Thank                  !YouYehuda Shoenfeld, MD,FRCP ( Hon.)
The prevalence of          helicobactor pylori in             obese subjects                            Arslan E et al    ...
Mycobacterium tuberculosis infection    precipitates SLE in patients from endemic areas                                   ...
Infección y Autoinmunidad
Infección y Autoinmunidad
Infección y Autoinmunidad
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Infección y Autoinmunidad

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Infección y Autoinmunidad

  1. 1. Infección y 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.)
  2. 2. Mechanism of ARIDs; Infections rolewhy SLE and why APS Yehuda ShoenfeldMD ,FRCP 03 03 11 Bogota Yehuda Shoenfeld, MD,FRCP ( Hon.)
  3. 3. Vaccines andautoimmune diseases Yehuda Shoenfeld MD ,FRCP Yehuda Shoenfeld, MD,FRCP ( Hon.)
  4. 4. Infectionsand autoimmunity?friends or foes – ,Kivity S ,Agmon-Levin N ,Blank M Shoenfeld Y 409:(8) 30 ;2009 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  5. 5. The mosaic of autoimmunity Yehuda Shoenfeld MD,FRCP 1989 Genetic ,HLA) Immune (Genes Environmental deficiency .Infection,Vacc) state Drugs, UVIgA def. Trg) Hormonal (Smoking( C‘ def., NK Estrogen) Testosterone prolactin Vit. D( , Smell Yehuda Shoenfeld, MD,FRCP ( Hon.)
  6. 6. The major pieces of the Mosaic of Autoimmunity Environmental: Infecting agents: viruses, bacteria, parasites Vit D. In all AIDs we have low Vit D levels. Drugs (e.g. idiopathic thrombocytopenia purpura, myasthenia, SLE). Toxins (e.g. scleroderma). Cosmetics (e.g. silicone). UV light (e.g. SLE). Smoking (e.g. Goodpasture’s syndrome,RA,Thyr). Stress (e.g. SLE) Nutritional influence;Vit D (e.g. RA, SLE). Yehuda Shoenfeld, MD,FRCP ( Hon.)
  7. 7. 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.)
  8. 8. Type-1 diabetes mellitus and multiple sclerosisDiabetes Mellitus type I Multiple sclerosis Yehuda Shoenfeld, MD,FRCP ( Hon.)
  9. 9. Mycobacterium tuberculosis infection precipitates SLE in patients from endemic areas Ghosh K et al Rheum Int 2009; 29:1047-50 In a cohort of 70 systemic lupus erythematosus patients diagnosed over 2 years period, 14 patients were found to have confirmed antecedent tuberculosis (20%) which was 40 times higher (p<0.001, 95%CI 36.2-48.6) than the prevalence of tuberculosis in the local population. The prevalence of preceding Tubercular infection in SLE patients which turned out to be 14/70 i.e. 40 times higher than the population prevalence (95%CI 36.2-48.6 p<0.001) Yehuda Shoenfeld, MD,FRCP ( Hon.)
  10. 10. ,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 suppressesAutoimmunity the antiB2GPI in .experimental APS .J Autoimmun 15: 381-385, 2000 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  11. 11. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  12. 12. Rheumatic FeverYehuda Shoenfeld, MD,FRCP ( Hon.)
  13. 13. .SLE APS RA SyS etc Yehuda Shoenfeld, MD,FRCP ( Hon.)
  14. 14. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  15. 15. Most consistent associations betweeninfecting agents and autoimmune disease n Epstein Barr Virus (MS, SLE, RA, Sjögren’s syndrome) n Cytomegalovirus (SLE, Atherosclerosis, Diabetes mellitus, Systemic sclerosis, IBD) n Helicobacter pylori (ITP, SSc, Crohn’s disease, GBS) n Chlamydia pneumoniae (Atherosclerosis, MS) n Parvovirus B19 (SSc?) n E. coli (RA) n P. mirabilis (RA) n Yersinia enterocolitica (IBD) n C.jejuni (GBS) Yehuda Shoenfeld, MD,FRCP ( Hon.)
  16. 16. Mechanisms that could lead to autoimmune disease upon exposure to infection Molecular mimicry Bystander activationPolyclonal Epitope spreadactivation Autoimmune Disease Super-antigens Cryptic antigen Yehuda Shoenfeld, MD,FRCP ( Hon.)
  17. 17. Infection and toll-like pathway Yehuda Shoenfeld, MD,FRCP ( Hon.)
  18. 18. Hepatitis-C and Autoimmune Diseases1) Mixed cryoglobulinemia. 80 70 60 50 402) Ch. Active hepatitis. 30 20 10 0 C RA D S S E S SS ls c o s3) Polyarteritis nodosa. us ia AP AP SL s PB IB M SS ve ot ro ie em ig im a nt th d- ph Gr in Co sh pa 2n m ul yo Ha pe ub .M gl m yo fla cr In4) Leukocytoclastic vasculitis. The prevalence of anti-HCVour cohort :was 9.5% (116/1228) in antibodies5) 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.)
  19. 19. Soluble BAFF levels in HCV Toubi et alJ Autoimmunity 2006;27;134-9 4 P = 0.001BAFF (ng/ml) 3 2 1 0 Control HBV HCV SLE
  20. 20. The major pieces of theMosaic of Autoimmunity Environmental:Infecting agents: viruses, bacteria, parasites. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  21. 21. 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.)
  22. 22. 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.)
  23. 23. Frequency (%) Po ly m y 80 85 90 95 SL osi 100 S E tis + * H yst as e hi m N APS m ic o * ot Sc rm o le a Th ro l yr sis M oi ul di ti ti In Pr pl s f l im e am ar S c SL m y le E a t Bi l ro or ia si y ry A s Pe Bo Ci P m w rrh S ph el o i g Di sis G us se ra V as D ve ulg e i a s be D a r te ise is s a M M se ix C el l it p>0.05 ed ry C u og s * ry lo G o g bu R A i a lo l in nt b u m Ce lin i a ll em Ar EBV Nuclear Antigen (EBNA) IgG th i a ri tisYehuda Shoenfeld, MD,FRCP ( Hon.)
  24. 24. Patients with systemic SLE have abnormally elevated Epstein-Barr virus load in blood Moon UY, et al. Arthritis Res Ther. 2004; 6: R295-302 Interestingly, the EBV burden in peripheral blood mononuclear cells (PBMCs) was over 15-fold greater in SLE patients than in healthy control individuals. EBV infection is abnormally regulated in SLE. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  25. 25. ELEVATED EBV ANTIBODIES CORRELATED WITH CUTANEOUS MANIFESTATIONS IN SLE PATIENTS 3.5 No manifestations 3.0 Manifestations 2.5 CUTANEOUS: p=0.024 RASH, 2.0 PHOTOSENSITIVITY,FIN 1.5 ALOPECIA, MOUTH ULCERS, SCLE 1.0 p=0.065 DLE 0.5 0.0 EBVIGM EBVEAG EBV ANTIBODIES Yehuda Shoenfeld, MD,FRCP ( Hon.)
  26. 26. anti-Ro and anti-La Cutaneous LupusSjögren Neonatal Lupus/CHB ( Hon.) Yehuda Shoenfeld, MD,FRCP
  27. 27. ELEVATED EBV-VCA IGG TITERS CORRELATED WITH JOINT MANIFESTATIONSFIN No manifestations8 Manifestations JOINTS7 JOINT p=0.0036 TENDERNESS5 JOINT4 SWELLING3 JACCOUD’S2 ARTHROPATHY10 EBV VIRAL CAPSID IGG Yehuda Shoenfeld, MD,FRCP (& SLE Zandman-Goddard G. EBV Hon.)
  28. 28. EBV infection associated with cutaneous and joint involvement EBVEAG was significantly elevated (p<0.024) and EBVIGM marginally elevated (p< 0.065) in subjects with vs. those without skin symptoms. EBVCAG was significantly elevated (p<0.003) in subjects with vs. those without joint involvement. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  29. 29. ELEVATED TITERS TO EBV EARLY ANTIGEN IGG CORRELATED WITH ANTI-RO AB 8FIN 7 Negative 6 Positive 5 4 3 2 p=0.03 1 p=0.005 p=0.04 0 EAG-Ro CAG-ANA HM-RNP(*10) AB to EBV AG- AB TO NUCLEAR COMPONENTS Yehuda Shoenfeld, MD,FRCP (& SLE Zandman-Goddard G. EBV Hon.)
  30. 30. EBV  anti-Ro skin involvement Anti-Ro antibody and cutaneous vasculitis in systemic lupus erythematosus. Marcio Veronesi Fukuda , et al. Clin Rheumatol 2009; 28: 301-304.• Five hundred and nine consecutive patientsfulfilled the revised American College ofRheumatology (ARA) criteria for the SLE.• Anti-Ro antibody was associated to anti-Laantibody, female, and cutaneous vasculitis.• In a multivariate analysis, patients with anti-Roantibody have 1.63 (95%) CI 1.07-2.50) more riskto develop cutaneous vasculitis than patientswithout this antibody. Yehuda Shoenfeld, MD,FRCP ( Hon.) Yehuda Shoenfeld, MD, FRCP.
  31. 31. EBNA-1 58-72 peptide immunized rabbits developAnti-Ro autoimmunity, lupus-like autoimmunity and Clinical features of SLEA EBNA-1 58-72 immunized rabbits B 3 Pre-imm une 2.5 Freund’s immunized rabbits 2 1.5 8 1 Absorbance 0.5 6 0WBC 1 44 87 130 173 216 259 302 345 388 431 474 517 4 3 2.5 2 2 1.5 0 0 1 2 3 4 1 3 0.5 0Creatinine 1 43 85 127 169 211 253 295 337 379 421 463 505 2 60kDa Ro Octapeptide Number 2.5 1 Pre-imm une 2 1.5 0 1 0 1 2 3 4 Absorbance 0.5 400 0 1 21 41 61 81 101 121 141 161 181 201 221Platelets 300 2.5 2 200 1.5 100 1 0.5 0 0 0 1 2 3 4 1 21 41 61 81 101 121 141 161 181 201 221 Months post-immunization Sm B‘ Octapeptide Number Yehuda Shoenfeld, MD,FRCP ( Hon.)
  32. 32. Helicobacter Pylori Infection rates vary in different parts of the world, from 50% in the western world to 90% in Asia and the far east. Most remain a-symptomatic, 10-15% develop peptic ulcers, chronic gastritis, autoimmune gastritis, or gastric lymphoma (MALT). Also associated with atherosclerosis, ITP, GBS and Systemic sclerosisSuerbaum S. et al, Helicobacter pylori infection, N Engl J Med, 2002Oshima T. et al, Association of Helicobacter pylori infection with systemic inflammation and endothelialdysfunction in healthy male subjects.J Am Coll Cardiol, 2005Showji Y. et al, Seroprevalence of Helicobacter pylori infection in patients with connective tissuediseases.Microbiol Immunol, 1996Franchini M. et al, Helicobacter pylori-associated immune thrombocytopenia. Platelets , 2006 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  33. 33. 0 10 20 30 40 50 60 70 80 90 100 No W rm eg al en er s G AP ra nu S lo G m at ian os tC is P<0.05 el lA rte ri t is Sy ste IB m D ic Sc P<0.05 P<0.001 P<0.01 ler os is SL E SL E Cr + yo AP M gl S i xe ob d ul ine Cr yo m glo ia bu li n G em H. Pylori Prevalence Europe ra ia ve s dis ea se Po l ym yo sit is Ha sh im ot o PB CYehuda Shoenfeld, MD,FRCP ( Hon.)
  34. 34. Helicobacter pylori colonization is inverselyassociated with childhood asthmaThe Journal of Infectious Diseases 2008;198:553-60
  35. 35. Disappearance of APSafter helicobacter pylori eradicationThe American Journal of Medicine 2001, 111: 163 Antonio Gasbarrini, Giovanni Gasbarini Yehuda Shoenfeld, MD,FRCP ( Hon.)
  36. 36. Helicobacter Pylori eradication therapy inthrombocytopenic purpura Ando T, et al. Helicobacter 2004;9:443–452
  37. 37. Platelet Response in ITP – Results HP eradication responders HP eradication nonresponders HP not-eradicated patients HP negative patients Yehuda Shoenfeld, MD,FRCP ( Hon.)
  38. 38. Eradication of H. Pylori and amelioration of autoimmunityAPS –Antonio Gasbarrini, Giovanni GasbariniDisappearance of APS after helicobacter pylori eradicationThe American Journal of Medicine 2001, 111: 163Sjogren – Gasbarrinin A, Franceschi F. Autoimmune diseaseand Helicobactor pylori infection. Biomed Pharmacother 1999;53:223-6.RA – Zentilin P, Seriolo B, Dulbecco P et al. Eradication ofHelicobactor pylori may reduce disease severity in rheumatoidarthritis. Aliment Pharmacol Ther 2002; 16:1291-9. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  39. 39. Implications for induction of autoimmunity via activation of B-1 cells by Helicobacter pylori urease Yamanishi S, et al. Infect Immun. 2006; 74: 248-56 H. pylori urease predominantly stimulates the B-1-cell population rather than B-2 cells, which produce antigen-specific conventional antibodies among splenic B220(+) B cells. The production of various B-1-cell-related autoreactive antibodies such as IgM-type rheumatoid factor, anti-single-stranded DNA antibody, and anti-phosphatidyl choline antibody was observed when the splenic B cells were stimulated with purified H. pylori urease in vitro. H. pylori components, urease in particular, may be among the environmental triggers that initiate various autoimmune diseases via producing autoreactive antibodies through the activation of B-1 cells. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  40. 40. Rate of seropositivity, Hepatitis B core IgG Lower prevalence 15% 10% p<0.001 2.5% 10.7% 5% 0% Controls (n=140) SLE (N-120) Yehuda Shoenfeld, MD,FRCP ( 40 Berkun, SLE & Abs to infectious agents Hon.)
  41. 41. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  42. 42. Hygiene and autoimmunityImproved hygiene in infancy and the presence of rheumatoid factor in adult life Edwards CJ, Syddall HE, Goswami P, et al. Arthritis Rheum. 2004; 50: S356 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  43. 43. SLE and malaria: Another look at an old idea Butcher GA, Clark IA. Parasitol Today. 1990;6:259-61 Where parasitic infections are common, autoimmune diseases are rare. Malaria may exert a protective effect against the autoimmune nephritis in systemic lupus erythematosus. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  44. 44. Toxoplasma gondii infection inhibits the development of lupus-like syndrome in autoimmune (New Zealand Black x New Zealand White) F1 mice. Chen M, et al. Int Immunol. 2004;16:937-46.Yehuda Shoenfeld, MD,FRCP ( Hon.)
  45. 45. Parasitic worms and inflammatory diseasesZaccone P, Fehervari Z, Phillips JM, Dunne DW, Cooke A. Parasite Immunol. 2006; 28: 515-23 Yehuda Shoenfeld, MD,FRCP ( Hon.)
  46. 46. Therapeutic immunomodulators from nematode parasites – clinical impliactions/applications Harnett W and Harnett MM Expert reviews 2008; 10:1-13 A “safe” species is Trichuris suis, which is similar to the human whipworm T.trichiura, but can persist only for a limited period in the human gastrointestinal tract following infection Human trials as a treatment for inflammatory bowel disease People suffering from inflammatory bowel disease have shown improvement in symptoms following ingestion of embryonated ova of this worm (Elliott DE et al. helminths as governors of immunomediated inflammation. Int J Parasitol 2007; 37:457-64; Reddy A and Fried B. the use of Trichuris suis and other helminths therapies to treat Crohn’s disease. Parasitol Res 2007; 100:921-7) Crohn’s disease was treated with with 50 larvae Disease showed some improvement (Croese J et al. a proof of concept study establishing necator americanus in Crohn’s patients and reservoir donors. Gut 2006; 55:136-7) Yehuda Shoenfeld, MD,FRCP ( Hon.)
  47. 47. Trichuris suis therapy in Crohn’s disease Open label Worms were isolated from pigs colons and cultured in vitro 24 weeks: 29 CD patients returned every three weeks to drink the ova suspended in a commercial drinkSummers RW, Elliott DE, et al. Trichuris suis therapy in Crohn’s disease. Gut 2005;54:87–90. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  48. 48. T Helper (CD4+ ) Subsets Antigen IL-4 Th0 Parasite IL-12 Suicide FasL Fas Th2 Th1 TRAIL DR4 Anti-InflammatoryPro-Inflammatory Cytokines Cytokines IL-4 IFN- IL-1 γ 0 IL-2 IL-1 LT Th1 response 3 Cellular Immunity IL-5 Th2 response DTH IL-6 Humoral Immunity Acute Hypersensitivity MD,FRCP ( Hon.) Yehuda Shoenfeld,
  49. 49. ResultsNo side effects or complications Yehuda Shoenfeld, MD,FRCP ( Hon.)
  50. 50. Therapeutic immunomodulators from nematode parasites Harnett W and Harnett MM Expert reviews 2008; 10:1-13 ES-62 can inhibit components of a Th2 response, such as IL-4 production Solely a Th2 polarizing agent was too simplistic (Diaz A and Allen JE. Mapping immune response profiles: the emerging scenario from helminth immunology. Eur J Immunol 2007; 37:3319-26) Mimic the activity of ES-62 for use as drugs for treating allergic and autoimmune diseases. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  51. 51. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  52. 52. Phosphorylcholine - a common denominator for bacteriae, fungi helminthes nematodes and apoptotic cells♣Gram-positive bacteriae: Streptococcuspneumoniae, Streptococcus spp. Clostridium spp.Lactococcus spp. Bacillus spp♣Gram negative bacteria: Haemophilus influenzae (Anti-PC Ab (Fab♣Eukaryotic organisms: protozoa Leishmaniaand Trypanosoma cruzi , a wide range of fungi, thetrematode Schistosoma mansoni , the tapewormDiphyllobothrium latum , several gastrointestinalnematodes and all species of filarial nematode(helminthes) (Wuchereria bancrofti, Brugia malayi andOnchocerca volvulus). PC♣Apoptotic cellsClinical features of Filarial nematode infection: elephantiasis,chronic skin lesions and eye damage leading to blindness Yehuda Shoenfeld, MD,FRCP ( Hon.)
  53. 53. Infections determine the type of autoimmune diseases-hypothesis (Hypothesis) HBC- sAPS CMV Yehuda Shoenfeld, MD,FRCP ( Hon.)
  54. 54. Infections and autoimmunity1. Infections can cause • The “burden of infections” autoimmune diseases. through life induces autoimmunity.2. Infections can trigger an an underlying immune • Infections during childhood disregulation to overt affect autoimmunity in autoimmune disease. adulthood.3. Viruses, bacteria and • Vaccines may induce parasites can determine autoimmunity depending on which autoimmune disease the type of vaccine, the will develop. adjuvant and the subject’s genetic susceptibility.4. Infections can alter the clinical manifestations of • Infections can protect from disease. some autoimmune disease (i.e. the hygiene theory)5. genetic susceptibility determines autoimmune • Infectious agent can induce a response to certain specific autoimmune disease, infectious agents. and protect from another.
  55. 55. Five Jews change theway we see the world:Moses: ‘’the Law is everything.’’Jesus: ‘’Love is everything.’’Marx: ‘’Money is everything.’’Freud: ‘’Sex is everything.’’Einstein: ‘’Everything is relative.’’ The Mosaic of autoimmunity
  56. 56. Thank !YouYehuda Shoenfeld, MD,FRCP ( Hon.)
  57. 57. The prevalence of helicobactor pylori in obese subjects Arslan E et al Eur J of Intern Med 2009; 20:695-7 Prevalence of H.pylori increased in subjects with obesity. We considered that obesity can be a risk factor for H.pylori infection. However, further studies evaluating more subjects are required. Yehuda Shoenfeld, MD,FRCP ( Hon.)
  58. 58. Mycobacterium tuberculosis infection precipitates SLE in patients from endemic areas Ghosh K et al Rheum Int 2009; 29:1047-50 Classical model of experimental autoimmune diseases such as myobacteria induced arthritis (Holoshitz J et al. arhtritis induced in rats by cloned T lymphocytes responsive to myobacteria but not to collagen type II. J Clin Invest 1984; 73:211-5. Van Eden U et al. arthritis induced by a T lymphocyte clone that respondes to myobacterium tberculosis and the cartilage proteoglycans. Proc Natl Acad SCI USA 1985; 82:5117-20. Thomson SJ et al. modulation of pristane induced arthritis by myobacterial antigens. Autoimmunity 1991; 11:35-43). Autoantibodies similar to that found in SLE patients have been regularly detected (Pradhan VD et al. spetrum of anti-neutrophil cytoplasmic antibodies in patients with pulmonary tuberculosis overlaps with that of Wegner’s Granulomatous. Int J Med Sci 2004; 58:283-8. Shoenfeld Y et al. Myobacterium and autoimmunity. Immunol Today 1988; 9:178-82. Shoenfeld Y et al. immunolgic and genetic factors in autoimmune disease. NEJM 1984; 311:1019-29). Monoclonal antibodies raised against M. tubersulosis can cross react with DNA. Myobacterial infection could lead to anti-DNA antibodies without clinical manifestation of SLE (Shoenfeld Y et al. Myobacterium and autoimmunity. Immunol Today 1988; 9:178-82. Shoenfeld Y et al. immunolgic and genetic factors in autoimmune disease. NEJM 1984; 311:1019-29.Shoenfeld Y et al. monoclonal antituberculosis antibodies react with DNA and monoclonal anti-DNA autoantibodies react with Myobacterium tuberculosis. Clin Exp Immunol 1986; 66:255-61. Yehuda Shoenfeld, MD,FRCP ( Hon.)

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