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ETIOLOGY VS PATHOGENESIS

ETIOLOGY VS PATHOGENESIS. Etiology - genetic predisposition - environmental factors: triggering/protective Pathogenesis - nature of autoantigen(s) - effector mechanisms - regulatory circuits. Monozygotic twins. INTRAFAMILY CONCORDANCE RATES FOR MAJOR AUTOIMMUNE DISEASES.

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ETIOLOGY VS PATHOGENESIS

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  1. ETIOLOGY VS PATHOGENESIS Etiology - genetic predisposition - environmental factors: triggering/protective Pathogenesis - nature of autoantigen(s) - effector mechanisms - regulatory circuits

  2. Monozygotic twins

  3. INTRAFAMILY CONCORDANCE RATES FOR MAJOR AUTOIMMUNE DISEASES Type I diabetes Graves disease Crohn’s disease Multiple sclerosis Systemic lupus erythematosus Rheumatoid arthritis Myasthenia gravis Monozygotic twins Siblings HLA identical siblings 35-50 % 30-60 % 40 % 10-20 % 25-50 % 10-30 % 40 % 7 % 7 % 4 % 0-4 % 2-10 % 5-10 % 1-2 % 15 % 15 % 15 %

  4. HLA ASSOCIATIONS WITH AUTOIMMUNE DISEASES Relative risk (Odd’s ratio) Disease Allele 90 50 25 16 14 10 7.5 6 4 3.5 3 3 3 B27 DQ2 DR3/4 DR2 DR4 B27 CW6 DR2 DR4 DR3 DR5 DR3 B8/DR3 Strong association ankylosing spondylitis celiac disease type 1 diabetes Goodpasture’s syndrome pemphigus vulgaris acute anterior uveitis Mild association psoriasis multiple sclerosis rheumatoid arthritis Grave’s disease Hashimoto’s thyroiditis Systemic lupus erythematosus Myasthenia gravis

  5. The autoantigen gene (CHRNA) : The a-subunit of AChR Microsatellites HB BB Intron I Exon I Exon II

  6. ETIOLOGY OF AUTOIMMUNE DISEASES Genetic Predisposition Environement Chance Epigenetics

  7. Comparative evolution of experimental allergic thyroiditis in CBA/J and congenic NOD.H2 k mice Thyroiditis score 4 3 k NOD.H2 CBA/J 2 1 0 3 4 6 8 10 28 52 weeks

  8. ANTIGEN MIMICRY AND GUILLAIN-BARRE SYNDROME_______ Galβ1-3GalNAcβ1-4(NeuAcα2-3)Galβ1- Lipooligosaccharide derived from Campylobacter jejuni Human GM1 ganglioside In human peripheral nerves (N. Yuki et al, PNAS 2004, 101, 31)

  9. Induction of Guillain-Barré syndrome by immunization against a Campylobacter jejuni lipooligosaccharide Yuki et al, PNAS 2004

  10. MULTIPLICITY OF AUTOANTIBODIES IN INSULIN-DEPENDENT DIABETES MELLITUS Insulin Glutamic acid decarboxylase (GAD) IA-2 (tyrosine phosphatase) p69 Gangliosides Carboxypeptidase H

  11. MULTIPLICITY OF AUTOANTIBODIES IN MYASTHENIA GRAVIS Acetylcholine receptor a chain e chain g chain Striated muscle actin a actinin myosin titin ryanodine receptor rapsyn

  12. Non immunologic inflammation APC + Ag2 Triggering Ag1 + APC APC + Ag1 TH1 / Ag2 TH1 / Ag1 TH1 / Ag1 T cell-mediated inflammation Amplification + chronicity Ag1 Ag2 TH1 Ag3 …

  13. CANDIDATE VIRUSES IN AUTOIMMUNE DISEASES Multiple sclerosis Measles HTLV-1 and other retroviruses (MSRV, HRES-1) HHV 6 Other viruses: EBV, JCV, varicella, HSV1/2, rubella Insulin dependent diabetes mellitus Rubella Enteroviruses (Cocksackie A and B, Echovirus 6 and 9) Endogenous retroviruses Other viruses: mumps, CMV, rotavirus

  14. High hygiene, + EBV High hygiene, No EBV Thacker et al. Annals Neurol 2006

  15. 225 219 110 175 135 198 100 159 145 126 124 175 100 141 116 178 136 112 112 116 93 119 119 140 129 88 60 75 106 107 75 89 130 69 102 95 115 60 43 66 61 60 75 70 57 67 57 42 52 57 69 48 Case/control ratios of MS *100 by state of EAD – based on > 5,300 MS cases in US Army Veterans Kurtzke et al. Neurology 1985,35, 672-678.

  16. Relative risk of MS for white males of World War II or the Korean conflict by tier of residence at birth and at entry into active duty (EAD), coterminous US only. Tier of birth North Middle South EAD Tier P for no change in birthplace risk: All=0.0003; North=0.003; Middle=0.002; South=0.57 Adapted from Kurtzke et al. Neurology 1985

  17. Incidence of IDDM (per 100,000) Incidence of multiple sclerosis (per 100,000)

  18. IDDM incidence in children of migrants from Pakistan to Yorkshire 12 10 Incidence of 8 5 diabetes / 10 6 4 2 0 Pakistan Migrant's Yorkshire children Staines A. (1997) and Bodansky H.J. (1992)

  19. IBD & Industrialization and urbanization

  20. Incidence of prototype infectious disease and immune disorders over 4 decades % % Asthma 100 300 Hepatitis A IDDM Tuberculosis Crohn's 50 200 disease Rheumatic fever Measles Multiple sclerosis 100 0 55 65 75 85 95 55 65 75 85 95 Infectious disease Immune disorders

  21. FACTORS CONTRIBUTING TO THE APPEARANCE OF INFECTIONS Sources of pathogenic agents - drinking water - food (cold storage) - climate - housing conditions - hygiene (worms….) Anti-infectious defense - nutrition - antibiotics - vaccination

  22. CAUSAL LINK • ANIMAL MODELS • CLINICAL TRIALS (PROOF OF CONCEPT)

  23. PREVENTION OF IDDM IN NOD MICE BY INFECTIOUS AGENTS Bacteria streptococci salmonella mycobacteria (CFA, BCG, …) Viruses LCMV MHV LDHV Parasites schistosoma oxyures

  24. Effect of malaria in B / W mice Controls Mice infected Mortality Proteinurie 100% 80 60 40 20 0 100 200 300 100 200 300 Age (days) B. M. Greenwood et al, 1970

  25. MECHANISMS

  26. 1. Antigenic competition Effect on antigen presentation - preemption (phagocytosis) - antigen processing - antigen binding to MHC molecules Competition for homeostatic signals

  27. 2. Antigen-induced immunoregulation (by-stander suppression) Th1/Th2 cells Th3 cells NKT cells CD25+ T cells

  28. 100 NOD IL-4-/- controls 80 60 % diabetes NOD IL-4-/- OM-85 40 , , , , NOD OM-85 Th2 cytokines are not involved , , , , , , 20 , , , , 0 , , , , , , , , , , , , , , , , 3 7 11 15 19 23 27 31 Age (weeks) OM-85 80 NOD témoins , , , , , , , , , , , , , , , , , , , , , , , 60 , % diabetes NOD OM-85 40 NOD OM-85+ anti-IL-10R , , 20 , , , , , , , , , , , , 0 3 7 1 1 15 18 23 27 31 35 38 43 Age (weeks) OM-85 anti-IL-10R

  29. TGF-b antibody treatment abrogates diabetes protection by OM-85 60 NOD controls , , , , , , , , , , , , , , 40 NOD OM-85 % diabetes + anti-TGF-b 20 NOD OM-85 , , , , , , 0 3 7 1 1 15 19 23 27 Age (weeks) OM-85 anti-TGF-b

  30. 60 NOD CD28-/- OM-85 40 NOD CD28-/- controls % diabetes 20 0 19 23 27 31 3 7 11 15 Age (weeks) OM-85 Rôle of natural regulatory CD4+CD25+T cells

  31. 3. Non-antigen-mediated effects Toll-like receptors (regulatory cytokines) Superantigens (depletion of T cell subsets) Immunosuppressive proteins

  32. v v v v v v v v v v v v v v v v v v v v Allergy & Autoimmunity Immune response of dendritic cell to TLR agonists lipopeptide Flagellin Endotoxins or LPS Mycobacterial soluble factor Proteine MMLV Mannan Fibrinogen HSP70, HSP60 Hyaluronan Beta-defensin Surfactant Protein A ssARN Poly(I:C) upec TLR3 TLR6 TLR11 TLR5 Imidazoquinoline dsARN TLR7 TLR4 MyD-88 Imidazoquinoline TRIF TLR8 Lipoproteins Zymosan P. Gingivalis LPS Lipoteichoic acid Lipoarabinomannan HCMV Trypanosoma cruzi GPI KOmpA HSP70 Bacterial DNA (CpG) Herpes simplex virus 2 NF-kB AP-1 TLR9 IRF3 TLR2 IFN TLR1 Lipopeptide Regulatory T cells Th1 IL-2, TNF-a, IFN-g Th2 IL-4, IL-5, IL-10, IL-13

  33. TLR2, TLR3,TLR4 and TLR7 agonists delay T1D onset Type 1 diabetes TLR2 TLR3 TLR4 TLR7 Diabetes incidence (%) Age (weeks) Similar protective results were obtained with TLR agonists : synthetic lipopetidePam3CSK4 (TLR2 agonist) or dsRNA Poly(I)Poly(C) …

  34. TLR2 agonist stimulates splenocytes to produce IL-10 and TGF-b via MyD88 TGF-b IL-10

  35. p=0,2848 p=0,0042 Protection mediated by a TLR3 agonist is dependent on iNKT cells NOD CD1d-/- NOD CD1d+/+

  36. TLR3-induced protection is IL-4-dependent Incidence of diabetes (%) Age (weeks)

  37. NOD.MyD88−/− mice are resistant to the development of type 1 diabetes Type 1 diabetes

  38. D0 D10 D7, D8, D9 Measurement of airway hyperreactivity to metacholine Sacrifice and collection of Sera (cytokines, IgE) BALFs (cells, cytokines) Lungs (cytokines) OVA challenge Immunization 100 µg OVA + Alum i.p. D6, D7, D8 : treatment with TLR agonist Allergic asthma model

  39. NOD.MyD88−/− mice are hyperreactive to allergic asthma Allergic asthma NOD.MyD88−/− mice died during the protocol of experimental allergic asthma at the time of the second challenge. When mice were decontaminated, death occured between the first and the second challenge. (5 independent experiments, 40 mice)

  40. Prevention of allergic asthma by a TLR2 agonist P40-treated Vehicle P40-treated Vehicle Allergic asthma Similar results using the TLR4 agonist LPS

  41. Acknowledgements • CNRS UMR 8147Paris • N. Thieblemont • A. Aumeunier • E. Bardel • M. Dy • F. Grela • A. Ramadan INSERM U580 Paris J. F. Bach M. A. Alyanakian L. Chatenoud C. Gouarin Department of Host disease Osaka S. Akira INSERM U564 Angers P. Jeannin

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