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IMMUNOPATHOLOGIE

IMMUNOPATHOLOGIE. Plan du cours. 1. Immunodeficiences primaires 2. Immunodeficiences secondaires 3. Autoimmunite 4. Atopie et inflammation 5. Transplantation et immunosuppreseurs 6. Cancer. Autoimmunite. => Immune Response: protection. => host damage.

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IMMUNOPATHOLOGIE

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  1. IMMUNOPATHOLOGIE

  2. Plan du cours • 1. Immunodeficiences primaires • 2. Immunodeficiences secondaires • 3. Autoimmunite • 4. Atopie et inflammation • 5. Transplantation et immunosuppreseurs • 6. Cancer

  3. Autoimmunite • => Immune Response: protection • => host damage • Response immune dirigee contre des antigens du soi (auto-antigenes)

  4. Autoimmunite • => Horror autotoxicus (1903) Paul Ehrich • 1902:Portier et Richet: anaphylaxis • 1903: Maurice Arthus • 1904: Donath et Landsteiner: first described autoimmune disease (paroxxysmal cold hemoglobinuria) • 1905: vonPirquet et Schick: serum sickness • 1906: aTreponema pallidum : crossreactivity cardiolipin • 1930s: RA patients: rheumatoid factor (IgM anti Fc of IgG-coated sheep RBSs) • 1940s: Peter Medawar: skin rejection • 1950s: William J Harrington: platelet depletion by serum transfer from patients with idiopathic thrombocytopenic purpura (‘autoantibodies’) • 1950s: peter Miescher&Henry kinkel: SLE patient serum: anti-nuclear (DNA, RNA, nucleoproteins) antibodies • 1956: Noel Rose: immunization of healthy rabbits with thyroid extracts -> thyroiditis • 1960s: NZB mice models (Marianne & Feliz Bielschowsky) - autoimmune hemolytic anemia; anti-kidney antibodies • 1970s: GF Bottazzo; WJ Irvine: anti-pancreatic beta-islet cell Abs in IDM • ORGAN SPECIFIC / SYSTEMIC AUTOIMMUNE DISEASES

  5. Autoimmunite • => WE Paul, 6th ed

  6. Autoimmunite • => WE Paul, 6th ed

  7. Autoimmunite • => • Hypersensitivity mechanism vers le self • Beakdown of immune tolerance • Presence of an autoimmune reaction • That reaction is of primary importance (not colateral) • absence of other causes • therapeutic effect

  8. Antigenes • A) Antigenes cryptiques • cristallin: ophtamie sympathique • testicule: vasectomie • B)Reactions croisee avec tissus de l’hote apres respose immune • S. beta-hemolytique: Abs anti-tissu cardiaque; RAA • C) Modification antigeniques des antigenes de l’hote • (physico-induites: UV) • (chimio-induites)

  9. Acteurs cellulaires • A) Cellules B • Autoanticorps naturesl: faible affinite; taus faibles, ^ des sujets ages • B1 cells • HMS • B) Cellules T • Cellules T autoreactives • Treg; NKT, Th17, Th9 • C) Extensions sur des cellules auxiliares • DCs; Mast cells; Macrophages • D) Celules cible • Cellules cible du soi normalles • Cellules cible du soi alteree • Cellules microbiennes • Allogeneic cells (fetal)

  10. Acteurs molleculaires • A) Antigenes • genetiques • B) MHCs • C) Cytokines • D) Corecepteurs • E) Molecules de transmission du signal • F) Facteurs transcriptionelles: FoxP3, T-bet, GATA-3, IFR4, • microbiens • E) interferant (cytokine homologues) • D) epitopes mimetiques

  11. Autoimmunite • => Types de reactions d’hypersensibilite • Burmester & Pezzuto, Atlas de poche d’immunologie

  12. Autoimmunite • => Kuby 5th Immunology

  13. Autoimmunite • => Defects in tolerance induction (central tolerance) • =>Defects in tolerance maintenance (peripheral tolerance) • =>Defects in isolating priviledged site self antigens • =>Immune deviation

  14. Autoimmunite • => Facteurs : • Inflammation: • cytokines proinflammatoires (IL-1b, TNF, LT, IL-6); IFN antivirale: NKT; Th17; pDCs, DCs • DC: tolerance / activatoire • eliberation du molecules d’allarme du soi (ADN, calreticulins, HMGB1, HSPs, ATP) • activation du recepteurs de l’immunitee innee: TLRs • Mimetisme antigenique:

  15. Autoimmunite • =>

  16. Autoimmunite • => Anomalies en Treg: IPEX (immune dysregulation, polyendochrinopathy, enteropathy X-linked ): FoxP3 Scurfy mice

  17. Autoimmunite • =>

  18. Autoimmunite • =>Anomalies en CPAs: • modele animal avec reduction en MHC II/B7 sur DCs/macrofages: • induction deficitaire ed Treg • infections • modele animal avec reduction en cellules B • anomalies en complement • modele animal avec production exageree en cytokines • hu: MS, RA: IL-6, TGFb, IL-23: Th17; mAbs peut bloquer • hu: glomerulonephrite, SLE, IL-15, IL-27 • =>Epitope spreading • PG: desmoglein 3 (mucouse) -> desmoglein 1 (peau) • GAD: glutamic acid decaboxylase

  19. Autoimmunite • =>SLE (fievre, malaise, fatigue, douleur musculaire, polyarthrite, ERYTHEME facial en aille de papillon/masque de loup; atteinte glomerulaire proliferative focale ou diffuse, SNC, pericardite, myocardite) • Ag: nucleosomes / spliceosomes / cumplexe ribonucleoproteiques cytoplasmique • IL10: stimulation du B (proliferation + differentiation)

  20. Autoimmunite • =>R. A. (arthrite rheumatoide) • Th17: IL17/TNF • RF: collection de anti-IgG

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