Basic Immunology. Hypersensitivity

Transcription

1 Basic Immunology Lecture 21 st 22 nd Hypersensitivity Cellular and molecular mechanism of allergies. T cell mediated macrophage activation, delayed type hypersensitivity (DTH).

2 Hypersensitivity Pathologic overreactions of the effector phase of immune response with sever tissue damage (necrosis). Different mechanisms can be detected in the background. Gell and Coombs proposed differentiating four types of hypersensitivity.

3 Hypersensitive reactions Immunoglobulin mediated hypersensitivities Type I. immediate form (allergies) Type II. cytotoxic form (serum sickness) Type III. immunocomplex disease Cell mediated hypersensitivities Type IV. Delayed Type Hypersensitivity

4 Basic mechanism of allergy

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6 IgE and the high affinity FcεRI

7 IgE binding receptors

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11 Pharmacologic Mediators of Immediate Hypersensitivity Preformed mediators in granules histamine tryptase kininogenase bronchoconstriction, mucus secretion, vasodilatation, vascular permeability proteolysis kinins and vasodilatation, vascular permeability, edema ECF-A (tetrapeptides) attract eosinophil and neutrophils Newly formed mediators leukotriene B 4 leukotriene C 4, D 4 prostaglandins D 2 PAF basophil attractant same as histamine but 1000x more potent edema and pain platelet aggregation and heparin release: microthrombi

12 Therapeutic relevance Allergen free environment Antihistamins Desensibilization Membrane stabilizing drugs Non-specific immunosuppression CD23 activation

13 Hypersensitivity Type II

14 Hypersensitivity Type II

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17 Hypersensitivity Type III.

18 Hypersensitivity Type III.

19 Hypersensitivity Type III.

20 Hypersensitivity Type IV.

21 Macrophage activation phases Resting Activated Hyperactivated >IFNgamma >LPS, Immuncomplex double stranded RNA Phagocytosis Antigen presentation killing Tumor cell and parasite Chemotaxis Tumor cell binding Proliferation decreased prolif. No proliferation. No cytotoxicity No APC MHC II -, MHC II+, O2 high MHCII -, O2high O2 low TNF,cytotoxic Protease secretion

22 Phases of DTH Sensitization phase: 1-2 weeks following primary contact with the antigen. APC (Langerhans cells vascular endothelial cells or macrophages) derived IL-12 induce Th cells Activation phase: Th1 activation, proliferation, sometimes CD8+ CTL activation. Effector phase: the secondary antigen contact causes Th cell activation, cytokine secretion (24h), recruitment and activation of macrophages and nonspecific inflammatory cells (peaks hours). Only 5% of the infiltrating cells are T cells, 95% is nonspecific.

23 Phases of DTH Granulomatosus reaction: if the pathogen is not easily cleared, survives in the cells, release their antigens into the cytoplasm: CD8+ CTL activation and prolonged DTH response continuous macrophage activation, they adhere closely to one another: epitheloid shape, giant cell formation: tissue damage, necrosis, fibrosis.

24 Sarcoidosis (Type IV Hypersensitivity)

25 Hypersensitivity Type IV.

26 Comparison of Different Types of hypersensitivity type-i (anaphylactic) type-ii (cytotoxic) type-iii (immune complex) antibody IgE IgG, IgM IgG, IgM None type-iv (delayed type) antigen Exogenous cell surface soluble tissues & organs response time minutes minutes-hours 3-8 hours hours appearance weal & flare lysis and necrosis erythema and edema, necrosis erythema and induration histology basophils and eosinophil antibody and complement complement and neutrophils monocytes and lymphocytes transferred with antibody antibody antibody T-cells examples allergic asthma, hay fever erythroblastosis fetalis, Goodpasture's nephritis SLE, farmer's lung disease tuberculin test, poison ivy, granuloma

27 Basic Immunology Lecture 22 nd Autoimmunity Miss-regulation of immune system: development of organ-specific and systemic autoimmune diseases

28 AUTOIMMUNITY Physiological autoimmunity: part of the normal immunological regulation Pathological autoimmunity: diseases caused by self reacting immune responses with permanent tissue/organ injury

29 Autoimmune diseases affect 5-7% of the population!

30 Pathomechanism of autoimmunity Inflammation and tissue necrosis - Cellular components: (T cells CD8 and Th1, NK, Mf, DC, Ne, Eo, Ba, Mc) - Humoral components: (Ig+complement, ADCC, cytokines, chemokines, tissue hormones and mediators)

31 Pathomechanism of autoimmunity Multifactor mechanism (general catastrophe of bio-regulation caused by external and internal factors) - Autoimmune steady state (failure of dynamic balance on self tolerance and autoimmunity) - Role of infections (molecular mimicry or inefficient natural antibody network)

32 Pathogens and human antigens Human cytomegalovirus IE2 HLA-DR molecule Poliovirus VP2 Acetylcholine receptor Papilloma virus E2 Insulin receptor Klebsiella pneumoniae nitrogenase enzym HLA-B27 molecule Adenovirus 12 E1B Alfa-gliadin HIV p24 Human IgG Measles virus P3 Myelin basic protein Peptid residues Overlaping sequences PDPLGRPDED VTELGRPDAE STTKESRGTT TVIKESRGTK SLHLESLKDS VYGLESLKDL SRQTDREDE KAQTDREDL LRRGMFRPSQCN LGQGSFRPSQQN GVETTTPS GVETTTPS EISDNLGQE EISFKLGQE

33 Pathomechanisms of autoimmune diseases - Autoimmunity by the antigen - Failed differentiation and selection of lymphocytes - Genetic background

34 Autoimmunity by the antigen Tissue injury or inflammation, leading to: - Release of sequestered self antigens - Structural alterations of self antigens - Increased costimulation on tissue APCs

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36 Autoimmunity by the failure of self tolerance Abnormal selection of lymphocyte repertoire Polyclonal activation of anergic selfreactive lymphocytes Stimulation by foreign antigens that cross-react with self

37 Th1 Th2

38 Pajzsmirigy Graves-kór Hashimoto thyreoiditis DR3 DR TSH receptor Tiroid mikroszóma peroxidáz, tiroglobulin Hasnyálmirigy IDDM DR4/ DR3 DQB Β-sziget-sejtek GAD, HSP60, junb, inzulin, pre/pro inzulin Idegrendszer Sclerosis multiplex Myasthenia gravis DR2 DR Agy fehérállomány, MBP, PLP, MOG, MAG Perifériás idegrostharántcsikoltizom Acetilkoloin receptor Szív: rheumás láz Vér: AHA, thrombocytopenia DR3, DR4 S. Β-haemoliticus M/miozin Vvs gp Thrombocyta gp

39 SLE Sjögren syndroma Rheumatoid arthritis (RA) DR3/ DR2 DR4 DR1 5.8 Vese, savós hártyák ds/ssdns, Sm-IC, SSA, SSB Exocrin mirigyek, nyálmirigy, máj, vese, agy, pajzsmirigy, szív, tüdő, bél, vese 4.2 Izületi kötőszövet, II kollagén, IgG RF Spondyloarthritis (SPA) Reiter-kór B27 B Gerincoszlop Clamydia, Yersinia Salmonella/Shigella arthritis B

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43 Hashimoto s thyroiditis

44 Myasthenia gravis

45 Raynaud's Syndrome

46 Progressive Systemic Sclerosis The artery shows early organization with "onion skin" change caused by lamellation and mucoid change with swelling of the intimal layer, with corrugation of the glomerular basement membrane. (Jones' silver stain, magnification X200). Fibrous organization of the intimal injury of arteries in a more chronic stage of progressive systemic sclerosis. (Periodic acid Schiff reaction, magnification X400).

47 Rheumatoid arthritis