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HYPERSENSITIVITY

HYPERSENSITIVITY

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HYPERSENSITIVITY

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  1. HYPERSENSITIVITY Lecture 9 Jan Żeromski

  2. POINTS TO BE DISCUSSED • Definition of hypersensitivity • Four types of hypersensitivity • Type I – anaphylactic • Type II – cytotoxic • Type III – immune complex mediated • Type IV – contact, tuberculin and granulomatous

  3. HYPERSENSITIVITY TYPE I – KEY POINTS • IgE antibody response directed against innocuous environmental Ag’s such as animal dander, house-dust mites, pollen, industrial pollutants, etc. • IgE becomes coated on mast cells or basophiles via their Fc receptors

  4. HYPERSENSITIVITY TYPE I – KEY POINTS - 2 • Binding of allergen by IgE results in degranulation of mast cells and mediator release • Allergic manifestations ensue such as hay fever, asthma, skin eczema, anaphylaxis

  5. TYPE I HYPERSENSITIVITY IN HOST DEFENSE IN THE AFFERENT IMMUNE RESPONSE • IgE-mediated allergen capture • IgE-mediated allergen processing • IgE-mediated allergen presentation • Immune deviation toward Th2 responses via release of key cytokines via innate immune responses

  6. EXAMPLES AND SYMBOLS OF PURIFIED ALLERGENS • Betula verrucosa (birch) - Bet v 1 • Corylus avellana (hazel) - Cor a 1 • Felis domesticus (cat) - Fel d 1 • Rattus norvegicus (rat) - Rat n 1, n 2 • Cavia porcellus (guinea pig) – Cav p 1 • Equus caballus (horse) - Equ c 1 • Gallus domesticus (hen) - Gal d 1 • Apis mellifera (honey-bee) - Api m 1 • Arachis hypogea (nuts) - Ara h 1

  7. TYPE I HYPERSENSITIVITY IN HOST DEFENSE IN THE EFFERENT IMMUNE RESPONSE • Induction of mast cells and basophil early phase by innate immunity (complement, defensins) • Induction of mast cells and basophile early phase by IgE antibody

  8. TYPE I HYPERSENSITIVITY IN HOST DEFENSE IN THE EFFERENT IMMUNE RESPONSE • Induction of IgE-mediated antibody-dependent cellular cytotoxicity (ADCC) and release of inflammatory molecules from macrophages, eosinophils and neutrophils • Induction of Th2 CD4+ cells with their direct and indirect participation in thehost response

  9. MCT tryptase positive Equivalent of mucosal mast cells in rodents Produce preferentially IL-5 and Il-6 Sodium cromoglycane (Intal) sensitive MCTC tryptase and chymase positive Equivalent of connective tissue MC Produce preferentially IL-4 Sodium cromoglycane insensitive Functionally more mature than MCT TWO TYPES OF MAST CELLS IN MAN

  10. FACTORS REGULATING THE LEVEL OF TYPE I HYPERSENSITIVITY • Genetic linkage controlling total IgE level • HLA-D encoded genes for allergen-specific response • Allergen-driven Th2 predominance • Effects of environmental exposures • Individual sensitivity to inflammatory mediators

  11. ASTHMA PATHOGENESIS • It is a chronic inflammatory disorder of the airways: mucosal inflammation, reversible airway obstruction, bronchial hyperresponsiveness • Bronchial epithelium, mast cells, T-helper cells and eosinophils are known to drive this process

  12. ASTHMA PATHOGENESIS • It is consequence of dysregulation of selective cytokine networks in the airways due to Th2 cells • Chronic mucosal inflammation, at least in part, leads to „airway remodeling”.

  13. ROLE OF MAST TRYPTASE IN ASTHMA Mast tryptase induces: • Bronchoconstriction and hyperresponsiveness • Stimulation of proliferation of fibroblasts, smooth muscle and epithelial cells • Generation of kinins • Stimulation of IL-8 release • Eosinophil chemotaxis

  14. TYPE II HYPERSENSTIVITY REACTIONS • Are caused by IgG and IgM antibodies directed against cell surface, extracellular matrix and intracellular antigens. The latter are usually non-pathogenic but diagnostically useful • Transfusion reactions to erythrocytes are due to antibodies to blood group antigens • The antibodies damage cells and tissues by activating complement and by binding and activating Fc receptor + effector cells

  15. TYPE II HYPERSENSITIVITY – EXAMPLES FROM PATHOLOGY • Hyperacute graft rejection • Hemolytic disease of the newborn (Rhesus D incompatibility) • Autoimmune hemolytic anemias • Goodpasture’s syndrome • Pemphigus • Myasthenia gravis • Lambert-Eaton syndrome

  16. CHARACTERISTICS OF IMMUNE COMPLEXES • Formed by the non-covalent union of antigen and antibody • Can be formed in the circulation or in tissues • Removed from the circulation by the host’s mononuclear phagocyte system • Can lodge in tissue, activate complement, and produce tissue damage • Tend to be solubilized by complement

  17. AGENTS IMPORTANT IN DEPOSITION AND CLEARANCE OF IMMUNE COMPLEXES • Complement deficiency impairs clearance • The size of IC affects their deposition • Immunoglobulin classes of IC affect the rate of their clearance (IgG vs. IgA)

  18. AGENTS IMPORTANT IN DEPOSITION AND CLEARANCE OF IMMUNE COMPLEXES • Phagocyte defects allow complexes to persist • An increase in vascular permeability, high blood pressure and local turbulence triggers deposition • Affinity of antigens for specific tissues may direct IC to particular sites

  19. THE VARIANTS OF TYPE IV (DELAYED) HYPERSENSITIVITY • Contact one–eczematous reaction at the point of contact with allergen, usually hapten, occurs within 72 hours of antigen challenge • Tuberculin one–an area of red firm swelling of the skin, 48-72 hrs after injection • Granulomatous one – formation of granuloma at 21-28 days following antigen exposure

  20. DISEASES WITH TYPE IV GRANULOMATOUS HYPERSENSITIVITY • Chronic pulmonary tuberculosis • Borderline leprosy • Sarcoidosis • Crohn’s disease • Schistosomiasis • Some fungal diseases

  21. THANK YOU!