Hypersensitivity : Hypersensitivity Lecturer: Xu Lin Introduction : Introduction What is hypersensitivity?
It is excessive immune response which leads to undesirable consequences, i.e. tissue or organ damage/ dysfunction.
Type: type?, ?, ?, ? hypersensitivity
Ab mediated: type?, ?, ?
T-cell mediated: type ? Type ? hypersensitivity : Type ? hypersensitivity IgE mediated, immediate hypersensitivity/ allergy
React and disappear quickly on re-exposure to Ag
Dysfunction rather than severe tissue and cell damage occurs
Obvious individual difference and genetic correlation Component and cells : Component and cells Allergen: An antigen that causes allergy.
Hapten can turn into allergen by carrier effect (hapten +carrier ?immunogen)
Common allergen: inhalant allergen (grass pollen, animal dander, feces from mites in house dust, etc.), some kinds of food and drugs Reaginic antibody (IgE) : Reaginic antibody (IgE) The main anaphylactic Ab in human
IgE can bind FceR?on mast cells and basophils by its CH4 domain, cause anaphylaxis Mast cells : Mast cells Express high affinity IgE Fc receptor FceR?, granules contain mediators.
Distribution: connective tissues, mucosa, skin
Anaphylaxis is triggered by clustering of IgE receptors (FceR?) on mast cells and basophils through cross-linking IgE-binding Fc recepors : IgE-binding Fc recepors FceR?: high affinity receptor of IgE on mast cell/ basophil, activate mast cell/ basophil
FceR?:low affinity Mediators released by mast cells : Mediators released by mast cells Primary mediators (preformed): heparin, histamine, neutral protease, eo-sinophil & neutrophil chemotactic factors, provoke early phase(immediate) reaction
Secondary mediators(newly synthesi-zed) : leukotrienes(LTB4, LTC4 and LTD4), PGD2, PAF, CKs(IL-4, GM-CSF), induce late phase reaction Mechanism of type?hypersensitivity : Mechanism of type?hypersensitivity Allergen?host?specific B-cell?IgE?Fc fragment of IgE binding FceR?on mast cells/ basophils
Allergen once again enter the host ?binding IgE ?cross-linking of IgE ? cross-linking of FceR?? mast cell activation? degranulation? mediators release? anaphylaxis symptoms Slide 10: Early phase response: short-lived, resolve within 1 hr. Increase of vasopermeability, smooth muscle contraction, gland hypersecretion and vasodilation
Late phase response: inflammation, peak at around 5 hrs, last for several days. Eosinophils, mast cells, basophils, T-cells and neutrophils infiltration. Slide 11: The mechanism of type?hypersensitivity Typical diseases of anaphylaxis : Typical diseases of anaphylaxis Systemic anaphylaxis(anaphylactic shock): fatal, venom from bee, wasp; drugs such as penicillin, antitoxins, etc.
Localized anaphylaxis(atopy): the tend-ency to manifest localized anaphylaxis is inherited and called atopy. typical diseases: asthma, hayfever, eczema, food allergy, etc. Atopy : Atopy Allergic rhinitis: Hay fever, airborn allergens, symptoms include shedding tears, sneezing, coughing, etc.
Asthma: airborn/blood-born allergens. Occur in lower respiratory tract
Cardinal clinic and physiological features: variable airflow obstruction, bronchial hyper-responsiveness. Slide 14: Food allergies: diarrhea, vomiting, wheal and flare reaction
Atopic dermatitis: eczema, urticaria. itch, desquamation, pachyderma Therapy of type?hypersensitivity : Therapy of type?hypersensitivity Allergen avoidance: best if possible, but often impractical. Skin test
Hyposensitivity: repeated injection of increasing doses of allergen. Allergic rhinitis
Drug: antihistamines; epinephrine (also called adrenaline), etc. Immediate injection of adrenaline could rescue anaphylactic shock Slide 17: Atopic allergies and their treatment Type ? hypersensitivity : Mediated by IgG and/or IgM
Ag present on the surface of cells? im-munity activation?Ab?tissue damage/ dysfunction
Tissue damage caused by:
Opsonic adherence: phagocytosis
Complement: membrane damage
ADCC: cell destruction Type ? hypersensitivity Slide 19: Mechanism of tissue damage of type? hypersensitivity Type ? associated diseases : Type ? associated diseases Transfusion reaction: mismatched blood transfusion cause complement-mediated hemolysis.
ABO blood group: isohemagglutinins(IgM)
Prevention: cross-matching between donor and recipient blood Heamolytic diseases of newborn : Heamolytic diseases of newborn Rh incompatibility: Rh blood groups
Rh- mother has the first Rh+ baby? mother sensitized by baby’s erythrocy-tes ?anti-Rh IgG
Mother has the second Rh+ baby? IgG enter the fetus through placenta? destruction of fetal RBC Slide 22: Hemolytic disease of the newborn due to rhesus incompatibility Drug-induced hemolytic anemia : Drug-induced hemolytic anemia Drug adsorb RBC proteins?Anti-RBC IgG/IgM?complement, opsonization, ADCC ?RBC lysis, anemia Grave’s disease and myasthenia gravis : Grave’s disease and myasthenia gravis Special class of type ? hypersensitivity, Autoimmune diseases, tissue/organ dysfunction
Grave’s disease: anti-TSH receptor
Myasthenia gravis: anti-acetylcholine receptors Slide 25: Myasthenia gravis Grave’s disease Type ? hypersensitivity : Type ? hypersensitivity Participate by IgG/IgM, induced by de-position of immune complex (IC)
Formation of IC: Excess of antigen over a protracted period
Deposition frequently observed: blood-vessel walls, synovial membrane of joints, glomerular basement of kidney Slide 27: Mechanism of type ? hypersensitivity Slide 28: Tissue damage caused by:
Complement activation and attraction of neu-trophils: release tissue damaging mediators
Stimulation of Mf: release proinflammatory cytokines
Aggregation of plate-lets: cause microthrombi and vasoactive amine release Slide 29: Immune complex-mediated (type ?) hypersensitivity Type ? associated diseases : Type ? associated diseases Localized type ? reaction: the Arthus reaction, erythematous and edematous, intense neutrophil infiltration
Generalized type ? reaction:
Serum sickness: injection of foreign protein (horse serum)
SLE: systemic lupus erythematosus, DNA/ anti-DNA/ complement Type ? associated diseases : Rheumatoid arthritis: rheumatoid factor (RF): anti-IgG autoantibodies, usually IgM. IgM-IgG complex deposit in joints
Immune complex glomerulonephritis: Ag-Ab-C3 deposit glomerular basement membrane
Others: drug reactions, infectious diseases Type ? associated diseases Type ? hypersensitivity : Type ? hypersensitivity Delayed-type(DTH), T-cell mediated, 24-72 hr after Ag contact, Ab not involve
Results from excessive CMI, secondary response, chronic granuloma
CD4+Th1: Tm?Ag:MHC??effector T-cell?MCP-1, IFN-?, TNF, IL-2?Mf attraction and activation?tissue damage Immune pathogenesis : Immune pathogenesis CD8+CTL: primed CTL?Ag:MHC?? perforin/ Fas-FasL?target cell death Type ? associated diseases : Insulin-dependent diabetes mellitus (IDDM): insulin-producing ßcells
Multiple sclerosis(MS): central nervous system, myelin Ag
Contact dermatitis: foreign low molecular weight materials, hapten-carrier, topical
Infectious diseases: tuberculosis
Others: hashimoto’s thyroiditis, IBD Type ? associated diseases Summary : Summary Hypersensitivity is excessive immune response which leads to undesirable consequences, i.e. tissue or organ damage/ dysfunction.
Type: type?, ?, ?, ? hypersensitivity
Ab mediated: type?, ?, ?
T-cell mediated: type ? Summary : Summary Therapy for type?hypersensitivity:
Drug treatment: antihistamines, adrenaline Slide 40: Thanks! Slide 41: Clustering of IgE receptors Slide 42: Patholo-gical changes in asthma Slide 43: An atopic eczema reaction Slide 44: ADCC mediated by NK Slide 45: The ABO system Slide 46: Histology of acute inflammatory reaction in type ? hypersensitivity Slide 47: IgE mediated mast cell activation and degranulation Slide 48: Skin reaction of atopic allergy (Skin prick tests) Slide 49: Deposition of immune complex in the kidney glomerulus Slide 50: Vasculitic skin rashes due to immune complex deposition Slide 51: Granuloma in tuberculosis infection