Hypersensitivity

Ag Immune response Eliminate Ag Tissue injury, function deviation Hypersensitivity

Definition: Hypersensitivity: A damage to host mediated by preexisting immunity to self or foreign antigen

Classification of hypersensitivity Type I: anaphylactic or immediate Type II:cytotoxic Type III:immune complex Type IV:cell mediated or delayed Type I: anaphylactic or immediate Type II:cytotoxic Type III:immune complex Type IV:cell mediated or delayed By Gell and Coombs classifications

Type-I hypersensitivity The common allergy

Sequence of events in type-I hypersensitivity B cell Histamine, tryptase, kininegenase, ECFA Leukotriene-B4, C4, D4, prostaglandin D, PAF Newly synthesized mediators TH2

Components that related to type I hypersensitivity Allergen Antibody Cells Biological mediators

Allergens:

Antibodies:

IgE crosslink Ag IgE γγβα γγ β α

Cells: High affinity Fc εR on the surface Granules in cytoplasm

Biochemical events and mast cell activation

Mast cell activation products  Histamine: bronchoconstriction, mucus secretion, vascular permeability, vasodilatation  Tryptase: proteolysis  Kininogenase: kinins - vascular permeability, vasodilatation, edema  ECF: attract neutrophils and basophils  Histamine: bronchoconstriction, mucus secretion, vascular permeability, vasodilatation  Tryptase: proteolysis  Kininogenase: kinins - vascular permeability, vasodilatation, edema  ECF: attract neutrophils and basophils Preformed mediators

Mast cell activation products Newly formed mediators  Leukotriene C4 & D4:  same as histamine but 1000 x potent  Prostaglandin D2:  kinins - vascular permeability, vasodilatation, edema  PAF:  platelet aggregation, microthrombi formation, heparin release  Leukotriene C4 & D4:  same as histamine but 1000 x potent  Prostaglandin D2:  kinins - vascular permeability, vasodilatation, edema  PAF:  platelet aggregation, microthrombi formation, heparin release

Biological effects of mast cell mediators

Immediate phase reactions Reactions of type I hypersensitivity Late phase reactions Vascular and smooth muscle responses to mediators. Characterized by leukocyte recruitment and inflammation.

The immediate and late phase reactions

Secondary reaction The reaction is characterized by infiltration of eosinophils, neutrophils, macrophages, lymphocytes, and basophils. The late phase reaction

Eosinophils Contribute to the chronic inflammation of the bronchial mucosa that characterizes persistent asthma.

Eosinophils in affected site 1.Accounting for 30% of the cells that accumulate. 2. Attracted by ECF. 3.Activated by antibody coated allergen as mast cell. 4.Releasing inflammatory mediators involve leukotrienes, major basic protein, platelet-activation factor, eosinophil cationic protein, etc. 5. Mediators both protecting against parasitic infections and contributing to extensive tissue damage.

Biological effects of eosinophil mediators

Allergic Diseases in Human  Systemic anaphylaxis (life-threatening)  Localized anaphylaxis (merely annoying) Allergic rhinitis Asthma Food allergies Atopic dermatitis

Systemic anaphylaxis Drugs, serum

Epinephrine counteracts the effects of mediators

Allergic Rhinitis Asthma Atopic dermatitis Food allergy Localized anaphylaxis

Many organ are be affected by “allergy” The nasophrynx Rhinorrhea

Many organ are be affected by “allergy” The nasophrynx Nasal polyps

Many organ are be affected by “allergy” The nasophrynx Tonsillitis

Many organ are be affected by “allergy” The lungs asthma

Many organ are be affected by “allergy” The skin Urticaria (hives)

Many organ are be affected by “allergy” The skin eczema

Many organ are be affected by “allergy” The eye conjunctivitis

Many organ are be affected by “allergy” The GI tract Vomiting and diarrhea

Genetic susceptibility to type I hypersensitivity 5q31 IL-4,IL-5, IL-9, IL-13, GM-CSF 5Q32 β2-adrenergic receptor 6p class II MHC 6p21.3 TNF-α 11q13 FcεRI βchain 12q IFN-γ 14q TCRα

Principles of prophylaxis and therapy Search for allergens to avoid contact them next time (skin test) Disturb one process of type I hypersensitivity.

Ragweed Control Histamine Skin test for allergy A wheal and flare response

The wheal and flare reaction in the skin

Traditional Treatments for allergy 1,Symptomatic Receptor blockers antihistamine, antileukotriene Bronchodialators β-agonists (inhalants, epinephrine) 2,Prevent mast cell degranulation Ca influx inhibitor (chromolyn sodium) Phosphodiesterase (theophylline) 3, Use of adrenaline to counteract the effects of system anaphylaxis 1,Symptomatic Receptor blockers antihistamine, antileukotriene Bronchodialators β-agonists (inhalants, epinephrine) 2,Prevent mast cell degranulation Ca influx inhibitor (chromolyn sodium) Phosphodiesterase (theophylline) 3, Use of adrenaline to counteract the effects of system anaphylaxis

Immunotherapy Hyposensitization Anti-IgE(Fc) Ab

Principles of immunotherapy

Hyposensitization

New therapy for asthma and allergy: blocking the Fc portion of IgE from binding to the Fc  R on mast cells

Other new therapies:  Il-12, induce Th1 polarization  DNA vaccine, induce Th1 polarization  Soluble IL-4 receptor

Summary of allergy: 1.A strong genetic predisposition. 2.Allergens are usually common environmental proteins and chemicals. 3.The immediate reactions are dependent on the activation of Th2 cells. 4.The clinical and pathologic manifestations consist of the vascular and smooth muscle reaction that develops rapidly after repeated exposure to the allergen and a delayed late-phase reaction consisting mainly of inflammation. 5. The reactions are manifested in different ways, including skin and mucosal allergies, food allergies, asthma, and systemic anaphylaxis.

Mechanism of Type I Hypersensitivity Primed stage Effector stage Allerg en Firstly Body Produce Bound to FcεR I of mast cells, basophils Secondly IgE on sensitized cells recognizes allergen Degranulation of biologic mediators Preformed mediators FcεR I crosslink Newly formed mediators HistamineKininogenase Kinin Leukotriene PAF Prostaglandin D2 Contraction of smooth muscle, vasodilation, vascular permeability, secretion of mucus Systemic anaphylaxis Skin Urticaria Respiratory tract Asthma GI Vomiting and diarrhea

Type II hypersensitivity (cytotoxic)

Introduction Antibody (IgM or IgG) directed mainly to cellular antigens (e.g. on erythrocytes) or surface autoantigens can cause damage through opsonization, lysis by complement activation or antibody dependent cellular cytotoxicity. Also called cytotoxic hypersensitivity

Sensitization for Type II hypersensitivity B cell TH2

Type II hypersensitivity role of complement and phagocytes

Effector mechanisms of antibody- mediated disease

Cellular or matrix Antigens: 1.Isotype antigens 2.Altered autoantigens 3.Absorbed haptens 4.Self antigens by cross-reaction

Type II hypersensitivity is caused by antibodies to altered cell-surface components

Type II hypersensitivity induced by exogenous agents

Antibodies: IgM, IgG

Major clinical diseases caused by type II sensitivity 1. Transfusion reactions 2. Hemolytic disease of the newborn 3. Autoimmune hemolytic anemia ： caused by infection and drugs 4. Autoimmune thrombocytopenic purpura 5. Goodpasture’s syndrome 6. Stimulatory hypersensitivity ： graves diseases, myasthenia gravis

Transfusion Reaction

Hemolytic disease of the newborn

ãRed cells: Penicillin, chloropromazine, phenacetin ãGranulocytes: Quinidine, amidopyridine ãPlatelets: sulphonamides, thiazides ãRed cells: Penicillin, chloropromazine, phenacetin ãGranulocytes: Quinidine, amidopyridine ãPlatelets: sulphonamides, thiazides Examples of drug-induced type II hypersensitivity

Goodpasture’s syndrome

Stimulatory autoantibody （ Graves disease ） Pituitary gland T3,T4 Normal personpatients Regulated production of thyroid hormones Up-regulated overproduction of thyroid hormones

Inhibitory autoantibody （ Myasthenia Gravis) Muscle activation Muscle activation inhibited Ach receptor muscle pulse