1、Chapter 16: Hypersensitive Reactions,Typically, inflammatory responses rid the body of Ag and resolves the infection within days In some cases, the inflam response can have harmful effects even result in death!-this type of IR is called hypersensitivity or allergy Hypersensitive reactions develop du
2、ring the course of either: Humoral IR response or Cell-mediated IR response Those reactions initiated by Ab or Ab-Ag complexes are called Immediate Hypersensitivities Those initiated by cell-mediated response are called Delayed-type Hypersensitivities,Gell and Coombs Classification,Four categories o
3、f hypersensitivity were proposed by G&C which recog differences in the effector molecules generated. They include: IgE mediated Type I IgG mediated Type II Immune complex mediated Type III Cell mediated (DTH) Type IV,General descriptions of the 4 types of hypersensitivity,Figure 16-1,IgE-Mediated (T
4、ype I) Hypersensitivity,Antibody class produced is different than the normal 1 response IgE is produced vs an “allergen”(not vs parasite) IgE binds to mast cells/basophils sensitized 2nd exposure to allergen cross-links IgEs and triggers degranulation of mast cells/basophils Effects may be systemic
5、or localized depending,Components of Type I Rxns:,Figure 16-2,1.,2.,3.,4.,5.,6.,Type I Rxns: 1. Allergens,IgE produced in response to parasites, typically Atopic individuals produce IgE vs common environmental Ags; genetic predisposition More susceptible to: hay fever, asthma, etc. Most rxns take pl
6、ace on mucus membranes Allergens are multi-antigenic; although only several are allergenic (E and K fractions)* Allergenicity is a function of dose, sensitizing route, possible adjuvant, and genetics*,Type I Rxns: 2. and 3. Reaginic Ab, Mast Cells and Basophils,IgE also called “reagin”, larger than
7、typical Ig due to extra H chain domain, low serumc IgE Fc binds to glycoprotein on Mast/Baso Basos 0.5-1.0% of circ WBC; granulocytes! Masts in conn tiss, near bvs and lvs Skin and mucus memb (esp resp & gi tracts) Upon activation, granules are released effects!,Type I Rxns: 4. IgE Crosslinkage by a
8、llergen,Cross-linking 2 FcRI receptors initiates degranulation of Mast/Basophils. This may occur several ways:,Typical trigger,Mast/Basophil Cell Activation and Degranulation,Type I Rxns: 5. Release of Pharmacologically active agents,Substances released from cell granules Substances act on: a) nearb
9、y tissueb) 2 effector cells Substances (chemical mediators) are categorized as either 1 or 2 : 1 are substances released from granules 2 are synthesized after activation or product(s) of membrane destruction,Type I Hypersensitivity: Main Bio effectors,Histamine major portion of granules- decarboxyla
10、tion of histidine-specific receptors (H1, H2, H3) on target cells*H1 - permeability of b.v.scontraction of intest/bronchial smooth musclesmucus secretion Goblet cells H2 vasc perm and vasodilation-suppression of degran if bound to Mast/Baso neg feedback,Type I Hypersensitivity: Main Bio effectors,2.
11、 Leukotrienes and prostaglandins -produced from P-lipid breakdown-longer lasting and more potent than histamineas effector chemicals-promote further contraction of smooth muscles3. Cytokines -various cytokines (IL-4,5,6, TNF-) released from Mast/Baso-attract neuts/eosinosIgE production from B cells-
12、TNF may contribute to systemic anaphylaxis,Type I Responses may be Systemic or Localized,Systemic response (Anaphylaxis): occurs w/i minutes; symptoms include: difficult resp. BP drop, smooth muscle contraction, massive edema Treat with epinephrineLocalized response (Atopy): Inherited; occurs in 20%
13、; rxn limited to target tissue often epithelial surfaces,Type I Rxns: Localized allegic responses,Allergic rhinitis (hay fever) Asthma Early response Late response Food allergy - Atopic dermatitis (eczema) -,Type I Hypersensitivity: Late-Phase Reactions,Caused by pharmacologic/vasoactive mediators -
14、 induce local inflammation.causes tissue damage Occurs 4-6 hrs after initial rxn; can persist 1-2 days TNF- and IL-1 increase CAMs on endothelia promote tethering/migration of: Neutrophils Eosinophils Monocytes Basophils Eosinos exhibit Fc receptors for IgE - triggers degran. Neutros release lytic e
15、nzymes, PAF, leukotrienes,Cytokines from Mast cells also contribute!,Type I Hypersensitivity: Regulatory factors,The following factors influence IgE response to allergens: Level of Ag dose Mode of antigen presentation Relative presence of TH1 and TH2 titres TH2s release IL-3,4,5, and 10 TH1s release
16、 IFN- Atopic vs non-atopic individuals express qualitatively different Type I responses to allergens Atopic responses involve TH2 production of IgE from B cells Non-atopic responses involve TH1 production of IgM or IgG,Type I Hypersensitivity: Detecting allergies,Skin tests- injections or scratching
17、s-Stim local Mast cells-Produces P-K rxn (wheal and flare)-Inexpensive and quick-May sensitize one to new Ags-May stim late-phase rxn in someImmunoassays for serum IgE-Radioimmunosorbent test (RIST)-Radioallergosorbent test (RAST),Immunoassays for IgE,RIST,RAST,Type I Hypersensitivity: Treatment methods,Antibody therapy Injected monoclonal anti-IgE Ab binds free and mIgE on B cells Hyposensitization Repeated injections of allergen causes a shift in Ig response,Drug treatments,Immunotherapy,
