Immunological aspects of Hypersensitivity reaction

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Immune responses

Figure 11-32

Hypersensitivity Reactions

Harmful immune responses against harmless environmental antigens (pollens, food, drugs) Classified into 4 type of reactions (Coombs & Gell) Gell), based on their effector mechanisms responsible for cell & tissue injuries

Classification
Allergy has many faces
Antibody/B cellmediated allergy

Classification (contnd)
T cell-mediated Allergy

Type I Hypersensitivity reactions

(immediate type)

* Allergy the commonest type * IgE IgE-mediated * Innocuous antigens: allergens

IgE antibodies

Mediate mast cell activation degranulation

Via their Fce that interact to FceRI with high affinity cytophilic (reaginic) Ab Can rise to over 1000g/mL in severe atopy and helminthic infections

Normal serum concentration: less than 1 mg/mL

Has totally 5 Ig domains (4 constant and 1 variable heavy chains)

Fce R
Fce
A

RI

high affinity receptor Mast cells, basophils basophils, , activated eosinophils

Fce
A

R II (CD23)

low affinity receptor B cells, activated T cells, monocytes monocytes, , eos, eos , platelets

Binding of IgE into its corresponding receptor: IgE-like domains of a-chain

Mediate signal transduction

Interaction of IgE antibodies to mast cell membrane

The nature of allergens

High soluble proteins Presented to immune system: at very low doses Enzymes frequently triggers allergy

Cysteine

protease of house dust mite(Der mite(Der p 1) Phospholipase A2 in bee venom Others: pollen, mold spores, latex, certain drug, ie ie. . penicillin

Enzyme triggers allergy of the airway

Dermatophagoides pteronyssimus Cysteine protease Der p 1

Enzyme allergens destroy airway epithelial cells

The role of protease & proteaseprotease-activated receptors (PARs)

Principles

Extracellular exoexo-and endogenous protease (mites, molds) react with cellcell-surface receptor leukocyte infiltration, amplify allergic responses

PARs

7-transmembrane proteins coupled to G proteins: PARPAR -1,2,3 and 4. PAR PAR-2 is the most important Expressed on the cells involved in allergic rhinitis and asthma: epithelium, mast cells, eosinophils, neutrophils, monocytesmonocytes-macrophages, lymphocytes, smooth muscle, endothelium, fibroblasts, neurons

Molecular changes of PAR

PAR stimulation

Increased intracell. Ca++, gene transcription Epith.: opens tight junction, desquamation, produces cytokine, growth factors Degranulates eosinophils, mast cells Fibroblast: promotes proliferation, maturation, increase collagen prod. Amplify IgE production Bronchial muscle: contraction, proliferation Trypsin (injured epith. cells), tryptase (mast cells)activ. PARPAR-2 Chymase (mast cells) activ. PARPAR-2

Factors leading to IgE production

Two main signals Polarization into Th2 phenotype
IL IL-4,

IL-5, ILILIL-9, ILIL-13

Stimulate
IL IL-4,

IgE switch by B cells

IL-13 IL-

Candidate genes associated with atopy

Chromosome location
5q31 5q32

Candidate genes
ILIL -4, ILIL-5, ILIL-9, ILIL-13 b2-adrenergic receptor Class II MHC TNFTNF -a

Role of gene products

IL-4 & ILILIL-3 IgE ILIL -5 eosinophils Regulates arterial & bronchial smooth muscle contraction Regulates T cell response Th2 Mast cell inflammatory mediator Mast cell IgE receptor

6p 6p21.3

11q13

Fce RI b -chain

Contribution of genes and environmental factors

Hygiene hypothesis (1989)

Infections in early childhood

Th1 response

Non atopic

Positive interaction between infection and development of atopy

RSV infection bronchiolitis

Th2 cytokine production: IL-4 (away from IFN-g)

New theory: Immunoregulatory disorders

Modern living reducing contact with pathogens that prime Th1 response (1989)

Modern living conditions defective maturation of Treg and APCreg

The changes of theory?

Clinical evidence
Simultaneous

autoimmunityautoimmunity -and IBD (Th1(Th1mediated), and allergies (Th2(Th2-mediated) Crucial factor: Teffector/Treg balance Absence of immunoregulation develop Th1 or Th2Th2-mediated inflammatory disorders
Depending

on own Th1/Th2 bias, genetic background, immunological history

The old friends hypothesis

Harmless microorganisms (helminths (helminths, , saprophytic mycobacteria mycobacteria, , lactobacilli) Less contact with old friends in modern living

Allergy:

less frequent in hookworm n schistosomiasis Less lactobacilli in the guts of children allergy; high doses of lactobacilli inhibits dev. of atopic eczema M.vaccae maturation of Treg treat prepreexisting allergy

 modification

of the hygiene

hypothesis

counter counter-regulation

hypothesis

CounterCounter -regulation hypothesis

All types of infection

Produce

ILIL -10, TGFTGF-b down regulate Th1 n Th2 responses

PAMP TLRs of DC
TLR TLR-4, CpG DNA TLR TLR-9, IFNIFN-g indoleamine 2,3 2,3-dioxygenase (IDO) DC IDO T reg suppress Th2Th2-driven inflammation
LPS

Regulatory T cells (T reg reg) )

Natural T reg (CD4CD25) Defective in atopy (no suppression of Th2 cytokine production) Defective in FoxP3 allergy, hyper IgE IgE, , airway inflammation

CD4 Th17 Allergy/inflammation

IL IL-17

IL-4 cytokine as IgE switch factor

Role of mast cells

Effector cells of immediate hypersensitivity Contain cytoplasmic granules, whose contents are the major mediators of allergic reaction

Vasoactive

amines, lipid mediators, cytokines tissue (CTMC) and mucosal (MMC)

Two subpopulations are detected

Connective Close

Specific locations within the tissues

to blood vessels, nerve, smooth muscles

Connective tissuetissue- vs Mucosal Mucosal-mast cells

Molecules released by activated mast cells

Mediators produced by mast cells

Mediator category Mediator
Preformed structure Histamine

Function(s)
Increases vascl. permeability., smooth muscle contraction Degrade microbial structure, tissue damage/remodelling Vasodilatation, bronchoconstriction, neutrophil chemotaxis Prolonged bronchoconstriction, mucus secretion, increased vascular permeability Promotes mast cell proliferation Promote inflammation/ late phase reaction Promote Th2 differentiation, and eosinophil production

Tryptase, acid hydrolase, cathepsin G, carboxypeptidase Lipid mediators produced on activation Prostaglandin D2

Leukotrien C4, D4, E4, PAF Cytokines ILIL -3 TNFTNF -, MIPMIP-1 ILIL -4, ILIL-13, and ILIL-5

Eosinophils
Reside Toxic

in the connective tissue

gut, urogenital

Respiratory,

granule proteins, radicals parasites Chemical mediators

Prostaglandins,

inflammation

leukotrienes, leukotrienes , cytokines

Chemokines
CXCL

8, Eotaxins Eotaxins: : CCL11, CCL24, CCL26

Toxic proteins and inflammatory mediators of eosinophils

, eotaxins

Sequence of events in allergic reaction

Initial exposure of antigen/allergen

Sampling by APC processing & presentation Stimulation of CD4+T cells Th2 ILIL -4 promotes B cells IgE AFC Sensitization of mast cells degranulation vascular permeability & vasodilatation, visceral and bronchial smooth muscle contraction

Immediate/early vascular & muscular changes

Late phase reactions, due to proinflammatory cytokines/chemokines

Infiltration & activation of inflammatory cells: eosinophils, basophils, neutrophils

Local reactions in the skin: Wheal and Flare

Approaches to the treatment of allergy

Concluding remarks

Contributing factors to type I hypersensitivity reactions

Allergens

Proteins/molecules-bound to protein, low MW, low dose, Proteins/moleculesenzymatically active, highly soluble

Combination of genetic and environmental factors CD4+ Th cells, esp. Th2 responses

ILIL -4 and ILIL-13 cytokine production IgE switch factor

IgE (cytophilic) antibodies Mast cells

FceRI