HYPERSENSITIVITY

t.mclaughlin2@herts.ac.uk
 Aim of lecture
 The Mechanisms of HYPERSENSITIVITY
 tissue damage and inflammation by

IgE Antibody production

Immune Complexes
 Antibody-Dependent Cytotoxicity

 Immune Complex

formation/deposition
Cell Mediated
 T cells, Cytokines & Macrophages
 Introduction
 Adaptive immune response is stimulated by antigens
not associated by infectious agents
 ‘Allergic disorders’ -immune responses to ordinary
‘environmental substances’ lead to intense reactions
 Intended destruction of Ag leads to incidental tissue
damage
 These can be life threatening
 Hypersensitivity reactions due to immunological
responses were classified into 4 broad types by
Coombs and Gell in 1963
 Type I hypersensitivity reactions
 Allergic reactions due to the production of IgE
 IgE is predominantly localised to the tissues tightly
bound to the surface of mast cells
(basophils/eosinophils)
 IgE binds the high affinity receptor FcεRI
 Mast cells are activated only when the bound IgE is
cross linked by multivalent antigens
 Results in the release of chemical mediators that can
lead to allergic disease
 Sensitisation is the first stage of the process
Defence against parasites
 Hygiene hypothesis
 Proposed the ‘epidemic of allergy’ (Strachan-1989)
 Allergy prevalent in countries where parasite
infections have been eliminated
 Causes-improved hygiene, widespread vaccination
 Immune system is poorly educated
 Supported with over 25 years of epidemiological data
 As a consequence controlled and deliberate helminth
infections are being considered as treatments for
severe allergic disease
Case study: Allergic asthma (e.g. Type I
hypersensitivity reaction)

 Results from chronic T cell driven inflammation of the

airways with episodic symptoms triggered by allergen
inhalation
 Leads to increased hypersensitivity of airway not only to
allergen re exposure but also to non-specific agents such
as exercise, pollutants, and cold air
 Involves CD4 Th2 cells, IgE ab formation, mast cell
sensitization and release of allergic mediators
(histamine/tryptase/neutral proteases)
 Immediate response followed by a late phase reaction
within 12 hours of contact with antigen
IL-4,IL-5 & TNF-α produced by activated mast cells and helper T cells help to
prolong the allergic reaction
Obstruction of airways in chronic asthma
 Immediate response followed by a late-phase
response

 IgE mediated allergic reactions

 Small quantities of allergen
introduced into the skin
 Wheal and flare
 Immediate reaction (IgE mediated
mast cell degranulation)
 Late phase reaction (leukotrienes,
chemokines and cytokines
synthesised by mast cells)
 Treatment strategies

Not to forget
avoidance
 Type II hypersensitivity reactions
 Antibody dependent cytotoxicity
 Caused by an IgG response to chemically reactive
small molecules
 Antigen is present on the surface of a cell leads to B
cell stimulation, antibody formation, complement
activation and phagocytosis
 Result is inflamed/damaged tissue
 E.g. Penicillin can induce type II responses in a small
fraction of individuals who are prescribed the drug
 Type III hypersensitivity reactions
 Pathology is caused by the formation of immune complexes
and reflects site of deposition (blood vessels/tissues)
 Complement activation (C3a and C5a) & cell recruitment
and activation
 Sites of high blood pressure, filtration or turbulence are
particularly affected
 Complexes can activate platelets and basophils to release
vasoactivate amines
 Phagocytes that are unable to internalise deposited
complexes release granule contents-local tissue damage
Factors that affect clearance
include…..

Factors Mechanisms
Relative proportions of Ag Small complexes formed in
and Ab Ag or Ab excess persist &
deposit in small vessels
Impairment of Complement Classical Pathway key role in
Classical Pathway solubilising, transporting and
removal of complexes
Isotype of Ab Isotype dictates ability to fix
Complement
Rate of complex formation If rate exceeds clearance,
deposition is enhanced
 Type IV hypersensitivity
 Cell mediated delayed type typically developing 24/48 hrs after
antigen challenge
 Unlike type I,II & III, IV is mediated by antigen specific effector T
cells
 Following earlier priming memory T cells recognise Ag/MHC
Class II on APCs and are activated
 Cytokine release-attract/activate macrophages (Th1) or eosinophils
(Th2)-Antibodies are not involved
 Fall into 2 classes-1st damage due to inflammatory response &
tissue destruction by Th1 cells & mΦ’s they activate
 2nd tissue damage caused mainly by direct action-specific cytotoxic
CD8 T cells on target cells
 Some terminology
 Allergy
Defined as a hypersensitivity reaction initiated by
immunological mechanisms
 Atopy

A genetic predisposition to produce prolonged IgE antibody

responses to commonly occurring antigens
 Hypersensitivity

Reaction that causes reproducible signs or symptoms,

following exposure to a defined stimulus in a susceptible
individual
 Risk factors for allergic disease
 Atopy
 Age
 Gender (more common in boys than girls)
 Family size-less common in large families
 Reduced microbial burden during childhood in
developed countries (HH)
 Smoking (active or passive)
 High levels of ag challenge
 Dietary factors-poor intrauterine nutrition
 Genetics
Chromosome Candidate gene
 Allergic diseases tend to run in
families 5q Th2 cytokine cluster
 80% of atopic individuals have a (IL-3,IL-4,IL-5,IL-13,GM-CSF)
family history
11q HA IgE receptor β-subunit
 Only 50% concordance in
monozygotic twins
 Evidence suggests there are many 16q IL-4 receptor α-subunit

genes with moderate effects

 Total serum IgE, prod of ag- 3q CD80/CD86
specific IgE & bronchial hyper-
reactivity (some degree of genetic
control) HLA-DRB1/HLA-DQB1
 Clinical diagnosis
 Accurate clinical history
 Points to be queried
 Respiratory allergy-seasonal or persistent-patient
identifies any triggers
 Food allergy (is reaction different depending on
whether food is raw or cooked)
 Suspected drug allergy (time lapse btwn drug intake &
onset symptoms-has patient taken same drug before &
after the allergic episode
 In clinic (tests)
 Skin prick test (Gold std)
 Allergens tested is determined by?

 Allergen applied to skin, removed &

pricked with a lancet

 Patient should not be taking anti-?

 Patch test-used for diagnosis of contact

dermatitis
 Lab diagnosis
 Allergen-specific IgE (sIgE)
 Total IgE-limited value (age dependent) varies
widely in allergic and non allergic individuals
 Mast cell tryptase-unique to mast cells α-tryptase
and β-tryptase-blood levels in circulation indicator
of mast cell activation
 Flow cytometry (Basophil activation test)
Upregulation of activation marker CD63