ALLERGY : CLASSIFICATION,

MECHANISMS AND TREATMENTS

Rebecca Dearman
School of Biological Sciences
Faculty of Biology, Medicine and Health
University of Manchester
OVERVIEW
ORCHESTRATION OF IMMUNE RESPONSES
Immune system must counter range of threats
Viruses

Bacteria

Fungi

Parasites
SHAPING IMMUNE RESPONSES FOR SPECIFIC THREATS

Th1 Th17 Th2

IFN- IL-2 IL-17 IL-22 IL-4 IL-5 IL-10 IL-13

cell-mediated immunity cell-mediated B cell responses

(DTH) immunity and inflammation

VIRUSES FUNGI MULTICELLULAR

INTRACELLULAR BACTERIA PARASITES
IMMUNE RESPONSES: ALLERGIC REACTIONS

CARDINAL CHARACTERISTICS
OF ADAPTIVE IMMUNE RESPONSES

memory
specificity
discrimination between self and non-self

specific immune responses to innocuous antigens

resulting in pathology (hypersensitivity)
 CLASSIFICATION OF ALLERGIC REACTIONS
specific immune responses to innocuous antigens
resulting in pathology (hypersensitivity)
Gell and Coombs classification
TYPE I TYPE II TYPE III TYPE IV
Mediator IgE IgG IgG T cells
IMMEDIATE DELAYED
Antigen soluble cell/matrix soluble soluble

Effector mast cells complement complement macrophages

Mechanism eosinophils FcR+ cells phagocytes

Example food allergy some drugs serum contact

allergic rhinitis sickness dermatitis
asthma
 TYPES OF ALLERGIC REACTION
specific immune responses to innocuous antigens
resulting in pathology (hypersensitivity)

ALL TRUE ALLERGIC REACTIONS DEVELOP IN TWO STAGES

INDUCTION/SENSITISATION
first exposure, individual is primed

ELICITATION
subsequent exposure to same allergen,
sensitised individual shows clinical manifestations
 ALLERGIC REACTIONS:TYPE II
specific immune responses to innocuous antigens
resulting in pathology (type II hypersensitivity)

IgG antibodies against cell/matrix associated antigens

causing cell lysis or phagocytosis eg some drug allergies

penicillin
 ALLERGIC REACTIONS:TYPE II
specific immune responses to innocuous antigens
resulting in pathology (type II hypersensitivity)

IgG antibodies against cell/matrix associated antigens

causing cell lysis or phagocytosis eg some drug allergies
SENSITISATION ELICITATION

penicillin

Drug binds eg platelets Antibody binds drug on

antibody produced cell
against cell-bound drug complement activated
(recognised as foreign) ingested by phagocytes
 ALLERGIC REACTIONS:TYPE III

specific immune responses to innocuous antigens

resulting in pathology (type III hypersensitivity)

antibody antigen immune complexes against soluble antigen

and deposition in small blood vessels
(complement/phagocyte involvement)

eg serum sickness
(use of therapeutic anti-venom Ig etc)
(more common in autoimmune disease)
eg systemic lupus erythematosus
 ALLERGIC REACTIONS:TYPE III
Antigen/antibody
complexes

antibody against
foreign serum
Plasma level
foreign proteins
serum
proteins

injection of Time (days)

foreign serum
symptoms of
fever, vasculitis,
arthritis, nephritis
 ALLERGIC REACTIONS:TYPE I
specific immune responses to innocuous antigens
resulting in pathology (immediate (IgE) hypersensitivity)

Atopy (out of place)

food allergy, asthma, rhinitis, systemic anaphylaxis, eczema
 IgE-MEDIATED ALLERGIC DISEASE

Prevalence in developed countries

Asthma: 5-17% (depending on the country: Croatia low; Portugal high)

~5 million currently treated for asthma in UK
(1 in 12 adults and 1 in 11 children)

Allergic rhinitis: 10-20%

Food allergy: 1-2% adults; 5-8% children (some reports 15-20%!!!)

Eczema: 1in 5 children, 1 in 12 adults

Systemic anaphylaxis (food allergy, insect stings, medications):

63-99 fatalities per year in US (5-15 per year in UK); >50% in teenagers
But of hospitalisation cases only ~0.3% fatal (4451 admissions in 2015-16)
 May 2015
Apprentice builder, 18, with nut allergy who
collapsed and died
Apprentice builder, 18, withan
nuthour
allergyafter
who eating a Korma
collapsed
curry and died
wasn't an hour after
carrying hiseating a Korma
EpiPen because he
curry wasn't
wanted tocarrying
keep histheEpiPen because
outline he skinny jeans
of his
wanted to keep the outline of his skinny jeans

Apr 2014
Father, 38, builder,
Apprentice dies from 18,severe
with nut allergic
allergy who
reaction from
collapsed and died curryan containing
hour after eating a Korma
peanuts
Police investigating the death of a father who had a severe allergic
curry wasn't carrying his EpiPen because he
reaction to nuts have arrested two men believed to work at the
wanted
takeaway whichtoserved
keep him athe outline
meal containing of his skinny jeans
peanuts.

Paul Wilson, 38, died after eating a curry from a takeaway which is
believed to have contained peanuts.
SHAPING IMMUNE RESPONSES FOR SPECIFIC THREATS

Th1 Th17 Th2

IFN- IL-2 IL-17 IL-22 IL-4 IL-5 IL-10 IL-13

cell-mediated immunity cell-mediated B cell responses

(DTH) immunity and inflammation

VIRUSES FUNGI MULTICELLULAR

INTRACELLULAR BACTERIA PARASITES
 Recruitment of
eosinophils and

Th2 cells
from circulation
ACUTE RESPONSE CHRONIC RESPONSE
mast cell degranulation Release of cytokines (Th2 cells)
airway obstruction eosinophil granule proteins
leaky blood vessels = chronic inflammation
 Th2 CYTOKINES IN TYPE I REACTIONS

IL-4/IL13 IgE antibody production

IL-13 hypersecretion of mucin

IL-5/IL-13 activation and recruitment

of eosinophils

IL-4/IL-5/IL-10 differentiation and

activation of mast cells
 ALLERGIC REACTIONS:TYPE I
IMMEDIATE TYPE HYPERSENSITIVITY

Skin Airways Gastrointestinal Blood vessels

tract
Increased blood flow Decreased diameter Increased fluid secretion Increased blood flow
increased permeability increased mucus increased peristalsis increased permeability

Increased fluid, Congestion /blockage Expulsion of Increased tissue fluid,

of airways (wheezing, gastrointestinal
redness, swelling, lymph flow to lymph
coughing, phlegm) tract contents
rashes swelling/mucus
nodes, cells/protein
(diaorrhea, in tissues
secretion
vomiting)
 SKIN INHALATION GUT
respiratory epithelium intestinal epithelium

blood bronchial intestinal

capillary smooth smooth
muscle muscle

MAST CELL MAST CELL MAST CELL

ACTIVATION ACTIVATION ACTIVATION

local histamine allergic rhinitis vomiting

wheal and flare asthma diarrhoea
 GUT
Intestinal epithelium
HIGH DOSE
INTRAVENOUS

intestinal
smooth
muscle

blood MAST CELL

MAST CELL MAST CELL BASOPHIL
capillary BASOPHIL
ACTIVATION ACTIVATION
ACTIVATION

systemic histamine
release
vomiting anaphylaxis
anaphylaxis
diarrhoea
 DIAGNOSIS
DETECTION OF IgE
Specific serum IgE ex vivo (RAST/IMMUNOCAP etc)
Skin prick tests/prick to prick tests

PROVOCATION CHALLENGE
Food allergy : DBPCFC (double blind placebo controlled food challenge)
Rhinitis : nasal challenge
Asthma : bronchial provocation test
 AVOIDANCE

IDENTIFICATION OF OFFENDING ALLERGEN

AND AVOIDANCE
 TREATMENT
PHARMACOTHERAPY (for symptoms)
anti-histamines
mast cell stabilising compounds (eg cromolyn sodium)
topical and systemic corticosteroids
generally provide moderate or partial relief; severe cases often refractory

FOR SYSTEMIC ANAPHYLAXIS : adrenalin (EpiPen)

 TREATMENT : IMMUNOTHERAPY
DESENSITISATION
Effective for allergic rhinitis (used for last 100 years)
Repeated subcut injections (SCIT)/sublingual applications (SLIT)
of small amounts of antigen

Induces altered immune response (IgG4/Tregs)

Disease modifying
Possible adverse systemic effects (SCIT)
Potential applications for food allergy?
 TREATMENT : IMMUNOTHERAPY
DESENSITISATION Study of induction of Tolerance to Oral Peanut
(STOP)

Oral exposure peanut flour

Anagnostou K et al, 2014. Study of induction of Tolerance to Oral Peanut: a

randomised controlled trial of desensitisation using peanut oral immunotherapy in
children (STOP II). Southampton (UK): NIHR Journals Library; 2014
 TREATMENT : IMMUNOTHERAPY
PREVENTION(LEAP; Learning Early about Peanut Allergy)

Primary prevention Secondary prevention

At 60 months :
Induces altered immune response (IgG4IgE)
Prevention and cure
Low incidence of adverse effects
Follow up : no difference in energy consumption
Du Toit et al, 2015. Randomized trial of peanut consumption in infants at risk for peanut allergy.
N Engl J Med. 372:803-13.
 TREATMENT : IMMUNOTHERAPY
PREVENTION LEAP follow up study (LEAP-On)

Avoiders

Consumers

After 12 months of peanut avoidance (72 months old)

Small increases in all populations BUT still lower in consumers
Altered immune response (IgG4IgE) still apparent

Du Toit et al, 2016. Effect of avoidance on peanut allergy after early peanut consumption.
N Engl J Med. 374:1435-43.
 TREATMENT : IMMUNOTHERAPY
MONOCLONAL ANTIBODY THERAPY (Omalizumab)
Humanised monoclonal antibody
Approved in US in 2003 for moderate/
severe uncontrolled allergic asthma
Also for chronic urticaria (Phase I/II/III/IV)
Omalizumab
Binds circulating IgE
IgER expression
mast cell degranulation IgE

Expensive
Subcutaneous administration
Food allergy and rhinitis trials :
An adjunct to SIT?
Tan et al, 2016. Novel biologicals for the treatment of allergic diseases and as
Curr Allergy Asthma Rep. 16:70 (Epublication)
 TREATMENT : NEW BIOLOGICS
Treatment Drug/agent Company Mechanism Development
Reduces free Phase I/II studies
QGE031 plasma IgE levels, Asthma, urticaria
Anti-IgE mAb Novartis
(ligelizumab) prevents IgE binding
to FcRI/II
Binds to IgE- Phase II study
expressing B cells Asthma, urticaria
Quilizumab Anti-M1 Genentech
and induces
apoptosis
Blocks CD23, Phase I study
reducing IgE
Lumiliximab Anti-CD23 Biogen
production and
transport
Phase III study
Mepolizumab
AntiIL-5 mAb GlaxoSmithKline Blocks IL-5 Approved for severe
(Bosatria)
eosinophilic asthma
Blocks IL-5 binding Phase II/III studies
Benralizumab AntiIL-5R MedImmune
to IL-5R Asthma, COPD
Phase II/III studies
Regeneron Blocks IL-4 and IL-13
Dupilumab AntiIL-4R mAb Asthma, atopic
Pharmaceuticals binding to IL-4R
dermatitis
Phase II/III studies
Lebrikizumab AntiIL-13 Genentech Blocks IL-13
Asthma
Blocks TSLP binding Phase I/II studies
AMG 157 Anti-TSLP Amgen
to receptor Asthma
Stimulates TLR9 and
AIC (CpG conjugated TLR9 agonist NIH Immune Phase II study
TH1 responses
to Amb a 1) (adjuvant) Tolerance Network Allergic rhinitis
during ragweed IT
Bauer et al, 2015. The future of biologics: applications for food allergy. J Allergy Clin Immunol.
 ALLERGIC REACTIONS: TYPE IV

specific immune responses to innocuous antigens

resulting in pathology (delayed type hypersensitivity)

Tuberculin (Heaf/Mantoux test)

poison ivy (US)
reactive chemicals (contact allergy)
~ 1% of GP visits
15% of occupational disease
 The epidemic in the bathroom:
Ban on chemical irritant used in skin creams manufacturers told to remove
after explosion in cases of allergic reactions chemical linked to skin allergies
and eczema
Cosmetic firms are ordered to remove
Preservative Methyl- a chemical from dozens of everyday
isothiazolinone (MI) products after it was linked to an
routinely added to epidemic of skin allergies
moisturisers. Cosmetics
Europe told members to
remove it from products
after reactions. Survey
found chemical in
products including
Nivea and L'Oreal cream
 ALLERGIC REACTIONS: TYPE IV

methylisothiazolinone (MI)
Allergen of the year 2013

uin self tanning agent

Baby wipe allerg

SHAPING IMMUNE RESPONSES FOR SPECIFIC THREATS

Th1 Th17 Th2

IFN- IL-2 IL-17 IL-22 IL-4 IL-5 IL-10 IL-13

cell-mediated immunity cell-mediated B cell responses

(DTH) immunity and inflammation

VIRUSES FUNGI MULTICELLULAR

INTRACELLULAR BACTERIA PARASITES
ALLERGIC CONTACT DERMATITIS
exposure to allergen
INDUCTION
delivery of allergen
PHASE

T clonal expansion of
T
T T allergen-specific T
T T lymphocytes
T

arrival of skin-homing
allergen-responsive
T lymphocytes ELICITATION
T T immune PHASE
T T activation

cutaneous inflammation
 ALLERGIC REACTIONS:TYPE IV

Antigen is processed by tissue APC and stimulates Th1/Tc1 cells

Th1 Tc1 Th17

Chemokines Cytokines Cytotoxins

IFN activates macrophages TNF cause local tissue

Recruit macrophages to IL17/GMCSF stimulate
site of antigen deposition destruction and increase
monocyte production adhesion molecule expression
IL17 attracts neutrophils
 DIAGNOSIS : PATCH TESTING

TREATMENT :

IDENTIFICATION OF ALLERGEN AND AVOIDANCE

MID TO HIGH POTENCY TOPICAL CORTICOSTEROIDS

EXTENSIVE (>20%) : SYSTEMIC STEROIDS

 RECOMMENDED READING
Textbooks available from the Library
Peter Wood: Understanding Immunology (3rd Edition) 2011 Prentice Hall
Janeways Immunobiology (7th Edition) 2008 Garland Science

Articles
Anagnostou et al, 2014. Assessing the efficacy of oral immunotherapy for the
desensitisation of peanut allergy in children (STOP II). Lancet 383:1297-1304.
Bauer et al, 2015. The future of biologics: applications for food allergy. J Allergy Clin
Immunol 135: 312-23.
Du Toit et al, 2015. Randomized trial of peanut consumption in infants at risk for peanut
allergy. N Engl J Med 372: 803-13.
Du Toit et al, 2016. Effect of avoidance on peanut allergy after early peanut consumption.
N Engl J Med 374:1435-43.
Johnston et al, 2014. The immunology of food allergy. J Immunol192:2529-34.
Martin SF, 2015. New concepts in cutaneous allergy. Contact Dermatitis 72:2-10.
McFadden et al, 2013. Why does allergic contact dermatitis exist? Br J Dermatol168:692-9.
Tan et al, 2016. Novel biologicals for the treatment of allergic diseases and asthma.
Curr Allergy Asthma Rep 16:70 (Epublication)
Wood, 2016. Food allergen immunotherapy: Current status and prospects for the future.
J Allergy Clin Immunol 137:973-82.