Asthma & Allergic Hypersensitivity

Asthma&AllergicHypersensitivity

DrThiruVanniasinkam
h
k
CharlesSturtUniversity,Australia

Outline
Hypersensitivity
H
iti it
Epidemiologyofasthma overview
Immunologicalmechanismsinvolvedin
hypersentivity/asthma
Treatmentstrategies:Immunological
mechanismsinvolved
Treatmentfuturedirections

What is Hypersensitivity?
WhatisHypersensitivity?
Inappropriate
Inappropriateorexaggeratedimmune
or exaggerated immune
response.
Alsocalledallergy(anaphylaxis)
Also called allergy (anaphylaxis)

4 types of hypersensitivity responses

4typesofhypersensitivityresponses

TypeII IgE(Antibody)mediated
Type
IgE (Antibody) mediated
TypeII ADCC(IgG)mediated
TypeIII Immunecomplexmediated
l
di d
TypeIV Cellmediated(DTH)

Fig 1515-1(2007; 16
16--1(2003)

Whathappensinhypersensitivity
reactions?
i ?
Significanttissuedamage,dueto:
vasoactivesubstances
phagocytosis
p g y
complement(inflammatory&cytolytic)
otherinflammatorymediators
other inflammatory mediators

Immunesystemcomponentsmediatingthis:
antibodies
Tcells

mastcells
mast cells
basophils

Type I hypersensitivity
TypeIhypersensitivity
Type
TypeIhypersensitivityoccurswhenhost
I hypersensitivity occurs when host
makesIgEresponsetononparasiticantigens
Asthma
Asthma exampleofTypeIhypersensitivity
example of Type I hypersensitivity

Type I reactions can be

TypeIreactionscanbe
Systemic
Systemic
shocklike/oftenfatal
Ags
Ags venom(bees,wasp,ants),drugs(penicillin),
venom (bees wasp ants) drugs (penicillin)
seafood,nuts
Treatmentepinephrine

Localised
specifictargettissue/organ
ifi t
t ti
/
atopy:hayfever,asthma,eczema,foodallergies

Genetic predisposition to allergies (atopy)

Geneticpredispositiontoallergies(atopy)
Genetic
Geneticsusceptibility:Genes
susceptibility: Genes Adam33
Adam33
(bronchialsmoothmuscle)
Resultsinanatopicindividualhaving:
HighlevelofIgE
Highnumberofeosinophils

Mechanism (Type I hypersensitivity)

Mechanism(TypeIhypersensitivity)
1st Exposure
E
to allergen

Plasma cells
produce IgE

IgE binds FcR

mast
cells/basophils

2nd exposure
to allergen

Allergen
crosslinks
sensitised
mast
cells/basophils

Degranulation
of mast
cells/basophils
ll /b
hil
Release of
mediators (causing
allergy symptoms)

TypeIHypersensitivity
(Allergic or Immediate)
(AllergicorImmediate)
Allergen
GeneticBasis (e.g.atopy)
Clinicaleffects
Mucosal
M
l
Subcutaneous
Blood

Table 16.1 Goldsby et al. 2003,

15-1 (2007)

Mechanismof
TypeIHypersensitivity

Fig 16.2 Goldsby et al. 2003; 152(2007)

Mediators of Type I HS
MediatorsofTypeIHS

Table 16.3 Goldsby et al. 2003,

15-3 (2007)

Asthma current status

Asthmacurrentstatus
Over
Over300millionpatientsworldwide(4.5%)
300 million patients worldwide (4 5%)
Increaseinincidenceoverlast50years
Anexampleofnewapproachtotreatment:
An example of new approach to treatment:
Omalizumab
Higherratesindevelopedcountries
Hi h
t i d l
d
ti
Commonestchronicdiseaseinadultsand
children
hild
Australiahighestrate(21%medicallydiagnosed)

To et al., 2012

Innate immune system and asthma

Innateimmunesystemandasthma

Th2
cells

Various
immune
cells

Kim et al., 2012. The

many parts to asthma .
Nat Immunol.

Asthmamorecomplexthaninitially
thought
h
h
MorethanjustTh2response
More than just Th2 response
IFNinvolved

Immune cells involved in asthma

Immunecellsinvolvedinasthma
Mastcells
Mast cells
Eosinophils
NKT
Thelper
DC
Neutrophil
Kimetal.,2012.Themanypartstoasthma.Nat
Immunol.

Kim et al., 2012. The

many parts to asthma .
Nat Immunol.

Kim et al., 2012. The

many parts to asthma .
Nat Immunol.
Immunol

Role of cytokines
Roleofcytokines
IL13
IL
13
RegulatesIgE
Mucoussecretion
i
Hyperresponsivenessofrespiratorytract
Importantincorticosteroidresistantasthma

Treg cells
Tregcells

CD4+CD25+Tcells(Treg)
CD4+
CD25+ T cells (Treg)
Suppressallergicresponses
Antiinflammatory
i i fl
SuppressTh1/Th2responses

Current therapy Corticosteroid

Currenttherapy
BindtoGCreceptor
Bind to GC receptor
Translocationtonucleus

Effectofglucocorticoidsonimmune
response

Receptor(GR) proteinthatbindsDNA/affects
transcription initiation
transcriptioninitiation
Repressionofgenesinleukocytes
Decrease
Cytokines
Adhesionmolecules

Activationofsomegenes
IL10(antiinflammatorycytokine)
IL 10 ( ti i fl
t
t ki )

Effectonprogeneitorimmunecells,DCs,macrophages
(e.g. increased phagocytosis of dead cells (anti
(e.g.increasedphagocytosisofdeadcells(anti
inflammatory)

Corticosteroid therapy
Corticosteroidtherapy
Sideeffects(e.g.osteoporosis)
Side effects (e g osteoporosis)
Somecasessteroidresistant

Need for new approaches to treatment

Approachtodevelopingnew
treatments
SuppressTh2response
Suppress Th2 response
EnhanceTregcellactivity

Therapies for asthma

Therapiesforasthma
Currentapproaches
Current
approaches
Immunomodulation/Immunotherapy
(Th1vsTh2responses)
( h
h2
)
BlockingtheeffectofTh2cytokines(e.g.
monoclonalantibodies)

Parasites in therapy
Parasitesintherapy
Discussedat2012AnnualMeetingofthe
Discussed
at2012 Annual Meeting of the
AmericanAcademyofAllergy,Asthma&
Immunology
Immunology
EE.g.Heligmosomoidespolygyrusproteins
H li
id
l
i
dampenTh2response

Biologicimmuneresponsemodifiers
e.g. monoclonal antibodies
e.g.monoclonalantibodies
Example:Omalizumab(Xolair;Genentech,South
San Francisco Calif)
SanFrancisco,Calif)
95%humanizedmAb
formssolubleimmunecomplexeswithfreeIgE
preventingcrosslinkingofFcRI
preventsbasophilandmastcellactivation
Doesnotworkinapprox.40%ofpatients

Allergen specific immunotherapy

Allergenspecificimmunotherapy
Transient
TransientincreaseinIgE(potentiallyfatalside
increase in IgE (potentially fatal side
effectsinsomecases)
Aim
Aim increaseallergenspecificIgG(IgG1,IgG4)
increase allergen specific IgG (IgG1 IgG4)
IncreaseinTregcells
IncreaseinIL12
Treatforatleast3yrsforsuccessfuloutcome
y

Viswanathan and Busse, 2012

Future directions
Futuredirections
More
Moreresearchrequiredonimmune
research required on immune
mechanismse.g.roleofTolllikereceptors
(TLRs)
Investigategenesinvolvedthatmayaffect
response to treatments
responsetotreatments
Monoclonalantibodiesthatcanbe
administeredorally
d i i
d
ll

References

Coutinho AE,ChapmanKE,Theantiinflammatoryand
immunosuppressive effects of glucocorticoids recent developments and
immunosuppressiveeffectsofglucocorticoids,recentdevelopmentsand
mechanisticinsights. MolCellEndocrinol. 2011.335(1):213.
Goldsby etal.,Kuby Immunology.2009
KimHY,DeKruyff
,
y RH,Umetsu,DT.Themanypathstoasthma:phenotype
,
,
yp
p
yp
shapedbyinnateandadaptiveimmunity.N.ature Immunology.2010.
11(7):577584.
ToT,StanojevicS,MooresG,GershonAS,BatemanED,CruzAA,BouletLP.
BMC Public Health 2012Globalasthmaprevalenceinadults:findings
BMCPublicHealth.
2012 Global asthma prevalence in adults: findings
fromthecrosssectionalworldhealthsurvey.12:204.
Viswanathan Rk,Busse WW.Allergen immunotherapyinallergic
respiratorydiseases:frommechanismstometaanalyses.
i
di
f
h i
l
Chest.2012.141(5):130314.
Xu W,LanQ,ChenM,ChenH,ZhuN,ZhouX,WangJ,FanH,YanCS,Kuang
W Lan Q Chen M Chen H Zhu N Zhou X Wang J Fan H Yan CS Kuang
JL,WarburtonD,TogbeD,RyffelB,ZhengSG,ShiW.2012.Adoptive
transferofinducedtregcells effectivelyattenuatesmurineairwayallergic
inflammation.PLoSOne.2012;7(7):e40314.