Asthma & Allergic HypersensitivityAsthma & Allergic Hypersensitivity

h kDr Thiru Vanniasinkam

Charles Sturt University, Australia

Outline H iti it• Hypersensitivity

• Epidemiology of asthma – overview• Immunological mechanisms involved in hypersentivity/asthma

• Treatment strategies: Immunological mechanisms involved

• Treatment –future directions

What is Hypersensitivity?What is Hypersensitivity?

• Inappropriate or exaggerated immuneInappropriate or exaggerated immune response.

• Also called allergy (anaphylaxis)• Also called allergy (anaphylaxis)

4 types of hypersensitivity responses4 types of hypersensitivity responses

• Type I – IgE (Antibody) mediatedType I  IgE (Antibody) mediated

• Type II ‐ ADCC (IgG) mediated

l di d• Type III ‐ Immune complex mediated

• Type IV – Cell mediated (DTH)

Fig 15Fig 15--1(2007; 161(2007; 16--1(2003)1(2003)

What happens in hypersensitivity i ?reactions?

• Significant tissue damage, due to:– vasoactive substances 

– phagocytosisp g y

– complement (inflammatory & cytolytic)

– other inflammatory mediatorsother inflammatory mediators

• Immune system components mediating this:antibodies mast cells– antibodies ‐mast cells

– T cells        ‐ basophils

Type I hypersensitivityType I hypersensitivity

• Type I hypersensitivity occurs when hostType I hypersensitivity occurs when host makes IgE response to non parasitic antigens

• Asthma example of Type I hypersensitivity• Asthma ‐ example of Type I hypersensitivity

Type I reactions can be…Type I reactions can be…

• SystemicSystemic – shock like / often fatal

Ags venom (bees wasp ants) drugs (penicillin)– Ags ‐ venom (bees, wasp, ants), drugs (penicillin), seafood, nuts

– Treatment‐epinephrine– Treatment‐epinephrine

• Localised ifi t t ti /– specific target tissue/organ

– atopy: hay fever, asthma, eczema, food allergies

Genetic predisposition to allergies (atopy)Genetic predisposition to allergies (atopy) 

• Genetic susceptibility: Genes –Adam33Genetic susceptibility: Genes  Adam33 (bronchial smooth muscle)

• Results in an atopic individual having:– High level of IgE

– High number of eosinophils

Mechanism (Type I hypersensitivity)Mechanism (Type I hypersensitivity)

11stst EE11stst Exposure Exposure to allergento allergen

Plasma cells Plasma cells produce IgEproduce IgE

IgE binds FcR IgE binds FcR mast mast

cells/basophilscells/basophilscells/basophilscells/basophils

22ndnd exposure exposure to allergento allergen

Allergen Allergen crosslinks crosslinks sensitisedsensitised

Degranulation Degranulation of mast of mast

ll /b hilll /b hilsensitised sensitised mast mast

cells/basophilscells/basophils

cells/basophilscells/basophils

Release of Release of mediators (causing mediators (causing allergy symptoms)allergy symptoms)

Type I Hypersensitivity(Allergic or Immediate)(Allergic or Immediate)

• Allergen

• Genetic Basis (e.g. atopy)

• Clinical effectsM l– Mucosal

– Subcutaneous– Blood

Table 16.1 Goldsby et al. 2003, 15-1 (2007)

Mechanism of Type I Hypersensitivity

Fig 16.2 Goldsby et al. 2003; 15-2(2007)

Mediators of Type I HSMediators of Type I HS

Table 16.3 Goldsby et al. 2003, 15-3 (2007)

Asthma current statusAsthma current status

• Over 300 million patients worldwide (4 5%)Over 300 million patients worldwide (4.5%)

• Increase in incidence over last 50 years

• An example of new approach to treatment:• An example of new approach to treatment: Omalizumab

Hi h t i d l d t i• Higher rates in developed countries

• Commonest chronic disease in adults and hildchildren

• Australia highest rate (21% medically diagnosed)

To et al., 2012

Innate immune system and asthmaInnate immune system and asthma

Th2 Various immune

cellsimmune

cells

Kim et al., 2012. The many parts to asthma .many parts to asthma .

Nat Immunol.

Asthma more complex than initially h hthought

• More than just Th2 responseMore than just Th2 response

• IFN involved

Immune cells involved in asthmaImmune cells involved in asthma

• Mast cellsMast cells• Eosinophils• NKT• NKT• T helperDC• DC

• NeutrophilKim et al., 2012. The many parts to asthma . Nat Immunol. 

Kim et al., 2012. The many parts to asthma .many parts to asthma .

Nat Immunol.

Kim et al., 2012. The many parts to asthma .

Nat ImmunolNat Immunol.

Role of cytokinesRole of cytokines 

IL‐13IL 13

• Regulates IgE

i• Mucous secretion

• Hyper responsiveness of  respiratory tract

• Important in corticosteroid resistant asthma

Treg cellsTreg cells

• CD4+ CD25+ T cells (Treg)CD4+ CD25+ T cells (Treg)

• Suppress allergic responses

i i fl• Anti inflammatory

• Suppress Th1/Th2 responses

Current therapy‐ CorticosteroidCurrent therapy Corticosteroid

• Bind to GC receptorBind to GC receptor

• Translocation to nucleus

Effect of glucocorticoids on immune response

Receptor (GR)‐ protein that binds DNA/affects transcription initiationtranscription initiation

• Repression of genes in leukocytesDecreaseDecrease

– Cytokines– Adhesion molecules

• Activation of some genesIL 10 ( ti i fl t t ki )– IL‐10 (anti inflammatory cytokine) 

• Effect on progeneitor immune cells, DCs, macrophages (e.g. increased phagocytosis of dead cells (anti(e.g. increased phagocytosis of dead cells (anti inflammatory)

Corticosteroid therapyCorticosteroid therapy

• Side effects (e g osteoporosis)Side effects (e.g. osteoporosis)

• Some cases steroid resistant

Need for new approaches to treatment

Approach to developing new treatments

• Suppress Th2 responseSuppress Th2 response

• Enhance Treg cell activity

Therapies for asthmaTherapies for asthma

Current approachesCurrent approaches

• Immunomodulation/ Immunotherapy

( h h2 )• (Th1 vs Th2 responses)

• Blocking the effect of Th2 cytokines (e.g. monoclonal antibodies)

Parasites in therapy…Parasites in therapy…

Discussed at2012 Annual Meeting of theDiscussed at2012 Annual Meeting of the American Academy of Allergy, Asthma & ImmunologyImmunology 

E H li id l i• E.g. Heligmosomoides polygyrus proteins dampen Th2 response

Biologic immune response modifiers e.g. monoclonal antibodiese.g. monoclonal antibodies

Example: Omalizumab (Xolair; Genentech, South San Francisco Calif)San Francisco, Calif)

• 95% humanized mAb

• forms soluble immune complexes with free IgE– preventing cross‐linking of FcεRI

– prevents  basophil and mast cell activation

Does not work in approx. 40% of patients

Allergen specific immunotherapyAllergen specific immunotherapy

• Transient increase in IgE (potentially fatal sideTransient increase in IgE (potentially fatal side effects in some cases)

• Aim increase allergen specific IgG (IgG1 IgG4)• Aim‐ increase allergen specific IgG (IgG1, IgG4)

• Increase in T reg cells

• Increase in IL‐12 

• Treat for at least 3yrs for successful outcomey

Viswanathan and Busse, 2012

Future directionsFuture directions

• More research required on immuneMore research required on immune mechanisms e.g. role of Toll like receptors (TLRs)(TLRs)

• Investigate genes involved that may affect response to treatmentsresponse to treatments

• Monoclonal antibodies that can be d i i d lladministered orally

ReferencesReferences• Coutinho AE, Chapman KE, The anti‐inflammatory and 

immunosuppressive effects of glucocorticoids recent developments andimmunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 2011. 335(1):2‐13. 

• Goldsby et al.,Kuby Immunology. 2009• Kim HY, DeKruyff RH, Umetsu, DT. The many paths to asthma: phenotype , y , , y p p yp

shaped by innate and adaptive immunity.  N.ature Immunology. 2010.  11(7): 577‐584.

• To T, Stanojevic S, Moores G, Gershon AS, Bateman ED, Cruz AA, Boulet LP. BMC Public Health 2012 Global asthma prevalence in adults: findingsBMC Public Health. 2012 Global asthma prevalence in adults: findings from the cross‐sectional world health survey. 12:204.

• Viswanathan Rk, Busse WW.Allergen immunotherapy in allergic i di f h i lrespiratory diseases: from mechanisms to meta‐analyses. 

• Chest. 2012. 141(5):1303‐14.

• Xu W Lan Q Chen M Chen H Zhu N Zhou X Wang J Fan H Yan CS Kuang• Xu W, Lan Q, Chen M, Chen H, Zhu N, Zhou X, Wang J, Fan H, Yan CS, Kuang JL, Warburton D, Togbe D, Ryffel B, Zheng SG, Shi W. 2012. Adoptive transfer of induced‐treg cells effectively attenuates murine airway allergic inflammation. PLoS One. 2012;7(7):e40314.