Allergy Genes and Poo Mark Hopley ABCD

Outline  Asthma and rhinitis United airwaysUnited airways  T helper lymphocyte T h 1 vs. T h 2T h 1 vs. T h 2  CD14 endotoxin receptor (M  ) Genetic polymorphism (CC, CT, TC, TT)Genetic polymorphism (CC, CT, TC, TT)  Endotoxin exposure Environmental interactionEnvironmental interaction  Hygiene hypothesis

Atopy and allergens  Asthma and atopic conditions – closely linked  "Atopic march" –Infancy and childhood DermatitisDermatitis –Childhood and adolescence Allergic rhinitis and asthmaAllergic rhinitis and asthma – 1 / 3 atopic dermatitis develop asthma  Raised IgE – Atopy –Closely linked with airway hyper-responsiveness –Indicate the presence of allergic sensitization

Asthma  Chronic inflammatory condition T cells, mast cells and eosinophilsT cells, mast cells and eosinophils –Reversible airflow obstruction treatment or timetreatment or time –Characterised by wheeze, breathlessness, chest tightness and coughwheeze, breathlessness, chest tightness and cough particularly at night / early morningparticularly at night / early morning –Hyper-responsiveness

Precipitating Factors  AAllergy  EEnvironment Emotion Exercise  IInfection  OOccupation  UDrugs

Pathological Features

Cells and Mediators

Mast cell Eosinophil IgEPrecipitin Mediators of inflammation + Contraction of airway smooth muscle Oedema Mucus Stimulation of nerves Damage to epithelium Inflammation (Pathophysiology)

Inflammation (Aetiology) Inhaled allergen Antigen presenting & T cells Cytokines Mast cell Eosinophil IgE Permissive host

T helper subtypes

T cells, allergy and interleukins

IL-12 and T h 1

Source of IL-12 ?  CD14 endotoxin receptor on MФ –Activation by endotoxin Raised IL-12Raised IL-12 T h 1 responseT h 1 response  Endotoxin or lipopolysaccharide Outer membrane of Gram -ve bacteriaOuter membrane of Gram -ve bacteria GIT floraGIT flora

Endotoxin and T h 1 response CD14 IL-12T h 1

Could CD14 be involved ?  CD14: Single nucleotide polymorphism –C or T (CD14/-159) promoter region of gene  Three genotypes: CC or CT or TT –Phenotype: T dominant T (TT or CT) – Numerous CD14 receptorsT (TT or CT) – Numerous CD14 receptors  T (TT or CT) – high IL-12 lower allergy ?

Mendelian inheritance (Peas in a pod)

Mendelian inheritance CD14  Two genes variants: C or T  Each individual has two copies: –CC or CT or TC or TT  T (TT, CT, TC) –Numerous CD14 receptors –Lots of IL-12 –Th 1 response –Low allergy

The “early” evidence –TT  Hypersensitivity in Hutterites  Reduced risk for Scandinavian dog owners

TT protective CC risk No association Specific T, all C No association C risk T risk, CC low TT risk TT with dog low risk C with Stable animal low risk TT exposed to tobacco smoke Meta-analysis showed no association

Could it be nurture ?  Conflicting results with C/T SNP CD14  Environmental endotoxin may be the answer –Low early life exposure – Allergy –Not reproducible in all population  Could it be both TOGETHER ? 442 children recruited prior to birth442 children recruited prior to birth Followed up to age 5Followed up to age 5 Genotyped for CD14 C/T SNPGenotyped for CD14 C/T SNP Environmental endotoxin assayedEnvironmental endotoxin assayed

Gene-environment interaction Nature / Genetics Clean  Nurture – environment  Dirty Allergy (Rhinitis and asthma) 

Hardy – Weinberg principle

Replicated gene-environment interaction  Endotoxin exposure, CD14 and allergic disease Simpson et al. AJRCCM 2006  The A endotoxin Alex study… Eder et al. J Allergy Clin Immunol 2005  Gene-environment interaction with CD14… Williams et al. J Allergy Clin Immunol 2006  CD14 polymorphism and endotoxin exposure Zambelli-Weiner et al. J Allergy Clin Immunol 2006

Hygiene hypothesis  Strachan (BMJ 1989) –Allergic diseases – less common in larger families Exposed to more infectious agents by their siblingsExposed to more infectious agents by their siblings Higher incidence of allergy in developed countries Higher incidence of allergy in developed countries Increase in allergic diseases – urbanization Increase in allergic diseases – urbanization  CD14 SNP and endotoxin –Consistent reproducible gene-environment interaction

Genes, asthma and allergy  Pathogenesis genes (ILs, IgE, CD14) Different genes – same phenotypeDifferent genes – same phenotype Multiple genesMultiple genes Environment – gene interactionEnvironment – gene interaction  Severity modifying genes  Treatment modifying genes β 2 adrenergic receptor, IL-4 receptorβ 2 adrenergic receptor, IL-4 receptor

β 2 adrenergic receptor Adrenergic stimulus – endogenous or therapeutic Bronchodilation Arg/Arg SNP

Arg/Arg β 2 adrenergic receptor  SABA impair asthma control  LABA less improvement in lung function  Increased risk of exacerbation  No association  Less nocturnal asthma  Two meta analyses – conflicting results

Hardy – Weinberg dys-equilibrium

Genes, asthma and allergy  Pathogenesis genes (ILs, IgE, CD14) Different genes – same phenotypeDifferent genes – same phenotype Multiple genesMultiple genes Environment – gene interactionEnvironment – gene interaction  Severity modifying genes  Treatment modifying genes β 2 adrenergic receptor, IL-4 receptorβ 2 adrenergic receptor, IL-4 receptor

CD14 IL-12 N fn(C or T) Endotoxin

Summary  Asthma and rhinitis United airwaysUnited airways  T helper lymphocyte T h 1 vs. T h 2T h 1 vs. T h 2  CD14 endotoxin receptor (M  ) Genetic polymorphism (CC, CT, TC, TT)Genetic polymorphism (CC, CT, TC, TT)  Endotoxin exposure Environmental interactionEnvironmental interaction  Hygiene hypothesis

 Germaphobe –“Paranoid about hygiene” –“The twins’ wing is totally sterile” –“Antiseptic hand lotion” –“Surgical masks”