1. Allergy Genes and Poo Mark Hopley ABCD

2. 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

3. 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

4. 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

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

6. Pathological Features

7. Cells and Mediators

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

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

10. T helper subtypes

11. T cells, allergy and interleukins

12. IL-12 and T h 1

13. 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

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

15. 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 ?

16. Mendelian inheritance (Peas in a pod)

17. 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

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

20. 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

21. 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

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

23. Hardy – Weinberg principle

24. 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

25. 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

26. 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

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

28. 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

29. Hardy – Weinberg dys-equilibrium

30. 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

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

32. 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

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