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Indoor Allergens why is the dust mite such an Excellent Source of Allergens

Indoor Allergens why is the dust mite such an Excellent Source of Allergens. Thomas A E Platts -Mills, MD PhD FRS University of Virginia Disclosures : We are grateful to NIAID for generous support: AI-20565 and UO1-100799-2 and to Thermo Fisher for grant support

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Indoor Allergens why is the dust mite such an Excellent Source of Allergens

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  1. Indoor Allergens why is the dust mite such an Excellent Source of Allergens Thomas A E Platts-Mills, MD PhD FRS University of Virginia Disclosures: We are grateful to NIAID for generous support: AI-20565 and UO1-100799-2 and to Thermo Fisher for grant support DrPlatts-Mills is a consultant for IBT/Viracor and speaker for ALK .

  2. From mites and cats (and oak trees) to allergenic molecules: what are the next steps? Molecules Proteins: Que a 1 Proteins: Lol p 1 Molecules Glycosylation: Mux f 3 Molecules Proteins: Der p 1, 2,…14 Proteins: Fel d 1, 2,…8 Molecules Glycosylation: Alpha-Gal

  3. Why is the dust mite such a “good” allergen? • Is the form in which dust mite allergen is inhaled critical to the IgE antibody response? • The fecal particle is 20-30 microns in diameter (i.e., 1,000 times larger than an Aspergillusspore). • Der p 1 is a potent cysteine protease that can cleave CD23, CD25, and open tight junctions. • The fecal particle also contains: endotoxin (TLR-4), mite and bacterial DNA that are not fully methylated (TLR-9), and the peritrophic membrane is made of chitin (TLR-2 and dectin 1).

  4. Composition of Mite Fecal Particles

  5. Potential Immunological Effects of Biologically Active Components in Mite Fecal Particles * Der p 1 Endotoxin Der p 2 Chitin Mite DNA Bacterial DNA (unmethylated) MyD88 independent: type I IFNs, IL-10 and IFN-inducible genes GM-CSF, IL-1β, IL-6, IL-12, IL-18, IL-25, IL-33, TNF-α, TSLP IL-5, IL-6, IL-13, IL-15, IL-23, TNF-α, type I IFNs * Cysteine protease can open tight junctions and cleave CD23 and CD23 Adapted from Yang and Seki, 2012

  6. Atopy, Mite Sensitization and Exposure to Dust Mites in Early Childhood as Risk Factors for Asthma at Age 11 Early* Current Asthma wheezing Never* Relative Yes No only wheezed risk Current asthma = wheeze in the last year & bronchial reactivity to histamine * Subgroups of no current asthma. Sporik et al, NEJM 1990 ; 323: 502

  7. “ The Asthma Epidemic” Australia, NZ, UK. ...>20% (and Harlem NYC) Germany, Sweden, Spain.…<10% Prevalence of Asthma: from Eder, Ege and Von Mutius:N E J Med 355;21 2006

  8. New Zealand: very high exposure to both mite and cat allergens. • Wheezing ~20%; mite sensitization dominates risk for asthma*. • Sera from 224 children enrolled in an ISAAC based study on 1,500.$ Cat ownership (50%) was associated with decreased sensitization to cat, but had no effect on mite IgEab • Of the 55 with asthma living in a home with a cat, 34 were sensitized to mite, but not cat. *Sears et al., Clin. Exp. All. 1989: 19:419; *Peat, Li & Woolcock, JACI 1999: 103:1; $Erwin, Crane, Wickens, Barry et al., JACI ’05: 115:74 .

  9. N=112 Erwin,Crane, et al. JACI 119;359 2007 N=112

  10. Hygiene in action: IgE antibodies to dust mite in sera from wheezing (○) and non-wheezing (●) children attending two schools one mile apart in the city of Kumasi, Ghana Ghana Both the prevalence and titer of IgE antibodies to mite were strongly associated with asthma in the affluent school, but not in the poor school. Addo-Yobo, Stevens James, Platts-Mills, and Custovic. ClinExp Allergy; 2011

  11. Der Spiegel 49/2012, p. 138

  12. H h Patients presenting with anaphylaxis, or recurrent urticaria who have IgE specific for alpha-gal have normal lung function no increase in asthma symptoms and normal FeNO. This ectoparasite induced IgE response cross reacts with cat, can make major contributions to total IgE, and appears to be a model for IgE responses to parasites that do not create or increase the risk for asthma. The results explain previous enigmatic IgE antibodies to cat in a Kenyan village and in the ED in Virginia. AJRCCM on line Feb 2012

  13. 1000 100 10 1 0.35 0.35 0.1 Alpha-gal specific IgE titers in patients presenting to clinic with anaphylaxis or asthma AJRCCM 2012,185:723 Alpha-gal specific IgE (IU/mL) Red dots indicate subjects with a history of anaphylactic reactions Limit of detection • x 8 • x 13 • x 58 • x 55 Number <0.35 Cat in home No cat in home Asthma Controls Anaphylaxis, urticaria, or angioedema subjects

  14. All subjects with IgE Ab greater than 0.35 are included in the >0.35 group. Odds ratio (95% CI) is that for asthma compared with control subjects. Commins et al. AJRCCM. 2012;185:723.

  15. Cat extract (and IgE assays) can be made from dander and/or epithelium, which contain many different proteins. Dander Epithelium Tick Bites** Alpha-gal on a a protein (e.g., cat IgA*) Fel d 1 (uteroglobin) 18 kDa Fel d 2 (cat albumin) 69 kDa 200kDa 69 kDa Cross reacts Pork-albumin Cross reacts with Lions! Cross reacts with all Non-primate mammals *Gronlund H, et al. The carbohydrate galactose-α-1,3-galactose is a major IgE-binding epitope on cat IgA. JACI. 2009; 123:1189. **Commins et al JACI 2011 Cat IgA is Fel d 5. See www.allergen.org.

  16. Rural / Urban Comparisons in Ethiopia First Study: Skin tests only related to asthma in the Urban area. Positive skin tests n “Asthma” n Odds ratio for asthma Urban 2,372 98 (4.1%) 88 11 (6.4-18.9) Rural 990 12 (1.2%) 111** - ** None of the skin test positive individuals reported symptoms. Second Study:# Worm load for hookworm but not Ascaris was inversely related to the risk of asthma: O.R. 0.48 (C.I. 0.3-0.8). Conclusions: In the rural area the parasite load may interfere with the relationship between allergy & asthma. In Jimma mite sensitization and exposure strongly related to asthma, i.e. Western model. Yemaneberhan, et al, Lancet 1997, 350:85; # Scrivener et al, Lancet 2001, 358.

  17. San Jose, Costa Rica: Manuel Soto-Quiros, Lydiana Avila, and Peter Heymann Esmeraldas, Ecuador: Phil Cooper

  18. San Jose, Costa Rica: *Values <3.5 IU/ml classified as negative #Histories of wheezing Esmeraldas, Ecuador: Phil Cooper

  19. San Jose, Costa Rica: Manuel Soto-Quiros, Lydiana Avila, and Peter Heymann San Jose Costa Rica Hospital. Acute Wheezing n= 95 Stable asthma n= 63 Controls n= 123 total non wheezing =186 Serum for IgE antibodies by Immunocap Nasal secretions for viral identification by PCR and sequencing. Esmeraldas, Ecuador: Phil Cooper

  20. Costa Rica: Titers of allergen-specific IgE antibody (wheezing children 7-12 years; n=96) *GM values (in blue) include only children whose titers were ≥ 0.35 IU/ml

  21. High Titers of IgEAb to Dust Mite Allergen and the Risk for Wheezing Among Asthmatic Children, in San Jose, Infected with Rhinovirus* Non-wheezing children, n=186; includes 63 with stable asthma and 123 children entering the ER without any history of asthma *Soto-Quirós M, Avila L, Platts-Mills T, Hunt J, Erdman D, … and Heymann PW. J Allergy ClinImmunol. June 2012

  22. High Titers of IgEAb to Dust Mite and the Risk for Wheezing Among Children, in San Jose, Infected with Rhinovirus of clade A or C* * Non-wheezing children, n=186; includes 63 with stable asthma and 123 children entering the ER without any history of asthma *Soto-Quirós M, Avila L, Platts-Mills T, Hunt J, Erdman D, … and Heymann PW. J Allergy ClinImmunol. June 2012

  23. Percent of children by current wheeze status with positive PCR for rhinovirus (RV), enterovirus (HEV), or RSV in San Jose, Costa Rica February (dry): RV October (rainy): RV October (rainy): HEV October (rainy): RSV

  24. Rhinovirus negative Rhinovirus positive Soto-Quirós, Avila, Hunt, Erdmann, Platts-Mills,… and Heymann. JACI 2012

  25. Conclusions and Questions • In many post hygiene countries mite sensitization with high titerIgEab, is the strongest association with asthma. • The faecal particles contain multiple TLR agonists that act as adjuvants, as well as the mite proteins that induce IgE antibodies. • Daily exposure to a few (~50-200) faecal particles may be ideal to induce BHR without the patient being aware of exposure. • Sensitization of the lungs (as judged by IgEab ) and inflammation (as judged by BHR, eosinophils and exhaled NO) are major predictors of asthma exacerbation during rhinovirus infection.

  26. Colleagues: 2006-2013 University of Virginia Scott Commins Libby Kelly Peter Heymann Anubha Tripathi Jake Hosen Sharma Satinover Hayley James Lisa Workman Josh Kennedy Elizabeth Erwin/Ohio Matt Perzanowski/Columbia Gus Litonjua, Harvard Diane Gold, Harvard Africa and Europe Eva Ronmark, Sweden Bo Lundback, Sweden Lucy N’Ganga, Kenya Joseph Odiambo, Kenya Adnan Custovic, Manchester Alpha-Gal Research Christine Chung, Nashville BelooMirakhur, BMS Qinwei Zhou; ImClone Tina Hatley, Bentonville Phil Cooper Ecuador & Liverpool Manuel Soto-Quiros Costa Rica.

  27. Sequential rises in three different allergic diseases 20% Seasonal Allergic Rhinitis Pre-Hygiene ? Pediatric Asthma 2% Peanut Allergy hi 0.2% 1870: Blackley (UK) and Wyman (USA) define hay fever 1911: Noon starts immunotherapy for hay fever 1946: New York initiates ragweed eradication 1969: Increased asthma in Birmingham (UK) schools 1995-2000: Peak of asthma prevalence and severity 2003: First recognition of rise in peanut allergy

  28. Why is the dust mite such a “good” allergen? Does titer of IgE antibodies alter the relationship to asthma? • For dust mite, how much is this a function of exposure? • Does the same relationship apply to other allergens in environments where dust mite is not dominant? • Can you add up the effects of different allergens? • Are all allergens created equal?

  29. Mite Fecal Particlesa Der p 1 ~ 0.2ng….. cysteine protease b,c Der p 2 ~ 0.1ng….. mimics MD2 d Mite DNA………. TLR-9 e Bacterial DNA......TLR-9 Endotoxin………. TLR-4 and MD2 f Chitin…………… TLR-2 and Dectin 1 g a Tovey et al Nature 1982, 289: 592 b Gough et al J.Exp Med 1999. 190:1897 c Wan et al J Clin Invest 1999, 104:123 d Trompette et al, Nature 2009, 457:589 e Satinover et al, JACI 2007 f Eisenbarth et al, J Exp Med. 2002, 196:1645 g Lee et al Current Op. Imm, 2008, 20: 684 Tovey et al Nature 1982 a Ribbon structure of Der f 1, Chrusz et al J Mol Biol 2009

  30. Question 1 Which aspect of exposure to mite allergen is critical to the IgE antibody response? • The faecal particle is 20-30 microns in diameter • Der p 1 is a potent cysteine protease that can cleave CD23, CD25, and open tight junctions • The faecal particle also contains endotoxin (TLR-4), and the peritrophic membrane is made of chitin (TLR-2) • All of the above

  31. Question 2 Which of the following aspects of changes in hygiene that are necessary for an increase in allergic rhinitis is least likely to be true? • Clean water supplies so that enteric infections are controlled • Houses with climate control and electronic media to keep children indoors • Control of helminths in food supplies and/or regular anti-helminthic treatment • Shoes to control hookworm

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