The role of indoor allergens in chronic allergic disease
2007; Elsevier BV; Volume: 119; Issue: 2 Linguagem: Inglês
10.1016/j.jaci.2006.12.647
ISSN1097-6825
Autores Tópico(s)Asthma and respiratory diseases
ResumoIn parallel with extensive changes in lifestyle over the last 50 years, there has been a steady increase in our awareness of the importance of perennial indoor allergens. Although the immune response to these proteins, that is, immediate hypersensitivity, is similar to the response to pollens, the simple temporal relationship to exposure is not obvious. This has created problems in understanding the role of exposure in chronic allergic disease, particularly asthma and atopic dermatitis (AD). Thus, although the patients may be aware of being allergic, for example, sneezing during bed making, they are usually unaware of the relationship between exposure in the home and chronic inflammation in their lungs or skin. The importance of house dust as a source of allergens was known from 1920, but none of the allergens had been studied in any detail before 1965, and without specific allergens, it was difficult to define the role of house dust. Our current understanding of the role of indoor allergens was made possible by a series of major discoveries. First, the identification of IgE by Dr Ishizaka led to the development of assays for IgE Abs that today are fully quantitiative.1Ishizaka K. Ishizaka T. Hornbrook M.M. Allergen-binding activity of gamma-E, gamma-G, and gamma-A antibodies in sera from atopic patients. In vitro measurements of reaginic antibody.J Immunol. 1967; 98: 490-501PubMed Google Scholar, 2Wide L. Bennich H. Johansson S.G. Diagnosis of allergy by an in vitro test for allergen antibodies.Lancet. 1967; 2: 1105-1107Abstract PubMed Google Scholar Second, dust mites of the genus Dermatophagoides, and in particular their fecal pellets, were identified as a major source of allergens in the home.3Voorhorst R. Spieksma R. Varekamp H. Leupen M.J. Lyklema A.W. The house dust mite (Dermatophagoides pteronyssinus) and the allergens it produces: identity with the house dust allergen.J Allergy. 1967; 39: 325Abstract Full Text PDF Scopus (375) Google Scholar, 4Tovey E. Chapman M.D. Platts-Mills T.A.E. Mite faeces are a major source of house dust allergens.Nature. 1981; 289: 592Crossref PubMed Scopus (474) Google Scholar Third, the demonstration that allergen exposure can be an important cause of nonspecific bronchial hyperreactivity led to evidence that decreasing bronchial hyperreactivity should be a target of allergen avoidance.5Altounyan R.E.C. Changes in histamine and atropine responsiveness as a guide to diagnosis and evaluation of therapy in obstructive airways disease.in: Pepys J. Edwards A.M. Disodium chromoglycate in allergic airways disease. Butterworth, London1970: 47-55Google Scholar, 6Platts-Mills T.A. Tovey E.R. Mitchell E.B. Moszoro H. Nock P. Wilkins S.R. Reduction of bronchial hyperreactivity during prolonged allergen avoidance.Lancet. 1982; 2: 675-678Abstract PubMed Scopus (576) Google Scholar Finally came the evidence that the increase in asthma had occurred primarily among patients with allergy.7Sporik R. Holgate S.T. Platts-Mills T.A. Cogswell J.J. Exposure to house-dust mite allergen (Der p 1) and the development of asthma in childhood: a prospective study.N Engl J Med. 1990; 323: 502-507Crossref PubMed Scopus (1474) Google Scholar, 8Platts-Mills T.A.E. de Weck A.L. Dust mite allergens and asthma: a worldwide problem.J Allergy Clin Immunol. 1989; 83: 416-427Abstract Full Text PDF PubMed Scopus (563) Google Scholar, 9Platts-Mills T.A. Asthma severity and prevalence: an ongoing interaction between exposure, hygiene, and lifestyle.PLoS Med. 2005; 2: e34Crossref PubMed Scopus (34) Google Scholar Taken together, the studies on exposure, immune responses, epidemiology, and avoidance strongly supported a causal relationship between chronic exposure to indoor allergens and asthma.8Platts-Mills T.A.E. de Weck A.L. Dust mite allergens and asthma: a worldwide problem.J Allergy Clin Immunol. 1989; 83: 416-427Abstract Full Text PDF PubMed Scopus (563) Google Scholar, 9Platts-Mills T.A. Asthma severity and prevalence: an ongoing interaction between exposure, hygiene, and lifestyle.PLoS Med. 2005; 2: e34Crossref PubMed Scopus (34) Google Scholar During the 1970s, Marsh and his colleagues in Baltimore calculated the quantity of allergen in individual pollen grains and estimated that the quantity inhaled was ∼1 μg/y. At that time, many different names were in use for allergens, such as Cat 1, Antigen p 1, Antigen E, and Rye 1. It was David Marsh who argued strongly for the system that was accepted by the International Union of Immunological Societies and is now used worldwide: www.allergen.org (see Chapman et al10Chapman M.D. Pomes A. Breiteneder H. Ferreira F. Nomenclature and structural biology of allergens.J Allergy Clin Immunol. 2007; 119: 416-422Abstract Full Text Full Text PDF Scopus (226) Google Scholar in this issue of the Journal). A major problem in investigating the indoor environment is that the particles carrying allergens are not identifiable under the light microscope, so there is no indoor equivalent of the pollen count. Thus, measurement of exposure to allergens inside homes depends on sensitive immunoassays, which can also play an important role in standardizing allergen extracts. mAbs to allergens provide unlimited supplies of high-affinity antibodies and assays that can measure down to a few nanograms of protein. However, the exquisite specificity of the mAb can create problems if the extract includes isoallergens that are not recognized by the specific antibody (see van Rhee11van Ree R. Indoor allergens: relevance of major allergen measurements and standards.J Allergy Clin Immunol. 2007; 119: 270-277Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar in this issue of the Journal). The only way in which protein allergens can become airborne is on particles, and the aerodynamic properties of these particles define how allergens are inhaled. Dust mite fecal particles, the debris from dead insects, dander particles from the skin of dogs or cats, and particles of dust contaminated by proteins from rodent urine are each distinct in their characteristics. Both cockroach and dust mite allergens fall rapidly after disturbance. Thus, all measurements of airborne exposure require an element of domestic disturbance (eg, vacuum cleaning, bed making, and so forth), and the concentration of allergen in floor or reservoir dust provides a simpler surrogate measurement of exposure.12Platts-Mills T.A. Vervloet D. Thomas W.R. Aalberse R.C. Chapman M.D. Indoor allergens and asthma: report of the Third International Workshop.J Allergy Clin Immunol. 1997; 100: S2-S24Abstract Full Text Full Text PDF PubMed Scopus (667) Google Scholar Estimates of the quantity of mite allergen inhaled are around 10 ng/d, which translates to ∼50 fecal particles/d. By contrast, exposure to animal dander allergens is on smaller particles that remain airborne for prolonged periods after disturbance. For these allergens, estimated exposure is closer to 1.0 μg/d.13Platts-Mills J.A. Custis N.J. Woodfolk J.A. Platts-Mills T.A. Airborne endotoxin in homes with domestic animals: implications for cat-specific tolerance.J Allergy Clin Immunol. 2005; 116: 384-389Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar Deposition of inhaled particles depends on the route (ie, nasal compared with oral), the velocity of the airstreams, and the particle size. Nasal deposition approaches 100% for all particles >2 μm in diameter. By contrast, during gentle mouth breathing, lung deposition may be as high as 30% for particles between 2 and 5 μm and ∼10% for particles of 10 to 30 μm in diameter.14Svartengren M. Falk R. Linnman L. Philipson K. Camner P. Deposition of large particles in human lung.Exp Lung Res. 1987; 12: 75-88Crossref PubMed Scopus (55) Google Scholar The contrast between natural exposure to a small number of "large particles" per day and bronchial provocation with ∼108 droplets of 2 μm diameter over a period of 10 minutes may explain why patients are not aware of short-term changes in lung function in relation to mite or cockroach exposure. For many years, we considered that the mite fecal particle was simply an efficient method of delivering a high concentration of foreign antigens. When it became clear that Der p 1 was an active cystein protease, several groups focused on understanding the relevance of enzymatic activity to immune responses.10Chapman M.D. Pomes A. Breiteneder H. Ferreira F. Nomenclature and structural biology of allergens.J Allergy Clin Immunol. 2007; 119: 416-422Abstract Full Text Full Text PDF Scopus (226) Google Scholar, 15Wan H. Winton H.L. Soeller C. Tovey E.R. Gruenert D.C. Thompson P.J. et al.Der p 1 facilitates transepithelial allergen delivery by disruption of tight junctions.J Clin Invest. 1999; 104: 123-133Crossref PubMed Scopus (633) Google Scholar, 16Ghaemmaghami A.M. Robins A. Gough L. Sewell H.F. Shakib F. Human T cell subset commitment determined by the intrinsic property of antigen: the proteolytic activity of the major mite allergen Der p 1 conditions T cells to produce more IL-4 and less IFN-gamma.Eur J Immunol. 2001; 31: 1211-1216Crossref PubMed Scopus (82) Google Scholar However, the fecal particles also carry Der p 2, which is not an enzyme; endotoxin; bacterial DNA; and mite DNA, which, like bacterial DNA, is relatively unmethylated. Unmethylated DNA contains immunostimulatory sequence motifs that are recognized by human Toll-like receptor (TLR)–9.17Horner A.A. Toll-like receptor ligands and atopy: a coin with at least two sides.J Allergy Clin Immunol. 2006; 117: 1133-1140Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Thus, mite allergens are being delivered to the respiratory tract in the context of 3 potential adjuvants: endotoxin (TLR-4), mite DNA (TLR-9), and bacterial DNA (TLR-9). By contrast, cat allergen is carried on smaller particles (that stay airborne) containing cat DNA (which, like human DNA, is fully methylated), and the dominant allergen, Fel d 1 has no enzymic activity.18Kaiser L. Gronlund H. Sandalova T. Ljunggren H.G. vanHage-Hamsten M. Achour A. et al.The crystal structure of the major cat allergen Fel d 1, a member of the secretoglobin family.J Biol Chem. 2003; 278: 37730-37735Crossref PubMed Scopus (91) Google Scholar To extend the contrast further, this cat allergen has structural homology with Clara cell secretory protein, which has immunomodulatory activity.18Kaiser L. Gronlund H. Sandalova T. Ljunggren H.G. vanHage-Hamsten M. Achour A. et al.The crystal structure of the major cat allergen Fel d 1, a member of the secretoglobin family.J Biol Chem. 2003; 278: 37730-37735Crossref PubMed Scopus (91) Google Scholar, 19Mandal A.K. Ray R. Zhang Z. Chowdhury B. Pattabiraman N. Mukherjee A.B. Uteroglobin inhibits prostaglandin F2alpha receptor-mediated expression of genes critical for the production of pro-inflammatory lipid mediators.J Biol Chem. 2005; 280: 32897-32904Crossref PubMed Scopus (15) Google Scholar IgE antibodies are part of an immune response that also includes IgG1, IgG4, and IgA antibody as well as T cells. It is important to understand that IgG4 antibodies are functionally, if not in fact, monovalent and may well play an important role in preventing immune complex formation.20Aalberse R.C. Schuurman J. IgG4 breaking the rules.Immunology. 2002; 105: 9-13Crossref PubMed Scopus (384) Google Scholar The gene for IgG4 lies directly upstream from the gene for IgE, and the expression of these 2 genes is equally dependant on the cytokine IL-4. Thus, the production of the 2 isotypes (IgE and IgG4) that are characteristic of the response to allergens is dependent on TH2 cells. It is possible to evaluate in vitro responses of circulating CD3+CD4+ cells to allergens and peptides in culture, but it is more difficult to define how they contribute to in vivo antibody responses.21Reefer A.J. Carneiro R.M. Custis N.J. Platts-Mills T.A. Sung S.S. Hammer J. et al.A role of IL-10 mediated HLA-DR7 restricted T cell dependant events in development of the modified Th2 response to cat allergen.J Immunol. 2004; 172: 2763-2772PubMed Google Scholar, 22Aalberse R.C. Platts-Mills T.A. How do we avoid developing allergy: modifications of the TH2 response from a B-cell perspective.J Allergy Clin Immunol. 2004; 113: 983-986Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Furthermore, the identification of different subsets of T-regulatory cells has made the situation more complex21Reefer A.J. Carneiro R.M. Custis N.J. Platts-Mills T.A. Sung S.S. Hammer J. et al.A role of IL-10 mediated HLA-DR7 restricted T cell dependant events in development of the modified Th2 response to cat allergen.J Immunol. 2004; 172: 2763-2772PubMed Google Scholar (see Woodfolk23Woodfolk J.A. T-cell responses to allergens.J Allergy Clin Immunol. 2007; 119: 281-295Abstract Full Text Full Text PDF Scopus (105) Google Scholar in this edition). Persistent high-dose exposure to cat allergens, that is, living with a cat in the house, can give rise to a form of tolerance that includes IgG4 antibody without IgE antibody.24Platts-Mills T. Vaughan J. Squillance S. Woodfolk J. Sporik R. Sensitization, asthma and a modified Th2 response in children exposed to cat allergen: a population based cross sectional study.Lancet. 2001; 357: 752-756Abstract Full Text Full Text PDF PubMed Scopus (748) Google Scholar, 25Perzanowski M.S. Ronmark E. Platts-Mills T.A. Lundback B. Effect of cat and dog ownership on sensitization and development of asthma among preteenage children.Am J Respir Crit Care Med. 2002; 166: 696-702Crossref PubMed Scopus (263) Google Scholar A recent report on serological responses to rat urinary allergens has confirmed that a "modified TH2 response" can also occur among animal handlers.26Jeal H. Draper A. Harris J. Taylor A.N. Cullinan P. Jones M. Modified Th2 responses at high-dose exposures to allergen: using an occupational model.Am J Respir Crit Care Med. 2006; 174: 21-25Crossref PubMed Scopus (71) Google Scholar The reason for calling the response to cat, dog, mouse, or rat allergens a "modified TH2 response" is both that expression of IgG4 is IL-4–dependent and that this response does not include evidence for a TH1 response.24Platts-Mills T. Vaughan J. Squillance S. Woodfolk J. Sporik R. Sensitization, asthma and a modified Th2 response in children exposed to cat allergen: a population based cross sectional study.Lancet. 2001; 357: 752-756Abstract Full Text Full Text PDF PubMed Scopus (748) Google Scholar, 25Perzanowski M.S. Ronmark E. Platts-Mills T.A. Lundback B. Effect of cat and dog ownership on sensitization and development of asthma among preteenage children.Am J Respir Crit Care Med. 2002; 166: 696-702Crossref PubMed Scopus (263) Google Scholar, 26Jeal H. Draper A. Harris J. Taylor A.N. Cullinan P. Jones M. Modified Th2 responses at high-dose exposures to allergen: using an occupational model.Am J Respir Crit Care Med. 2006; 174: 21-25Crossref PubMed Scopus (71) Google Scholar, 27Matsui E.C. Diette G.B. Krop E.J. Aalberse R.C. Smith A.L. Curtin-Brosnan J. et al.Mouse allergen specific immunoglobulin G and immunoglobulin G4 and allergic symptoms in immunoglobulin E-sensitized laboratory animal workers.Clin Exp Allergy. 2005; 35: 1347-1353Crossref PubMed Scopus (49) Google Scholar The reason for regarding it as a form of tolerance is that individuals who have allergen-specific IgG4 antibody without IgE antibody do not experience symptoms. The mechanisms by which high exposure to one type of allergen could give rise to tolerance are not clear. However, it is known that culturing human tonsil lymphocytes with IL-4 and IL-10 enhances IgG4 production and can suppress IgE compared with cultures with IL-4 alone.28Jeannin P. Lecoanet S. Delneste Y. Gauchat J.F. Bonnefoy J.Y. IgE versus IgG4 production can be differentially regulated by IL-10.J Immunol. 1998; 160: 3555-3561PubMed Google Scholar In addition, in vitro T-cell responses to peptides of Fel d 1 include high levels of IL-10 production.21Reefer A.J. Carneiro R.M. Custis N.J. Platts-Mills T.A. Sung S.S. Hammer J. et al.A role of IL-10 mediated HLA-DR7 restricted T cell dependant events in development of the modified Th2 response to cat allergen.J Immunol. 2004; 172: 2763-2772PubMed Google Scholar The IgE antibody response to cat allergens is not only less common than the response to dust mites or pollen but also lower in titer.29Erwin E.A. Wickens K. Custis N.J. Siebers R. Woodfolk J. Barry D. et al.Cat and dust mite sensitivity and tolerance in relation to wheezing among children raised with high exposure to both allergens.J Allergy Clin Immunol. 2005; 115: 74-79Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Erwin et al30Erwin E.A. Ronmark E. Wickens K. Perzanowski M. Barry D. Pollart S.M. et al.Contribution of dust and cat specific IgE to total IgE: relevance to asthma prevalence.J Allergy Clin Immunol. 2007; 119: 361-367Abstract Full Text Full Text PDF Scopus (72) Google Scholar have gone further to argue that IgE antibody responses to dust mite allergens can make a major contribution to elevated levels of total IgE, whereas responses to cat allergens do not. The fact that specific IgE antibody responses can be high enough to increase total serum IgE was first pointed out by Gleich and Jacob31Gleich G.J. Jacob G.L. Immunoglobulin E antibodies to pollen allergens account for high percentages of total immunoglobulin E protein.Science. 1975; 190: 1106-1108Crossref PubMed Scopus (68) Google Scholar in 1975. In fact, the titers of IgE antibody to dust mite in some sera are 50 to 300 IU/mL, which makes it obvious that they contribute to total IgE.30Erwin E.A. Ronmark E. Wickens K. Perzanowski M. Barry D. Pollart S.M. et al.Contribution of dust and cat specific IgE to total IgE: relevance to asthma prevalence.J Allergy Clin Immunol. 2007; 119: 361-367Abstract Full Text Full Text PDF Scopus (72) Google Scholar Taking our results further, it is possible to identify many sera in which greater than 50% of the total IgE is explained by specific IgE antibody responses.32Platts-Mills TAE, Naccara L, Satinover SM, Litonjua AA, Phipatanakul W, Carter MC, et al. Relevance and titer of IgE antibodies to mouse urinary proteins. J Allergy Clin Immunol 2007. In press.Google Scholar Taking the properties of different allergens together, it appears that (1) lower prevalence of IgE antibody responses, (2) lower titers of IgE antibody, and (3) the appearance of the tolerant "modified TH2" response are most common with cat, dog, mouse, and rat allergens. The obvious feature of these animals is that they are all mammals. This has led to the hypothesis that the immune response to allergens derived from a mammalian source is different from the response to arthropod, pollen, or fungal allergens (Table I). An obvious feature of mammalian proteins is that they are evolutionarily closer to human proteins and thus that they may be inherently less immunogenic (Fig 1).33Dawkins R. The ancestor's tale. Houghton Mifflin, New York2004Google ScholarTable IComparison of mammalian, arthropod, and other allergensMammals∗Evolutionary distance is length of time (in millions of years) since there was a common ancestor with human beings. Birds and reptiles separated from mammals 310 million years ago. Dates derived from Dawkins.33ArthropodsPollens/fungiEvolutionary distance∼75600>1000Major allergensFel d 1Der p 1†Der p 1 is a cystein protease; Bla g 2 is homologous to an enzyme but may not be active.Lol p 1Can f 1Bla g 2Bet v 1Mus m 1Der p 2DNAMethylatedUnmethylatedMixedDaily exposure∼1.0 μg2-10 ng2-10 ngImmune response IgE prevalence5% to 15%As high as 35%As high as 30% IgE antibody titerGenerally lowAs high as 300 IU/mL‡IgE response high enough to contribute to total IgE.Can be very high‡IgE response high enough to contribute to total IgE. Tolerance§Tolerance as judged by an IgG and IgG4 antibody response without IgE antibody, and with no effect on total serum IgE.CommonUnusualUnusual∗ Evolutionary distance is length of time (in millions of years) since there was a common ancestor with human beings. Birds and reptiles separated from mammals 310 million years ago. Dates derived from Dawkins.33Dawkins R. The ancestor's tale. Houghton Mifflin, New York2004Google Scholar† Der p 1 is a cystein protease; Bla g 2 is homologous to an enzyme but may not be active.‡ IgE response high enough to contribute to total IgE.§ Tolerance as judged by an IgG and IgG4 antibody response without IgE antibody, and with no effect on total serum IgE. Open table in a new tab In keeping with the view that evolutionary distance matters, there are some human proteins that are not immunogenic in mice. For example, with some of the TLRs, mAbs are best raised in chickens.34Zhu L. van de Lavoir M.C. Albanese J. Beenhouwer D.O. Cararelli P.M. Cuison S. et al.Production of human monoclonal antibody in eggs of chimeric chickens.Nat Biotechnol. 2005; 9: 1159-1169Crossref Scopus (179) Google Scholar The most recent common ancestor between human beings and chickens lived ∼300 million years ago.33Dawkins R. The ancestor's tale. Houghton Mifflin, New York2004Google Scholar, 34Zhu L. van de Lavoir M.C. Albanese J. Beenhouwer D.O. Cararelli P.M. Cuison S. et al.Production of human monoclonal antibody in eggs of chimeric chickens.Nat Biotechnol. 2005; 9: 1159-1169Crossref Scopus (179) Google Scholar It may be relevant that the DNA of all vertebrates is methylated, and also that some carbohydrate determinants on nonmammalian proteins can stimulate innate immune response receptors.35Tweedie S. Charlton J. Clark V. Bird A. Methylation of genomes and genes at the invertebrate-vertebrate boundary.Mol Cell Biol. 1997; 17: 1469-1475PubMed Google Scholar, 36Shreffler W.G. Castro R.R. Kucuk Z.Y. Charlop-Powers Z. Grishina G. Yoo S. et al.The major glycoprotein allergen from Arachis hypogaea, Ara h 1, is a ligand of dendritic cell-specific ICAM-grabbing nonintegrin and acts as a Th2 adjuvant in vitro.J Immunol. 2006; 177: 3677-3685PubMed Google Scholar However, equally important is the fact that ambient exposure to mammalian allergens is in general much higher. Although it has been proposed that the effect of pets can be explained by increased indoor endotoxin, the bulk of published experiments do not support this.13Platts-Mills J.A. Custis N.J. Woodfolk J.A. Platts-Mills T.A. Airborne endotoxin in homes with domestic animals: implications for cat-specific tolerance.J Allergy Clin Immunol. 2005; 116: 384-389Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 37Ownby D.R. Johnson C.C. Peterson E.L. Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age.JAMA. 2002; 288: 963-972Crossref PubMed Scopus (604) Google Scholar, 38Sohy C. Lieutier-Colas F. Casset A. Meyer P. Pauli G. Pons F. et al.Dust and airborne endotoxin exposure in dwellings in the Strasbourg metropolitan area (France).Allergy. 2005; 60: 541-542Crossref PubMed Scopus (17) Google Scholar Another apparent feature of the immune response to mammalian allergens is that there are only a small number of significant or major allergens from each source. By contrast, responses to dust mite or cockroach allergens that occur at very low exposure39Sporik R. Squillace S.P. Ingram J.M. Rakes G.P. Honsinger R.W. Platts-Mills T.A. Mite, cat and cockroach exposure, allergen sensitization and asthma in children: a case control study of three schools.Thorax. 1999; 54: 675-680Crossref PubMed Scopus (200) Google Scholar often include IgE antibodies to many different proteins (see www.allergen.org). Perhaps the extreme examples of this difference are dust mite and dog. Despite large quantities of the dog allergen Can f 1 in homes, schools, and other public buildings, IgE antibody responses to dog allergens are less common and lower in titer than for many other allergens.30Erwin E.A. Ronmark E. Wickens K. Perzanowski M. Barry D. Pollart S.M. et al.Contribution of dust and cat specific IgE to total IgE: relevance to asthma prevalence.J Allergy Clin Immunol. 2007; 119: 361-367Abstract Full Text Full Text PDF Scopus (72) Google Scholar Furthermore, only 2 major dog allergens have been defined. At least 14 allergens from Dermatophagoides pteronysinus have been defined, and many of these can give rise to high titer IgE antibody. How much the argument can be extended to pollens and fungi is not clear. However, the original results from the Mayo Clinic identified IgE antibody to ragweed allergens as a large proportion of total IgE.31Gleich G.J. Jacob G.L. Immunoglobulin E antibodies to pollen allergens account for high percentages of total immunoglobulin E protein.Science. 1975; 190: 1106-1108Crossref PubMed Scopus (68) Google Scholar We have recently found that IgE antibody responses to grass pollen and to Lol p 1 in sera from patients presenting with asthma during the pollen season in northern California can make a significant contribution to total serum IgE (Erwin E et al, unpublished data, June 2006). Over the period 1918 to 1990, the Asian ladybug, Harmonia axyridis, was repeatedly introduced into the United States as a biological control for aphids. In the fall, they seek shelter from the cold and have become a major pest in houses over much of the East Coast and Midwest. In 1998, Yarbrough et al40Yarbrough J.A. Armstrong J.L. Blumberg M.Z. Phillips A.E. McGahee E. Dolen W.K. Allergic rhinoconjunctivitis caused by Harmonia axyridis (Asian lady beetle Japanese Beetle, or lady bug).J Allergy Clin Immunol. 1999; 104: 704-705Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar reported 2 cases of rhinitis apparently caused by allergy to ladybugs. Since then, reports have become common (Fig 2).41Albright D.D. Jordan-Wagner D. Napoli D.C. Parker A.L. Quance-Fitch F. Whisman B. et al.Multicolored Asian lady beetle hypersensitivity: a case series and allergist survey.Ann Allergy Asthma Immunol. 2006; 97: 521-527Abstract Full Text PDF PubMed Scopus (17) Google Scholar In this issue of the Journal, Nakazawa et al42Nakazawa T. Satinover S.M. Naccara L. Carter M. Goddard L. Dragulev B.P. et al.Asian ladybugs (Harmonia axyridis): a new seasonal indoor allergen.J Allergy Clin Immunol. 2007; 119: 421-427Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar report on the first purification and characterization of proteins from this new seasonal indoor allergen. The important features of the results are (1) the introduction of a new species in homes has led to sensitization of adults within a few years; (2) IgE antibody responses to proteins from this beetle can be high in titer; and (3) in keeping with their evolutionary distance, the allergens of this insect are highly immunogenic in human beings but will cross-react with proteins from Blatella germanica.42Nakazawa T. Satinover S.M. Naccara L. Carter M. Goddard L. Dragulev B.P. et al.Asian ladybugs (Harmonia axyridis): a new seasonal indoor allergen.J Allergy Clin Immunol. 2007; 119: 421-427Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar When Coca first used the term atopic dermatitis, he meant both that the patients were allergic and that allergens played an important role in the disease. Tuft43Tuft L.A. Importance of inhalant allergens in atopic dermatitis.J Invest Dermatol. 1949; 12: 211PubMed Scopus (75) Google Scholar took the argument 1 step further, emphasizing the importance of inhalant allergens in patients older than 7 years and reporting the positive effects of avoidance as a treatment. However, arguments over the role that allergens played in the disease continued. In 1982, the atopy patch test was developed to prove that allergens could cause an eczematous response.44Mitchell E.B. Chapman M.D. Pope F.M. Crow J. Jouhal S.S. Platts-Mills T.A. Basophils in allergen-induced patch test sites in atopic dermatitis.Lancet. 1982; 1: 127Abstract PubMed Scopus (379) Google Scholar There are 2 main reasons why the role of allergens in the disease remains controversial.45Akdis C.A. Adkis M. Bieber T. Bindslev-Jensen C. Boguniewicz M. Eigenmann P. et al.Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergy and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report.Allergy. 2006; 61: 969-987Crossref PubMed Scopus (349) Google Scholar•There are significant numbers of nonatopic patients who present with a rash that has many features of AD.•In the severe forms of the disease, multiple factors contribute to the disease. The etiologic factors include food allergens, contact sensitivity to ointments, skin infection with both bacteria and yeasts, and inhalant allergens.45Akdis C.A. Adkis M. Bieber T. Bindslev-Jensen C. Boguniewicz M. Eigenmann P. et al.Diagnosis and treatment of atopic dermatitis in children and adults: European Academy of Allergy and Clinical Immunology/American Academy of Allergy, Asthma and Immunology/PRACTALL Consensus Report.Allergy. 2006; 61: 969-987Crossref PubMed Scopus (349) Google Scholar, 46Salt B.H. Baguniewicz M. Leung D.Y.M. Severe refractory atopic dermatitis in adults is highly atopic.J Allergy Clin Immunol. 2007; 119: 508-509Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar The letter from Salt et al46Salt B.H. Baguniewicz M. Leung D.Y.M. Severe refractory atopic dermatitis in adults is highly atopic.J Allergy Clin Immunol. 2007; 119: 508-509Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar in this issue of the Journal strongly reinforces the idea that allergen sensitization is almost universal in the severe forms of the disease. Interestingly, there are striking differences in the circulating T cells in patients with AD that relate to their cell surface markers, their regulatory activity, and their in vitro responses to allergens.23Woodfolk J.A. T-cell responses to allergens.J Allergy Clin Immunol. 2007; 119: 281-295Abstract Full Text Full Text PDF Scopus (105) Google Scholar, 47Homey B. Steinhoff M. Ruzicka T. Leung D.Y. Cytokines and chemokines orchestrate atopic skin inflammation.J Allergy Clin Immunol. 2006; 118: 178-189Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar, 48Carneiro R. Reefer A. Wilson B. Hammer J. Platts-Mills T. Custis N. et al.T cell epitope-specific defects in the immune response to cat allergen in patients with atopic dermatitis.J Invest Dermatol. 2004; 122: 927-936Crossref PubMed Scopus (23) Google Scholar The results provide insight into control mechanisms in AD, but also raise major questions about the role of T-regulatory cells in vivo. 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Many of the subjects who are tolerant to cats or dogs have had an immune response that includes IgG1 and IgG4 antibody as well as T cells. However, this immune response on its own carries no risk of allergic symptoms and has no effect on total serum IgE. The clear implication is that high exposure to cat allergens does not give rise to symptoms unless the patient develops IgE antibody.
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