Structural Differences between Human Proteins and Aero- and Microbial Allergens Define Allergenicity Helton da Costa Santiago1, Sasisekhar Bennuru1, Jose´ M. C. Ribeiro2, Thomas B. Nutman1*¤ 1 The Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America, 2 Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America Abstract The current paradigm suggests that structural homology of allergenic proteins to microbial (particularly helminths) or human proteins underlie their allergenic nature. To examine systematically the structural relationships among allergens and proteins of pathogens (helminths, protozoans, fungi and bacteria) as they relate to allergenicity, we compared the amino acid sequence of 499 molecularly-defined allergens with the predicted proteomes of fifteen known pathogens, including Th2 inducing helminths and Th1-inducing protozoans, and humans using a variety of bioinformatic tools. Allergenicity was assessed based on IgE prevalences using publicly accessible databases and the literature. We found multiple homologues of common allergens among proteins of helminths, protozoans, fungi and humans, but not of bacteria. In contrast, 187 allergens showed no homology with any of the microbial genera studied. Interestingly, allergens without homologues or those with limited levels of sequence conservation were the most allergenic displaying high IgE prevalences in the allergic population. There was an inverse relationship between allergenicity and amino acid conservation levels with either parasite, including helminth, or human proteins. Our results suggest that allergenicity may be associated with the relative ‘‘uniqueness’’ of an antigen, i.e. immunogenicity, while similarity would lead to immunological tolerance. Citation: Santiago HdC, Bennuru S, Ribeiro JMC, Nutman TB (2012) Structural Differences between Human Proteins and Aero- and Microbial Allergens Define Allergenicity. PLoS ONE 7(7): e40552. doi:10.1371/journal.pone.0040552 Editor: Jacques Zimmer, Centre de Recherche Public de la Sante´ (CRP-Sante´), Luxembourg Received April 13, 2012; Accepted June 8, 2012; Published July 18, 2012 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Funding: This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funders of this research had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: tnutman@niaid.nih.gov ¤ Current address: Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, Brazil Introduction There is a relative paucity of knowledge about what confers allergenicity [1,2] to a given protein antigen. Nonetheless it has been observed that allergens are found within only 2% of all the known protein families [3] suggesting that not only host factors [4,5] define the development of allergies, but also some intrinsic factors of the allergens themselves may be associated with their allergenic properties. One common feature that defines allerge- nicity is the ability to induce measurable levels of allergen-specific IgE. It is the cross-linking of this IgE bound to FceR on the surface of mast cells and basophils that triggers the allergic reaction. However, the ability of a protein, or factor, to induce IgE is governed by the production of IL4, IL5 and IL13 (Th2 polarization) by T cells. Whether allergens per se have intrinsic properties required to polarize toward Th2-dominant response is still a matter of debate [6]. For example, some allergens, such as papain (an allergen of papaya, Car p 1) [7], and the helminth proteins, S. mansoni Omega 1 [8,9] and a particular set of S. mansoni glycoproteins [10,11], have been shown capable to cause Th2 polarization whereas for the majority of allergens or allergenic helminth proteins there is an extreme lack of information. Understanding the nature of allergenicity should provide new insights into therapy for and prevention of allergic diseases, conditions that are becoming increasingly more prevalent. It has been observed that the increases in the prevalence of allergies throughout the world may be related to the increasingly cleaner environment and the relative availability of anti-microbials (e.g. antibiotics). Indeed the ‘‘Hygiene Hypothesis’’ suggests that the prevalence of allergic diseases is inversely associated with the prevalence of infectious diseases [12]. For example, certain viral [13], bacterial [14] and protozoan [15] infections are thought to be associated with protection from allergic diseases in both humans and experimental models. In addition, there is even more compelling evidence that helminth (worm) infections can also prevent the development of atopic diseases (reviewed in [16]). Interestingly, while viral, bacterial and protozoan infections can skew the immune response away from a Th2-dominated CD4+ T cell response – which underlies the development of allergy – acute (or early) helminth infection, in contrast, can favor Th2 responses with production of IL-4, IL-5 and IL-13 and large amounts of pro- allergenic IgE [17]. This early, type-2 dominated immune response [18,19,20] is likely to promote rather than attenuate atopy. Immunological cross-reactivity among common allergens and helminth protein homologues has also been shown to contribute to the allergic sensitization that has been associated with acute helminth infection [21]. Indeed, there is clearly IgE cross-reactivity among helminth and aeroallergenic tropomyosins felt to reflect PLoS ONE | www.plosone.org 1 July 2012 | Volume 7 | Issue 7 | e40552