An exhaustive search for parasite allergens that may cross-react with aeroallergens has been performed. We have identified a number of parasite antigens and the allergens orthologues and have studied the IgE and IgG responses to these. We have demonstrated unequivocally that parasite infections induced both parasite-specific IgE and IgE that interacts with environmental allergens to which the parasite antigens are closely related. Specifically,we investigates the cross-reactivity between a major glutathione-S transferase allergen of cockroach (Bla g 5) and the glutathione-S transferase of Wuchereria bancrofti (WbGST), a major lymphatic filarial pathogen of humans. We compared the molecular and structural similarities between Bla g 5 and WbGST by in silico analysis and by linear epitope mapping. The levels of IgE, IgG, and IgG(4) antibodies were measured in filarial-infected and filarial-uninfected patients. Mice were infected with Heligmosomoides bakeri, and their skin was tested for cross-reactive allergic responses. We were able to show that these 2 proteins are 30% identical at the amino acid level with remarkable similarity in the N-terminal region and overall structural conservation based on predicted 3-dimensional models. Filarial infection was associated with IgE, IgG, and IgG(4) anti-Bla g 5 antibody production, with a significant correlation between antibodies (irrespective of isotype) to Bla g 5 and WbGST. Preincubation of sera from cockroach-allergic subjects with WbGST partially depleted (by 50%-70%) anti-Bla g 5 IgE, IgG, and IgG(4) antibodies. IgE epitope mapping of Bla g 5 revealed that 2 linear N-terminal epitopes are highly conserved in WbGST corresponding to Bla g 5 peptides partially involved in the inhibition of WbGST binding. Finally, mice infected with H bakeri developed anti-HbGST IgE and showed immediate-type skin test reactivity to Bla g 5. We next used an exhaustive bioinformatics approach to understand the interface between parasite proteins and allergenicty. Because the current paradigm suggests that structural homology of allergenic proteins to microbial (particularly helminths) or human proteins underlie their allergenic nature, we examined 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.

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Santiago, Helton da Costa; Nutman, Thomas B (2016) Role in Allergic Diseases of Immunological Cross-Reactivity between Allergens and Homologues of Parasite Proteins. Crit Rev Immunol 36:1-11
Santiago, Helton C; Nutman, Thomas B (2016) Human Helminths and Allergic Disease: The Hygiene Hypothesis and Beyond. Am J Trop Med Hyg 95:746-753
Gazzinelli-Guimarães, Pedro H; Bonne-Année, Sandra; Fujiwara, Ricardo T et al. (2016) Allergic Sensitization Underlies Hyperreactive Antigen-Specific CD4+ T Cell Responses in Coincident Filarial Infection. J Immunol 197:2772-9
Santiago, Helton da Costa; Ribeiro-Gomes, Flávia L; Bennuru, Sasisekhar et al. (2015) Helminth infection alters IgE responses to allergens structurally related to parasite proteins. J Immunol 194:93-100
O'Connell, Elise M; Nutman, Thomas B (2015) Eosinophilia in Infectious Diseases. Immunol Allergy Clin North Am 35:493-522
Herrick, Jesica A; Metenou, Simon; Makiya, Michelle A et al. (2015) Eosinophil-associated processes underlie differences in clinical presentation of loiasis between temporary residents and those indigenous to Loa-endemic areas. Clin Infect Dis 60:55-63
Makiya, Michelle A; Herrick, Jesica A; Khoury, Paneez et al. (2014) Development of a suspension array assay in multiplex for the simultaneous measurement of serum levels of four eosinophil granule proteins. J Immunol Methods 411:11-22
Mejia, Rojelio; Nutman, Thomas B (2012) Evaluation and differential diagnosis of marked, persistent eosinophilia. Semin Hematol 49:149-59
Santiago, Helton C; LeeVan, Elyse; Bennuru, Sasisekhar et al. (2012) Molecular mimicry between cockroach and helminth glutathione S-transferases promotes cross-reactivity and cross-sensitization. J Allergy Clin Immunol 130:248-56.e9
Santiago, Helton da Costa; Bennuru, Sasisekhar; Ribeiro, Jose M C et al. (2012) Structural differences between human proteins and aero- and microbial allergens define allergenicity. PLoS One 7:e40552

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