Tolerance to Self and Allergenicity Figure 1. Allergens display large number of homologues in the genomes of helminths, protozoa and fungi. A, The number of homologues; B, the number of allergen families (AllFams) with homologues; and C, the frequency distribution of the homologues binned by the level of identity were assessed between allergens and the predicted proteomes of various microbial genera. Each dot (A and B) or spike (C) represents each microbe listed. D, Identity level between allergens and microbial pathogen proteins. Each dot represents an individual allergen with the identity level on the y-axis for a particular pathogen listed on the x-axis. Dots are colored coded to represent helminths in brown, protozoans in green, bacteria in blue and fungi in orange. The horizontal line represents the geometric mean for each pathogen listed. doi:10.1371/journal.pone.0040552.g001 address this observation further, we compared the existing IgE prevalence data for 357 known allergens with the identity level found in the respective homologue in each organism. Surprisingly, we found a consistent inverse relationship between allergenicity and the degree of identity between the allergen and its microbial homologue. The higher the identity level with a particular organisms’ homologue, the lower the IgE prevalence in the population (p,0.0001; r values varying from 20.23 and 20.33; Figure 3). In addition, the majority of those allergens with IgE prevalences above 50% showed either an identity level below 40% or none at all. In principle, there were no major allergens with identity levels above 80% except when the defined allergens were of helminth (i.e., Ani s 2) or fungal origin. Allergens with Homologues Among Parasites are Likely to Display Homologues in Human Genome The finding that the prevalence of IgE to common allergens was inversely associated with the level of conservation with helminth and other organisms’ proteins prompted an examination of allergen/human protein conservation. Thus, we performed a similar search for homologues across the human genome. We found that half (250/499) of the allergens showed at least one homologue in humans; 86% of these (217/250) also had homologues in the HPF group. The percentage of human homologues increased from 18% for allergens without homologues in the HPF groups to 67% for those allergens that had homologues to any of the HPF group (Figure 2B). For the 180 allergens that showed homologues in the HPF, 82% also had homologues in the human genome suggesting that allergens conserved in HPF also were conserved in humans. To confirm this association, we analyzed the levels of amino acid identity between the allergens and a representative helminth (B. malayi), protozoan (P. falciparum) and fungal (C. albicans) organism as well as humans (Figure 4). We found highly significant positive correlations between the identity levels of allergens and the representative helminth (r = 0.70, P,0.0001), protozoan (r = 0.64, P,0.0001) and fungal (r = 0.47, PLoS ONE | www.plosone.org 3 July 2012 | Volume 7 | Issue 7 | e40552