Tolerance to Self and Allergenicity Figure 3. The level of allergenicity inversely correlates with the level of the conservation of the allergen. The IgE prevalence (y-axis) in a specific allergic population was plotted against the identity level (x-axis) between the allergen and its microbial homologue and correlation evaluated by Spearman rank test. Each dot represents one allergen and the lines represent the trend line. Allergens without homologues are stacked in the identity equal to zero area. doi:10.1371/journal.pone.0040552.g003 [36] have similar levels of homologous proteins to defined aero- allergens and at similar levels of amino acid identities. Importantly, 37% of the defined allergens had no homologues to proteins from any of the organisms evaluated in this study; most of these ‘‘unique’’ allergens were found to be among the highly prevalent or, what is termed, major allergens. We found that the level of allergenicity of a given allergen decreased with increasing level of conservation to microbial proteins presumably because the level of conservation with the microbial proteins reflected that observed with human proteins. These finding agree with the current model of self-tolerance in which auto-reactive B and T lymphocytes are deleted during their development. Therefore, it is not surprising that allergens highly conserved with human proteins show the least degree of allergenicity. Interestingly, the inverse relationship between homology to human proteins and allerge- nicity has been suggested previously [37], but did not gain much traction with a single study showing that tropomyosins with identity levels greater than 55% with human tropomyosin were rarely allergenic [38]. Although the majority of major and highly prevalent allergens did not show homologues among the genomes analyzed, our results suggests that there is a selective window which was found to be between 30% and 40% amino acid identity with human (or helminth proteins) where the development of protein-specific IgE is less severely impaired. Above 40% identity with human proteins, the number of allergens and the level of allergenicity (as measured by anti-allergen IgE prevalence in a specific allergic population) decreased dramatically. Interestingly, there are few major allergens with identities to human proteins above 50% (range 50–71%), most being calcium- binding proteins of fish (parvalbumins of the EF hand family), crustacea (tropomyosins) and fungi. Most of the environmental allergens showing a relative high level of identity with human proteins, however, were found to be minor allergens. Therefore, it is reasonable to speculate that for these groups structural differences per se may be sufficient to break immunologic self- tolerance and induce IgE optimally, or the presence of infection, such fungal infection, may drive a break of self-tolerance. Nevertheless, the general rule suggests that the failure of highly conserved allergens to induce IgE may reflect the deletion of T and B cells specific for cross-reacting self-proteins. At this point, it is important to make a distinction between allergenicity and the ability to induce Th2 response. Our data clearly demonstrate that structural dissimilarity leads to increased allergenicity (defined by the induction of specific IgE responses). It may still be possible, however, that a non-human protein that is highly similar to a human protein may act as a T cell adjuvant, either by deviating the T cell response towards Th2 responses [28] PLoS ONE | www.plosone.org 5 July 2012 | Volume 7 | Issue 7 | e40552