Molecular mimicry between cockroach and helminth glutathione S-transferases promotes cross-reactivity and cross-sensitization

Background: The extensive similarities between helminth proteins and allergens are thought to contribute to helminth-driven allergic sensitization. Objective: The objective of this study was to investigate 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. Methods: 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 IgG₄ 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. Results: 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 IgG₄ anti-Bla g 5 antibody production, with a significant correlation between antibodies (irrespective of isotype) to Bla g 5 and WbGST (P <.0003). Preincubation of sera from cockroach-allergic subjects with WbGST partially depleted (by 50%-70%) anti-Bla g 5 IgE, IgG, and IgG₄ 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. Conclusion: These data demonstrate that helminth glutathione-S transferase and the aeroallergen Bla g 5 share epitopes that can induce allergic cross-sensitization.