Molecular mimicry between cockroach and helminth glutathione S-transferases promotes cross-reactivity and cross-sensitization Helton C. Santiago, MD,

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Volume 139, Issue 5, Pages (November 2010)

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Molecular mimicry between cockroach and helminth glutathione S-transferases promotes cross-reactivity and cross-sensitization Helton C. Santiago, MD, PhD, Elyse LeeVan, BA, Sasisekhar Bennuru, PhD, Flavia Ribeiro-Gomes, PhD, Ellen Mueller, BA, Mark Wilson, PhD, Thomas Wynn, PhD, David Garboczi, PhD, Joseph Urban, PhD, Edward Mitre, MD, Thomas B. Nutman, MD Journal of Allergy and Clinical Immunology Volume 130, Issue 1, Pages 248-256.e9 (July 2012) DOI: 10.1016/j.jaci.2012.02.045 Copyright © 2012 Terms and Conditions

Fig 1 Sequence and structural similarities between Bla g 5 and WbGST. A, Alignment of Bla g 5 and WbGST sequences showing identical (shaded in black) and similar (shaded in gray) amino acids. B, Phylogenetic tree of allergenic GSTs. C, Predicted 3-D structure of Bla g 5 and WbGST color-coding basic structure for comparison. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions

Fig 2 Correlation between WbGST and Bla g 5 antibody levels. A, Level of anti–Bla g 5 and anti-WbGST IgE, IgG, and IgG4 antibodies in noninfected and nonatopic (Ni-NA), Ni-A, filaria-infected and nonatopic (Fil-NA), and Fil-A individuals. Individuals above the dotted lines (representing geometric mean + 3 SD of Ni-NA) were considered positive for anti–Bla g 5 antibodies. B, Correlation between anti-WbGST and anti–Bla g 5 IgE, IgG, and IgG4; each point represents an individual. n = 76. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions

Fig 3 WbGST-specific antibodies cross-react with Bla g 5 because of conserved epitopes. Sera of patients positive for anti–Bla g 5 IgE, IgG, and IgG4 were incubated in plates coated with a control antigen (OvTropomyosin), WbGST, or Bla g 5. Following incubation, sera were transferred to Bla g 5–coated plates and developed for IgE, IgG, and IgG4. Each dot represents 1 individual. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions

Fig 4 Linear epitope mapping of Bla g 5. A, Thirty-nine overlapping peptides spanning the entire sequence of Bla g 5 were used to perform western dot blots for IgE- and IgG-binding epitopes (numbers reflect peptide identity, S stands for serum and P for recombinant Bla g 5). B, The results were compared with in silico epitope prediction based on the Bla g 5 sequence. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions

Fig 5 Antigenic peptides can inhibit IgE binding to Bla g 5 and WbGST. Sera from infected patients positive for anti–Bla g 5 and anti-WbGST antibodies were incubated with DMSO (open squares) or specific peptides or recombinant proteins (closed circles) and then transferred to Bla g 5– or WbGST-coated multiwell plates. Optical densities (ODs) are shown for all sera tested. Differences were compared by using the Wilcoxon matched-signed rank test. Pep, Peptide. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions

Fig 6 Helminth infection can cause cross-sensitization to Bla g 5. Mice infected with Heligmosomoides bakeri developed IgE to Bla g 5 but not to Bla g 4 as measured by ELISA (A) and skin test reactivity by ear thickness (B) or by Evans' blue dye extravasation (C). Data represent 1 of 4 experiments performed (n = 4-5 per group per experiment). Bars (in Fig 6, A and B) represent means ± SE. In Fig 6, C, each dot represents 1 animal and the dotted lines represent the geometric mean of the Ni group + 3 SD. Hb, Heligmosomoides bakeri. ∗P < .05. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions

Fig E1 Predicted 3-D structure of Bla g 5 is identical to that of Drosophila's Sigma GST (1m0u). Perfect alignment of predicted monomeric structure of Bla g 5 (A and B, red) with the crystal model of the dimeric structure of Drosophila's sigma GST where Drosophila GST monomers are indicated in blue (left chain) or gray (right chain). Major IgE- and IgG-binding epitopes were marked in cyan (peptide 7), green (peptides 12/13), violet (peptides 22/23), and orange (peptides 27/29). C and D indicate the spatial distribution of the epitopes in the dimeric Drosophila 1m0u structure. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions

Fig E2 Structural and sequence similarities between Bla g 5, WbGST, and HbGST. A, Predicted 3-D structure of Bla g 5 and the correspondent region in WbGST and the crystal structure of HbGST highlighting the linear IgE- and IgG-binding epitopes. B, Alignment of the 3 sequences showing identical (shaded in black) and similar (shaded in gray) amino acids. Epitopes are highlighted in the color-coded boxes. Pep, Peptide. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions

Fig E3 Immunogenic peptides 7 and 12-13 of Bla g 5 and their equivalents in WbGST and HbGST can inhibit (A) Bla g 5 or (B) WbGST-specific IgE in an ELISA. Sera from individuals infected with filarial parasites and positive for anti–Bla g 5 IgE were used to perform the inhibition ELISA as described in the Methods section, except that IgG depletion was not performed for this experiment. Peptide 7 and peptides 12-13 of Bla g 5 and their equivalents in WbGST and HbGST (see Fig E1) were able to inhibit anti–Bla g 5 (Fig E3, A) or anti-WbGST (Fig E3, B) IgE antibody binding. Control (Neg CT) is a nonimmunogenic peptide sequence of Bla g 5. Pep, Peptide. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions

Fig E4 Immunogenic peptides 7 and 12 and 13 of Bla g 5 and their equivalents in WbGST and HbGST can inhibit Bla g 5–specific IgE in ELISA. Sera from BALB/c mice immunized intraperitoneally with Bla g 5 (3 injections of 10 μg on alternate days without adjuvant) were used to perform the inhibition ELISA as described in the Methods section for human serum, except that IgG depletion was not performed for this experiment. Peptides 7 and 12-13 of Bla g 5 and their equivalents in WbGST and HbGST (see Fig E1) were able to inhibit anti–Bla g 5 IgE binding in ELISA. Control is a nonimmunogenic peptide sequence of Bla g 5. Pep, Peptide. Journal of Allergy and Clinical Immunology 2012 130, 248-256.e9DOI: (10.1016/j.jaci.2012.02.045) Copyright © 2012 Terms and Conditions