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Polistes species venom is devoid of carbohydrate-based cross-reactivity and allows interference-free diagnostics

2012; Elsevier BV; Volume: 131; Issue: 4 Linguagem: Inglês

10.1016/j.jaci.2012.10.047

1097-6825

Simon Blank, C. Richard Neu, Daniel Hasche, Frank I. Bantleon, Thilo Jakob, Edzard Spillner,

Viral Infectious Diseases and Gene Expression in Insects

Allergy to venom of paper wasps (Polistinae) is common in North America as well as in Europe, especially in Mediterranean areas. The most important Polistes species in Europe are P dominula and P gallicus, whereas in Northern America other species such as P annularis, P apachus, P exclamans, P fuscatus, and P metricus are dominant. In the last few decades, P dominula has increasingly spread across the North American continent and the central and northern parts of Europe. This phenomenon has been suggested to be associated with environmental changes, explaining the increasing importance of Polistes venom allergy as a cause for anaphylactic Hymenoptera sting reactions. A lack of molecular tools and the neglect of specific diagnosis in northern regions classically dominated by other Hymenoptera such as yellow jackets and honeybees are likely to additionally contribute to underestimating Polistes venom (PV) allergy.1Caruso B. Bonadonna P. Severino M.G. Manfredi M. Dama A. Schiappoli M. et al.Evaluation of the IgE cross-reactions among vespid venoms: a possible approach for the choice of immunotherapy.Allergy. 2007; 62: 561-564Crossref PubMed Scopus (48) Google Scholar, 2Monsalve R.I. Vega A. Marques L. Miranda A. Fernandez J. Soriano V. et al.Component-resolved diagnosis of vespid venom-allergic individuals: phospholipases and antigen 5s are necessary to identify Vespula or Polistes sensitization.Allergy. 2012; 67: 528-536Crossref PubMed Scopus (76) Google Scholar Diagnosis of Hymenoptera venom allergy is based on a history of anaphylactic sting reactions, positive skin test responses, and/or detection of specific IgE to Hymenoptera venom. Positive results in skin and serological tests with conventional venom extracts, however, do not always reflect genuine sensitizations but are frequently caused by clinically irrelevant cross-reactive antibodies. Treatment modalities therefore often include different venoms, resulting in higher costs, increased risk of severe side effects, and possible de novo sensitizations.3Juarez C. Blanca M. Miranda A. Sanchez F. Carmona M.J. Avila M.J. et al.Specific IgE antibodies to vespids in the course of immunotherapy with Vespula germanica administered to patients sensitized to Polistes dominulus.Allergy. 1992; 47: 299-302Crossref PubMed Scopus (24) Google Scholar A high percentage of cross-reactivity has been attributed to IgE directed against cross-reactive carbohydrate determinants (CCDs), namely, to α1,3-linked core fucose residues of glycoproteins. Therefore, molecular diagnosis applying nonglycosylated species-specific allergens and strategies to circumvent α1,3-core fucosylation led to a significant advance in the dissection of true double sensitization versus irrelevant cross-reactivity.4Hofmann S.C. Pfender N. Weckesser S. Huss-Marp J. Jakob T. Added value of IgE detection to rApi m 1 and rVes v 5 in patients with Hymenoptera venom allergy.J Allergy Clin Immunol. 2011; 127: 265-267Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 5Seismann H. Blank S. Braren I. Greunke K. Cifuentes L. Grunwald T. et al.Dissecting cross-reactivity in hymenoptera venom allergy by circumvention of alpha-1,3-core fucosylation.Mol Immunol. 2010; 47: 799-808Crossref PubMed Scopus (89) Google Scholar The molecular cross-reactivity between European and American Polistes species is described as rather low because they belong to different subgenera. In contrast, cross-reactivity between Polistinae and Vespinae (Vespula, Dolichovespula, and Vespa) venoms and purified venom proteins2Monsalve R.I. Vega A. Marques L. Miranda A. Fernandez J. Soriano V. et al.Component-resolved diagnosis of vespid venom-allergic individuals: phospholipases and antigen 5s are necessary to identify Vespula or Polistes sensitization.Allergy. 2012; 67: 528-536Crossref PubMed Scopus (76) Google Scholar is frequently observed especially for Vespula and American as well as European PV.1Caruso B. Bonadonna P. Severino M.G. Manfredi M. Dama A. Schiappoli M. et al.Evaluation of the IgE cross-reactions among vespid venoms: a possible approach for the choice of immunotherapy.Allergy. 2007; 62: 561-564Crossref PubMed Scopus (48) Google Scholar Moreover, it is widely accepted that IgE cross-reactivity in a significant fraction of patients can be attributed to CCDs.1Caruso B. Bonadonna P. Severino M.G. Manfredi M. Dama A. Schiappoli M. et al.Evaluation of the IgE cross-reactions among vespid venoms: a possible approach for the choice of immunotherapy.Allergy. 2007; 62: 561-564Crossref PubMed Scopus (48) Google Scholar In this study, we addressed for the first time the CCD reactivity of European and American PV. We utilized Galanthus nivalis agglutinin, which indicates the general presence of N-linked glycans, and rabbit anti–horseradish peroxidase (HRP) serum that specifically detects α1,3-core fucosylation6Fabini G. Freilinger A. Altmann F. Wilson I.B. Identification of core alpha 1,3-fucosylated glycans and cloning of the requisite fucosyltransferase cDNA from Drosophila melanogaster: potential basis of the neural anti-horseradish peroxidase epitope.J Biol Chem. 2001; 276: 28058-28067Crossref PubMed Scopus (141) Google Scholar of insect venoms. Applying Galanthus nivalis agglutinin in AlaBlots (Siemens Healthcare Diagnostics, Los Angeles, Calif) with Polistes species (i4), A mellifera (i1), and V vulgaris (i3) venom demonstrated the presence of several glycoproteins in all 3 venoms (Fig 1, A). The use of anti-HRP serum in AlaBlots revealed pronounced α1,3-core fucosylation for honeybee venom (HBV) as well as for yellow jacket venom (YJV). In contrast, Polistes species venom, which is a mixture of venoms of different American Polistes species, did not show any α1,3-core fucosylation and hence CCD reactivity (Fig 1, A). Comparable results were obtained when we analyzed the individual venom of Polistes apachus compared with HBV and Vespula species venom (Fig 1, B). Immunoblot analyses demonstrated pronounced glycosylation of Polistes apachus venom allergens but the absence of CCD-based reactivity. ELISA analysis with anti-HRP serum corroborated the absence of any α1,3-core fucosylation and CCD reactivity of P apachus venom (Fig 1, C). In addition, we analyzed sera of 2 patient groups with known IgE reactivity to CCD (as determined by the detection of specific IgE to CCD markers) and a low probability to have carbohydrate-independent specific IgE to Polistes venom: (1) patients with confirmed HBV allergy but no history of YJV or PV allergy and (2) patients with grass pollen allergy without clinical history of Hymenoptera venom allergy. Overall, 17 sera of patients with confirmed HBV allergy displayed strong reactivity with sensitizing HBV (Fig 2, A) and medium to strong reactivity with MUXF and YJV, indicating the presence of CCD-specific IgE antibodies. In stark contrast, none of the sera showed any reactivity with Polistes apachus venom, suggesting the lack of interference by CCD reactivity. From the grass pollen–allergic patients without clinical history of Hymenoptera venom allergy, 5 sera were selected that exhibited pronounced specific IgE reactivity to the CCD markers MUXF (o214), HRP (o400), and bromelain (k202) as analyzed by ImmunoCAP (Thermo Fisher Scientific, Freiburg, Germany) (Fig 2, B). As expected, all patients exhibited additional reactivity with HBV (i1) and YJV (i3) extract. In contrast, none of the CCD-reactive sera showed reactivity with American (i4) and European (i77) PV. Only 1 serum exhibited a very low reactivity over the cut-off with European PV. Interestingly, this finding appears to be a result of genuine sensitization to YJV and cross-reactivity because this serum additionally showed minor reactivity with nonglycosylated Ves v 1 and Ves v 5 (not shown). Notably, our data are consistent with older findings of a limited cross-reactivity of different Polistes venoms and Vespula venom that already points to an absence of CCD.7Reisman R.E. Wypych J.I. Mueller U.R. Grant J.A. Comparison of the allergenicity and antigenicity of Polistes venom and other vespid venoms.J Allergy Clin Immunol. 1982; 70: 281-287Abstract Full Text PDF PubMed Scopus (52) Google Scholar We have demonstrated the absence of CCD for 6 Polistes species. While it seems likely that this phenomenon may be true for other Polistes species not included here, this has not formally been demonstrated and needs further validation. The molecular basis of the peculiar lack of CCD reactivity in Polistes species venom—specific downregulation of core fucosylation in the venom gland, a defective enzymatic activity, or peculiarities of Polistes glycosylation interfering with core fucosylation—so far remains unsolved and has to be evaluated in the future. Our finding nevertheless has clear clinical implications. Detecting specific IgE to the PV extract reliably shows true sensitization independent of CCD reactivity. Thus, specific IgE to the PV extract is either a direct parameter for PV sensitization or indicates carbohydrate-independent cross-reactivity with venom of phylogenetically close species such as yellow jacket (as seen for patient 3). Hence, it represents a much better diagnostic tool than previously anticipated.1Caruso B. Bonadonna P. Severino M.G. Manfredi M. Dama A. Schiappoli M. et al.Evaluation of the IgE cross-reactions among vespid venoms: a possible approach for the choice of immunotherapy.Allergy. 2007; 62: 561-564Crossref PubMed Scopus (48) Google Scholar Although facilitated by the lack of CCD-based interference in PV, the discrimination of PV and YJV allergy still remains difficult, and often requires additional laboratory tests (eg, IgE inhibition assays) to distinguish primary sensitization and protein-based cross-reactivity.1Caruso B. Bonadonna P. Severino M.G. Manfredi M. Dama A. Schiappoli M. et al.Evaluation of the IgE cross-reactions among vespid venoms: a possible approach for the choice of immunotherapy.Allergy. 2007; 62: 561-564Crossref PubMed Scopus (48) Google Scholar These tests are expensive, time consuming, difficult to interpret, and thus rarely used in clinical routine. The availability of CCD-free marker allergens from HBV and YJV has significantly improved the discrimination between primary HBV and YJV sensitization.4Hofmann S.C. Pfender N. Weckesser S. Huss-Marp J. Jakob T. Added value of IgE detection to rApi m 1 and rVes v 5 in patients with Hymenoptera venom allergy.J Allergy Clin Immunol. 2011; 127: 265-267Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 8Korosec P. Valenta R. Mittermann I. Celesnik N. Silar M. Zidarn M. et al.High sensitivity of CAP-FEIA rVes v 5 and rVes v 1 for diagnosis of Vespula venom allergy.J Allergy Clin Immunol. 2012; 129: 1406-1408Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 9Vos B, Köhler J, Müller S, Stretz E, Rueff F, Jakob T. Spiking venom with rVes v 5 improves sensitivity of IgE detection in patients with allergy to Vespula venom. J Allergy Clin Immunol 2013 [In press].Google Scholar Similarly, the use of phospholipases and antigen 5 has been suggested to facilitate the discrimination between primary PV and YJV sensitization2Monsalve R.I. Vega A. Marques L. Miranda A. Fernandez J. Soriano V. et al.Component-resolved diagnosis of vespid venom-allergic individuals: phospholipases and antigen 5s are necessary to identify Vespula or Polistes sensitization.Allergy. 2012; 67: 528-536Crossref PubMed Scopus (76) Google Scholar although the known degree of sequence homology still does not rule out peptide cross-reactivity and thus only allows the estimation of the probable sensitizing venom. Here, clearly additional marker allergens devoid of any cross-reactivity are required that allow us to reliably identify PV allergy and choose the appropriate therapy in all areas in which Polistes species are dominant or gain importance.