Molecular characterization of human IgG monoclonal antibodies specific for the major birch pollen allergen Bet v 1. Anti‐allergen IgG can enhance the anaphylactic reaction

Denépoux, Stéphane; Eibensteiner, Petra; Schmitz, Peter; Vrtala, Susanne; Visco, Vincenzo; Weyer, A.; Kraft, Dietrich; Banchereau, Jacques; Valenta, Rudolf; Lebecque, Serge

doi:10.1016/s0014-5793(99)01703-2

Cited by 57 publications

(58 citation statements)

References 26 publications

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“…In fact, administration of high concentrations of allergen has been shown to alter antibody affinity and specificity, as well as the quantity of antibodies produced [16, 17]. As recently reported, epitope specificity of IgG antibodies is decisive for their protective activity, in terms of blocking activity [18, 19], or negligible blocking activity, and even enhanced IgE recognition [20], respectively.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Recombinant and Native Timothy Pollen (rPhl p 1, 2, 5, 6, 7, 11, 12 and nPhl p 4)- Specific IgG4 Antibodies Induced by Subcutaneous Immunotherapy with Timothy Pollen Extract in Allergic Patients

Rossi

Monasterolo

2004

Int Arch Allergy Immunol

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Background: Allergen immunotherapy is a widely accepted treatment for IgE-mediated allergies. The evaluation of immunotherapy-induced IgG4 antibodies based on allergen extract is questionable because the amount of allergen-extract-specific IgG4 to individual disease-eliciting allergens cannot be determined using crude allergen extracts. In this study, we examined the specific IgE and IgG4 serum binding profiles to individual Phleum pratense allergens in grass-pollen-sensitive patients who had received grass-pollen-specific immunotherapy (SIT). Methods: The study included 33 patients from North-West Italy. All suffered from seasonal rhinoconjunctivitis and/or asthma. A modified ‘cluster’ regimen of injections of a standardized aluminium-adsorbed P.pratense extract, with once-weekly visits and 10 injections for 5 weeks followed by 3 weeks of maintenance injections was instituted. Patients’ sera were analyzed for specific IgE and IgG4 reactivity to individual P. pratense allergens (recombinant Phl p 1, Phl p 2, Phl p 5, Phl p 6, Phl p 7, Phl p 11, Phl p12 and native Phl p 4) and natural P. pratense extract using the Pharmacia CAP system. Results: IgE reactivities to new allergen components were not detected by CAP in treated patients after 15 weeks and a cumulative dose of approximately 65 µg of the major allergen Phl p 5. Patients lacking specific IgE reactivity towards individual allergens at the start of SIT did not produce significant levels of specific serum IgG4 to serum IgE-negative allergens. On the other hand, an increase in specific IgG4 only to allergens to which patients were previously sensitized was observed. Significant increases in specific IgG4 levels to rPhl p 1 (p < 0.05), 2 (p < (0.01), 5 (p < 0.0001), 6 (p < 0.0001), 7 (p < 0.05), 11 (p < 0.05) and nPhl p 4 (p < 0.01) were observed after P. pratense extract immunotherapy. No significant rPhl p 12-specific IgG4 antibody increase was documented after treatment. Conclusion: These findings suggest that Phl p 12 was underrepresented in the extract used, as indicated by the low specific IgG4 response induced by this grass-pollen-specific vaccine. Thus, the simple detection of specific serum IgG4 antibodies a few weeks after the start of SIT could represent a valuable tool to estimate the presence of relevant allergens in a given immunotherapeutic allergen extract.

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Section: Discussionmentioning

confidence: 99%

Evaluation of Recombinant and Native Timothy Pollen (rPhl p 1, 2, 5, 6, 7, 11, 12 and nPhl p 4)- Specific IgG4 Antibodies Induced by Subcutaneous Immunotherapy with Timothy Pollen Extract in Allergic Patients

Rossi

Monasterolo

2004

Int Arch Allergy Immunol

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“…One possibility for the efficient recognition of allergen by IgE Abs is that IgE recognizes different epitopes on allergens than IgG Abs. Evidence for different epitope recognition comes from epitope mapping studies performed with allergen fragments and the analysis of the binding specificities of defined allergen-specific human IgG Abs (19,20). Studies performed with allergen-specific serum IgE vs serum IgG report controversial results regarding possible differences between the binding strength of allergen-specific IgE and IgG Abs (21,22).…”

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confidence: 99%

High-Affinity IgE Recognition of a Conformational Epitope of the Major Respiratory Allergen Phl p 2 As Revealed by X-Ray Crystallography

Padavattan

Flicker

Schirmer

et al. 2009

The Journal of Immunology

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106

124

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We report the three-dimensional structure of the complex between the major respiratory grass pollen allergen Phl p 2 and its specific human IgE-derived Fab. The Phl p 2-specific human IgE Fab has been isolated from a combinatorial library constructed from lymphocytes of a pollen allergic patient. When the variable domains of the IgE Fab were grafted onto human IgG1, the resulting Ab (huMab2) inhibited strongly the binding of allergic patients’ IgE to Phl p 2 as well as allergen-induced basophil degranulation. Analysis of the binding of the allergen to the Ab by surface plasmon resonance yielded a very low dissociation constant (KD = 1.1 × 10−10 M), which is similar to that between IgE and Fcε;RI. The structure of the Phl p 2/IgE Fab complex was determined by x-ray crystallography to 1.9 Å resolution revealing a conformational epitope (876 Å2) comprised of the planar surface of the four-stranded anti-parallel β-sheet of Phl p 2. The IgE-defined dominant epitope is discontinuous and formed by 21 residues located mostly within the β strands. Of the 21 residues, 9 interact directly with 5 of the 6 CDRs (L1, L3, H1, H2, H3) of the IgE Fab predominantly by hydrogen bonding and van der Waals interactions. Our results indicate that IgE Abs recognize conformational epitopes with high affinity and provide a structural basis for the highly efficient effector cell activation by allergen/IgE immune complexes.

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“…Although the binding of murine Fab fragments against the birch major allergen Bet v 1 was reported to enhance the allergenicity of Bet v 1 in IgE binding and skin tests (62), no endogenous ligand has been reported to enhance the allergenicity of an allergen. Some allergens are proteases, and some endogenous inhibitors or substrates could interact with them (31, 40, 42-44, 63, 64).…”

Section: Discussionmentioning

confidence: 99%

Modulation of Allergenicity of Major House Dust Mite Allergens Der f 1 and Der p 1 by Interaction with an Endogenous Ligand

Takai¹,

Kato²,

Hatanaka

et al. 2009

The Journal of Immunology

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Although many allergens bind endogenous molecules other than Abs in the human body, whether the interaction can modulate allergenicity has been unknown. Here, we investigated the effect of the interaction of recombinant major mite group 1 allergens (Der f 1 and Der p 1), which belong to the papain-like cysteine protease family, with an endogenous protease inhibitor, cystatin A, on their allergenicity. Cystatin A bound reduced forms of the allergens, in which the cysteine residue at the catalytic center of the protease activity was reduced by treatment with l-cysteine, but did not bind oxidized forms. Cystatin A partially inhibited the binding of IgE in mite-allergic volunteers’ sera to the reduced forms, but unexpectedly enhanced the basophil histamine-releasing activity. A catalytic site-mutant of Der f 1 behaved in terms of histamine release, similarly to the reduced form. Molecular modeling showed that cystatin A interacts with the allergens within a narrow area. The results indicate that interaction with cystatin A reduces the limited number of IgE epitopes of the allergens but enhances their biological activity to release histamine, suggesting a new concept, that interaction between allergens and their endogenous ligands modulates the allergenicity even toward enhancement in the effector phase. On the other hand, i.p. immunization without alum of mice with cystatin A-treated reduced Der f 1 induced less serum Der f 1-specific IgE than immunization with reduced Der f 1 alone, suggesting that endogenous protease inhibitors suppress the induction of allergen-specific IgE, which is dependent on the enzymatic activity of cysteine protease-allergens, in the sensitization process.

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Molecular characterization of human IgG monoclonal antibodies specific for the major birch pollen allergen Bet v 1. Anti‐allergen IgG can enhance the anaphylactic reaction

Cited by 57 publications

References 26 publications

Evaluation of Recombinant and Native Timothy Pollen (rPhl p 1, 2, 5, 6, 7, 11, 12 and nPhl p 4)- Specific IgG4 Antibodies Induced by Subcutaneous Immunotherapy with Timothy Pollen Extract in Allergic Patients

Evaluation of Recombinant and Native Timothy Pollen (rPhl p 1, 2, 5, 6, 7, 11, 12 and nPhl p 4)- Specific IgG4 Antibodies Induced by Subcutaneous Immunotherapy with Timothy Pollen Extract in Allergic Patients

High-Affinity IgE Recognition of a Conformational Epitope of the Major Respiratory Allergen Phl p 2 As Revealed by X-Ray Crystallography

Modulation of Allergenicity of Major House Dust Mite Allergens Der f 1 and Der p 1 by Interaction with an Endogenous Ligand

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