Article

Mechanisms of allergen-specific desensitization.

Cytos Biotechnology AG, Zurich-Schlieren, Switzerland.
The Journal of allergy and clinical immunology (Impact Factor: 12.05). 08/2010; 126(2):375-83. DOI: 10.1016/j.jaci.2010.05.040
Source: PubMed

ABSTRACT Allergen-specific desensitization (SIT) is the most effective therapy for allergies. Although allergen-specific antibodies have an important role in the process, mechanisms of IgG-mediated inhibition of allergic reactions are not well defined.
We investigated mechanisms by which SIT-induced allergen-specific IgGs inhibit allergic reactions.
We generated mAbs that recognize 3 nonoverlapping epitopes of the major cat allergen Fel d 1. Each of the mAbs was produced as an IgE and different IgG isotype.
IgEs against 2 nonoverlapping epitopes on Fel d 1 are necessary and sufficient to sensitize mast cells for maximal FcepsilonRI signaling and degranulation on exposure to monomeric Fel d 1. IgE antibodies of a third specificity did not further increase mast cell degranulation, indicating that formation of large FcepsilonRI clusters are not required to induce maximal activation of mast cells. A single IgG that was specific for an epitope different from those recognized by the IgEs was a potent inhibitor of Fel d 1-mediated mast cell activation in vitro and in vivo. This inhibition required Fcgamma receptor-IIB. In human beings, IgGs of a single specificity were able to block degranulation of basophils from individuals with cat allergy. The inhibitory potential of these antibodies increased when larger allergen-IgG complexes were formed.
These data reconcile conflicting theories in the literature and might explain the reason IgE levels do not necessarily decrease during therapy, despite clinical efficacy. These findings have important implications for vaccine design.

0 Bookmarks
 · 
126 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Plant-made biotherapeutics are gathering momentum and some plant glycoproteins are allergens. Glycans with core β1-2xylose and α1,3fucose motifs and antennae terminated by mannose residues (e.g.: MMXF) are found on several plant allergens and can cross-react with glyco-epitopes from other sources. To date, reactivity to these cross-reactive determinants has not been associated with clinical symptoms.
    Vaccine 09/2014; · 3.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Allergen-specific IgGs are known to inhibit IgE-mediated mast cell degranulation by two mechanisms, allergen-neutralization and engagement of the inhibitory FcγRIIB recruiting the phosphatase SHIP-1. Here we unravel an additional mechanism of IgG-mediated mast cell desensitization in mice: down-regulation of allergen-specific IgE. Mast cells were loaded in vitro and in vivo with monoclonal IgE antibodies specific for Fel d1 and exposed to immune complexes consisting of Fel d1-specific IgG antibodies recognizing different epitopes. Down regulation of IgE was followed by flow cytometry. Mast cells loaded with 2 different IgE antibodies efficiently internalized the IgE antibodies if exposed to recombinant Feld d1. In contrast, no down-regulation occurred if mast cells were loaded with IgE antibodies exhibiting a single were before stimulation with recombinant Fel d1. Interestingly, however, IgEs of a single specificity were rapidly down-regulated in vitro and in vivo in the presence of Fel d1-specific monoclonal IgGs recognizing another epitope on Fel d1. Despite FceRI-internalization, little calcium flux or mast cell degranulation occurred. FcγRIIB played a dual role in the process since it enhanced IgE internalization and prevented cellular activation as documented by the inhibited calcium flux and mast cell degranulation. Similar observations were made in the presence of low concentrations of IgEs recognizing several epitopes on Fel d1. We demonstrate here that Fel d1-specific IgG antibodies interact with FcγRIIB which (i) promotes IgE internalization; and (ii) inhibits mast cell activation. These results broaden our understanding of allergen-specific desensitization and may provide a mechanism for long-term desensitization of mast cells by selective removal of long-lived IgE antibodies on mast cells.
    Allergy 12/2013; · 6.00 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Immunoglobulin E (IgE)-mediated food allergy, such as egg white allergy, is common in young children (<3 years old), but not all young children sensitive to egg white present with allergic symptoms. This study investigated the relationship between sensitization to egg white component allergens and clinical manifestations of allergic diseases in young children. Methods From March to December 2010, 2256 children with physician-diagnosed allergic diseases were tested for serum levels of egg white, ovalbumin, and ovomucoid-specific IgE in the Pediatric Allergy and Asthma Center of Chang Gung Memorial Hospital. Serum was analyzed for specific IgE antibodies to egg white, ovalbumin, and ovomucoid by ImmunoCAP (Phadia, Uppsala, Sweden). Allergen-specific IgE levels ≥0.35 kUA/L were defined as positive. Results There was a significantly higher sensitization rate to egg white and its components in children aged 2–4 years old. The sensitization rate to egg white, ovalbumin, and ovomucoid in this age group was 53.5%, 48.3%, and 37.2%, respectively, and the trend of the sensitization decreased with age (p < 0.001). After adjusting for age, sensitization to egg white and ovalbumin was associated with children with dermatitis [egg white: odds ratio (OR) = 1.28, 95% confidence intervals (CI) = 1.03–1.58, p < 0.05; ovalbumin: OR = 1.30, 95% CI = 1.04–1.62, p < 0.05]. Children with ovomucoid sensitization had no statistically significant risk among different groups in the current study. Conclusion Children aged 2–4 years old have higher sensitivity to egg white, ovalbumin, and ovomucoid. Children with egg white and ovalbumin sensitization have a higher risk for atopic dermatitis, and ovalbumin has a more important contribution. Furthermore, we suggested that in children with atopic dermatitis, if they are aged 2–4 years old and are having egg white and ovalbumin sensitization, avoiding eating raw or slightly heated eggs might have a beneficial effect.
    Journal of microbiology, immunology, and infection = Wei mian yu gan ran za zhi 03/2014; · 1.63 Impact Factor