Determinants and Mechanisms of Human Immune Responses to Bee Venom Phospholipase A₂

Abstract

The elicitation of an immune response to protein antigens depends on the specific recognition of antigenic determinants (epitopes) by T and B lymphocytes. Bee venom phospholipase A₂ (PLA) represents the major antigen/allergen of honey bee venom. It displays three dominant immunogenic peptide and one glycopeptide T cell recognition sites. These epitopes are equally recognized by both allergic and nonallergic individuals. A mixture of the three epitope containing peptides was successfully used in specific immunotherapy of bee venom–allergic patients. Both peptide and whole bee venom immunotherapy induced a state of specific anergy in T cells. The production of specific IgE and IgG4 antibodies directly correlated with the secreted interleukin–4:γ–interferon (IL–4:IFNγ) ratio, which itself depended on the concentration of available antigen and the strength of the T cell–activating signal. This signal comprises accumulated molecular interactions delivered by engagement of the antigenic peptide/MHC class II complex with the T cell receptor (TcR). Indeed the thermodynamic laws of chemical equilibrium reactions reveal that the antigen concentration, together with the equilibration constant K_i and the related Gibbs standard free energy ΔG° of the MHC–II/Ag/TcR complex reaction, may govern the secreted IL–4:IFNγ ratio, and in consequence, differential IgE and IgG4 antibody formation. K_i includes epitope and MHC–II haplotype variability and therefore represents a measure of immunological individuality. A major B cell epitope was determined by using point–mutated PLA. Specific antigen recognition by B cells can trigger distinct cytokine profiles in T cells and contribute to the differential regulation of specific IgE and IgG4 antibodies. Our results indicate that distinct cytokine profiles inducing allergic and nonallergic responses can be attributed to thresholds of T cell activation generated by the specific binding properties of individual MHC–II molecules to immunogenic T cell epitopes and their presentation to TcR.

Wasp Venom Rush Immunotherapy Induces Transient Downregulation of B Cell Surface Molecule Expression

“…The transiently downregulated expression of HLA-II during VIT indicates a reduced ability of B cells to present Ag during this time period. It is worth noting that the type of the APC influences the immune response since monocytes enhance, for example, a TH1 response, whereas B cells enhance a TH2 response and IgE production [22, 23]. The fact that B cells are important APCs in situations with low Ag concentrations [24]is also interesting in view of our findings since the cumulative Ag dose is high during the initiation phase of VIT and would support APC other than B cells, and hence TH1.…”

“…Although most studies regarding the mechanisms of IT have described allergen-specific effects [2, 25], there is also evidence of allergen-nonspecific effects [3, 22, 26]. These unspecific effects can be partially explained by a reduced IL-4/IFN-γ ratio as described in IT [2, 3].…”

Mathematical Modelling of Venom Immunotherapy

“…The effectiveness of immunotherapy has been proven in several clinical studies (Hunt et al, 1978;Reisman, 1992). In patients undergoing venom immunotherapy (VIT) a shift from a Th2 to a Th1 profile and an increase of the specific IgG4/IgE ratio (Blaser et al, 1998;McHugh et al, 1995;Schuerwegh et al, 2001;Tari et al, 1994) has been observed.…”

Mechanism of IL-10-Induced T Cell Inactivation in Allergic Inflammation and Normal Response to Allergens

“…Bee venom (BV) phospholipase A 2 (PLA) represents the major antigen and allergen of BV [4]. The response to PLA provides a specifically suitable model for studying the cellular and molecular mechanisms of specific immune response regulation in humans [1, 2, 3, 4, 5, 6], reviewed in 7, 8]). In both BV-SIT and peptide immunotherapy (PIT), successfully treated patients showed specific T cell unresponsiveness to the entire PLA allergen as well as to the three T cell epitope-containing peptides [1, 2, 3].…”