Allergen dose dependent cytokine production regulates specific IgE and IgG antibody production.
The elicitation of a specific immune response against allergens depends on the recognition of antigenic determinants (epitopes) by specific T and B lymphocytes. In order to determine the relevant epitopes for human T and B cells and their features in the regulation and production of specific IgE and/or IgG antibodies, we have investigated the immune response to bee venom phospholipase A2 (PLA) in allergic and non-allergic subjects. This enzyme represents the major allergen in bee sting allergy. It consists of 134 amino acid residues with a carbohydrate side chain at position 13 and is available as recombinant protein. We have developed PLA-specific T-cell clones from bee sting allergic and non-allergic human subjects. Using a panel of dodecapeptides overlapping in 10 residues and a large set of 18-25 mer overlapping peptides, we detected three epitopes that were recognized by peripheral blood T-cells and T-cell clones. A fourth determinant involved the carbohydrate moiety on Asn13 of PLA. Whereas the CHO-depending epitope seems to be mostly active in allergics, the other three epitopes are equally recognized by peripheral blood mononuclear cells (PBMC) of both allergic and non-allergic individuals. In T-cell clones, the ratio of IL-4/IFN gamma cytokines and the quality of the activating signal depend on the strength of the binding of the MHC-II/Ag/TcR complex between APC and T-cells. The number of antigen-specific APC-T-cell contact sites can be varied in vitro by changing the dose of antigen added to the cell culture. While isotype switch for both IgE and IgG4 requires IL-4, this cytokine suppresses antigen-specific IgG4 production by already switched B-cells. Therefore, IL-4 and IFN gamma display counter-regulatory effects on the production of IgE being responsible for atopic states and IgG4 antibodies which are signs of a normal immune response to allergen and act as protective antibodies. The combination of this counter-regulation of IgE and IgG4 antibodies with the fundamental law of mass action for chemical equilibrium reactions revealed that the antigen concentration governs to a great part the ratio of IL-4/IFN gamma secretion and therefore the formation of IgE and IgG and allergy or protection, together with the equilibrium constant K, which represents immunological individuality and a measure of Ag presentation.
Blaser
K
K
Swiss Institute of Allergy and Asthma Research (SIAF), Davos, Switzerland.
D000485:Allergens / Q000276:immunology*; D000818:Animals; D001514:Bee Venoms / Q000276:immunology*; D002241:Carbohydrates / Q000276:immunology; D002999:Clone Cells; D016207:Cytokines / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology*; D010641:Phenotype; D010741:Phospholipases A / Q000276:immunology*; D054467:Phospholipases A2; D013601:T-Lymphocytes / Q000276:immunology*
D000485:Allergens; D001514:Bee Venoms; D002241:Carbohydrates; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010741:Phospholipases A; D054467:Phospholipases A2