Attenuation of IgE affinity for FcepsilonRI radically reduces the allergic response in vitro and in vivo.
The high affinity of IgE for its receptor, FcepsilonRI (K(a) approximately 10(10) M(-1)), is responsible for the persistence of mast cell sensitization. Cross-linking of FcepsilonRI-bound IgE by multivalent allergen leads to cellular activation and release of pro-inflammatory mediators responsible for the symptoms of allergic disease. We previously demonstrated that limiting the IgE-FcepsilonRI interaction to just one of the two Cepsilon3 domains in IgE-Fc, which together constitute the high affinity binding site, results in 1000-fold reduced affinity. Such attenuation, effected by a small molecule binding to part of the IgE:FcepsilonRI interface or a distant allosteric site, rather than complete blocking of the interaction, may represent a viable approach to the treatment of allergic disease. However, the degree to which the interaction would need to be disrupted is unclear, because the importance of high affinity for immediate hypersensitivity has never been investigated. We have incorporated into human IgE a mutation, R334S, previously characterized in IgE-Fc, which reduces its affinity for FcepsilonRI approximately 50-fold. We have compared the ability of wild type and R334S IgE to stimulate allergen-induced mast cell activation in vitro and in vivo. We confirmed the expected difference in affinity between wild type and mutant IgE for FcepsilonRI (approximately 50-fold) and found that, in vitro, mast cell degranulation was reduced proportionately. The effect in vivo was also marked, with a 75% reduction in the passive cutaneous anaphylaxis response. We have therefore demonstrated that the high affinity of IgE for FcepsilonRI is critical to the allergic response, and that even moderate attenuation of this affinity has a substantial effect in vivo.
Hunt
James
J
King's College London, Medical Research Council, Randall Division of Cell and Molecular Biophysics, Guy's Campus, London SE1 1UL, United Kingdom.
Bracher
Marguerite G
MG
Shi
Jianguo
J
Fleury
Sébastien
S
Dombrowicz
David
D
Gould
Hannah J
HJ
Sutton
Brian J
BJ
Beavil
Andrew J
AJ
D000818:Animals; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology; D007073:Immunoglobulin E / Q000737:chemistry*; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D009154:Mutation; D017455:Receptors, IgE / Q000737:chemistry*; D013997:Time Factors
D017455:Receptors, IgE; D007073:Immunoglobulin E