Kinetic immunodominance: functionally competing antibodies against exposed and cryptic epitopes of Escherichia coli beta-galactosidase are produced in time sequence.
The murine antibody response to Escherichia coli beta-galactosidase (GZ) was analyzed in vivo and in vitro by focusing on two families of antibodies that exert distinct conformational/functional activity on the antigen. Activating antibodies--defined by their capacity to increase the enzymatic activity of defective GZ produced by mutant strains of E. coli--are detected early after secondary challenge. Inhibiting antibodies, which interfere with antibody-mediated enzyme activation, appear later and cause the abrupt fall of activating titer, a scenario suggesting either idiotype/anti-idiotype interaction or opposite pulsions exerted on the antigen molecule. Supporting the latter mechanism, the confrontation of mAbs of the two families produced classical competitive inhibition curves when the readout was enzyme activation, although they recognize two different epitopes of the same molecule: the activating mAb a quaternary conformation-dependent site of wild-type GZ, the inhibiting mAb a sequential determinant exposed only in denatured or in defective enzyme. The different timing of generation of these antibodies during the response may depend on a processing step necessary for unfolding of native antigen and consequent display of certain cryptic epitopes before they can trigger specific B cells. A picture emerges where the response to the various epitopes of a complex antigen is sequentially connected and where the uptake by antigen-presenting cells of antigen complexed with antibodies specific for the exposed epitopes may favor revelation of the cryptic ones.
Kunkl
A
A
Department of Immunology, University of Genoa, Italy.
Fenoglio
D
D
Manca
F
F
Li Pira
G
G
Cambiaggi
C
C
Strom
R
R
Celada
F
F
D000818:Animals; D000907:Antibodies, Bacterial / Q000032:analysis*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000939:Epitopes; D004926:Escherichia coli / Q000276:immunology*; D005260:Female; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011487:Protein Conformation; D001616:beta-Galactosidase / Q000276:immunology*
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000939:Epitopes; D001616:beta-Galactosidase