Fine structural recognition specificities of IgE antibodies distinguishing amoxicilloyl and amoxicillanyl determinants in allergic subjects

Abstract

IgE antibodies in the sera of subjects allergic to beta-lactam antibiotics detect a spectrum of specificities ranging from side-chain groups to an entire penicillin or cephalosporin molecule. In addition to such structural heterogeneity of allergenic determinants, IgE antibodies in the sera of different allergic subjects show heterogeneous recognition responses. Detailed immunochemical studies were carried out on the sera of penicillin-allergic subjects that showed selective and unexpected reactions with the frequently prescribed penicillin, amoxicillin. Antibodies from one subject reacted only with the amoxicilloyl determinant while IgE from another subject showed multiple reactivity with penicilloyl and penicillanyl determinants of different penicillins but not with the amoxicilloyl determinant. Quantitative hapten inhibition studies revealed that the combining sites of the former antibodies were complementary to amoxicillin in a form that permits binding to the hydroxyaminobenzyl side-chain and the thiazolidine ring carboxyl. These conditions are satisfied with the drug in the '-oyl' but not in the '-anyl' form which involves linkage through the 2-carboxyl of the thiazolidine ring. With the second serum, adsorption studies showed that the wide-ranging reactivity of IgE was due to a single population of antibodies that detected a common specificity on the different penicillins. Combining site studies revealed clear recognition of the benzyl portion of the side-chain of benzylpenicilloyl, benzylpenicillanyl, ampicilloyl, ampicillanyl and amoxicillanyl determinants when free antibody access to the side-chain was possible but little or no recognition of the ring hydroxyl of amoxicillin. Such uninhibited access may not occur, however, when amoxicillin is conjugated in the '-oyl' form since opening the beta-lactam ring allows increased flexibility and rotation of the molecule and the possibility of close association of the hydroxyaminobenzyl side-chain of amoxicillin with the linked peptide carrier. In such close steric association, H-bonding involving the ring hydroxyl and amino acids of the carrier may prevent antibody access to the side-chain region of the amoxicilloyl determinant.

Development of an enzyme-linked immunosorbent assay for fentanyl and applications of fentanyl antibody-coated nanoparticles for sample preparation

“…Usually the antibodies elicited against a hapten-carrier conjugate recognize a partial structure on the hapten molecule that is remote from the coupling position. The remote carrier is better than the structure near the coupling site because of better steric accessibility [39]. From the structural relationship it is plausible that carboxyfentanyl and hemocyanin conjugates, at or close to the R 4 position, render R 3 and R 4 less significant to recognition by this antibody.…”

IgE and Drug Allergy: Antibody Recognition of ‘Small’ Molecules of Widely Varying Structures and Activities

“…Examination of the specificities of penicillin-reactive IgE antibodies in the serum from a number of allergic patients revealed a heterogeneous group of allergenic determinants consisting exclusively, or in part, of the side chain groups of penicillins, the β-lactam ring and the thiazoline ring [16][17][18][19][20]. In some patients the entire penicillin molecule comprises the IgE-binding determinant structure.…”

Antibiotic allergy: Immunochemical and clinical considerations

“…Different allergic subjects may recognize different determinants, and account must be taken of side-chain and core-structure determinants and possible cross-reactions within and between the two families of drugs [18]. Indeed, an additional and even finer level of specificity may sometimes occur: for example, a patient who shows allergic recognition of a penicilloyl but not the corresponding penicillanyl determinant and another allergic patient who shows the reverse [22]. In light of these insights, investigators should be working toward achieving the "ideal" diagnostic protocol for the accurate diagnosis of immediate hypersensitivity reactions to -lactam antibiotics [18].…”

“…This suggests the need to employ not only a wider variety of individual drugs but also drugs in different hapten-conjugate linkages in skin and antibody tests. We base this conclusion on findings that include demonstration of allergic sensitivity and positive skin and IgE tests to flucloxacillin but not to benzyl penicillin [16]; antibody recognition of the amoxicilloyl but not the amoxicillinanyl determinant in one allergic subject but the reverse recognition pattern in another patient [22]; and demonstration of fine structural recognition differences on R1 and R2 side chains of cefaclor by IgE antibodies from cefaclor-allergic subjects [14].…”

“…Side chain determinants on penicillins and cephalosporins and some important small antigenic differences have been identified, demonstrating the power and resolution of the careful application of classical quantitative hapten inhibition studies [13]. For example, for the penicillins, allergic specificities distinguish structural differences between benzylpenicillin and amoxicillin [12,15], ampicillin and amoxicillin [12], and amoxicilloyl and amoxicillanyl determinants [22]. A similar spectrum of specificities has been found with cephalosporins [14,18,27], and at the level of crossreactivity of -lactams, structures that at first appear not closely related, namely benzylpenicillin and cephalothin, were shown to share a common allergenic structure recognized by cross-reacting IgE antibodies [27,28].…”