The idiotypic network and the internal image: possible regulation of a germ-line network by paucigene encoded Ab2 (anti-idiotypic) antibodies in the GAT system.

Abstract

and 1D6partement d'Immunologie de l'Institut Pasteur, 28. rue du Docteur Roux, 75724 Paris Cedex 15, France Communicated by M.FougereauHeavy and light chain variable regions from eight monoclonal Ab2 (anti-idiotypic) antibodies of the GAT antigen, a (Glu60 Ala30 Tyr10)n co-polymer, have been analyzed by direct mRNA sequencing. Three mAb2s were directed against private idiotopes and used various VH-D-JH and Vk-Jk combinations. By contrast, the five 'anti-public' mAb2 antibodies used a very restricted repertoire, including all gene segments. Interestingly, within their D regions, Glu-Glu-Tyr or Tyr-Tyr-Glu sequences were reminiscent of the original (GAT) antigen and may act as possible internal images. A striking observation was that two mAb2 antibodies shared the same V-D-J sequence although derived from separate fusions. As this D sequence, 33 nucleotides long, has not been described so far, it is suggested that it may be encoded by a new germline D gene, acting as a crucial regulatory element in a GAT germ-line idiotypic network. An alternative model that may lead to the construction of this D segment by 'odd' rearrangements from pre-existing already reported sequences is also presented.

Camel single-domain antibody inhibits enzyme by mimicking carbohydrate substrate

“…To compare lysozyme's interactions with cAb-Lys3 to those with substrate, we have superimposed lysozyme models from crystal structures of complexes with cAb-Lys3 30 and three independent carbohydrate ligands. [33][34][35] To best understand interactions in lysozyme's carbohydrate binding subsites B, C, and D, we considered the structure 33 containing the product consisting of N-acetyl muramic acid (NAM) 2 50 nM 50 nM 65 nM 7.7 µM a 7.1 µM b 170 µM b a After Nakano et al 59 b After Imoto et al 60 and N-acetyl glucosamine (NAG) in which NAM, NAG, and NAM occupy these subsites (respectively). Subsite A interactions were studied using structures containing (NAG) 3 and (NAG) 4 occupying subsites A to C 34 and A to D, 35 respectively.…”

“…1 Such naturally occurring examples, however, are generated under evolutionary pressures that help to optimize a functional molecular mimicry. Antibodies, which can be generated and optimized in vivo in a matter of days or weeks, have been shown to mimic proteins, 2,3 haptens, 4,5 and even oligosaccharides, [6][7][8] but a general lack of structural data has left many details of the molecular mimicry up to speculation. Structures are known, however, for both complexes in one well-studied [9][10][11][12][13][14][15] mimicking system in which the antibody E5.2 mimics lysozyme in binding to the antibody D1.3.…”

Immunogenicity of an engineered internal image antibody.

“…Whereas the structural basis for this phenomenon remains by and large unclear, few reports exist to suggest that functional mimicry can be associated with shared primary structure between an antibody's CDR and the respective nominal antigen (15)(16)(17).…”

“…Structurally, the immunogenic property of immunoglobulins resides in the complementarity-determining regions (CDRs) of their variable (V) domains, sites where changes in sequence and conformation are tolerated with little, if any, effect on the framework of the molecule (9). For instance, the CDRs of one antibody grafted into another immunoglobulin molecule maintain in the new molecular environment the antigen-binding property of the donor antibody (10-12).Mimicry of antigens by antibodies has been reported in many systems and internal image antibodies generated through a conventional idiotypic cascade served to immunize animals against bacteria, viruses, and parasites (131 14).Whereas the structural basis for this phenomenon remains by and large unclear, few reports exist to suggest that functional mimicry can be associated with shared primary structure between an antibody's CDR and the respective nominal antigen (15)(16)(17).In the study presented here we used protein engineering techniques to verify whether an antibody expressing a "foreign" peptide epitope as an integral part of a V region could be used to induce immunity of predetermined specificity in vivo. We tested this hypothesis using a chimeric mouse/ human antibody (y1NANP) constructed to express three copies of the tetrapeptide Asn-Ala-Asn-Pro (NANP) of malaria's Plasmodium falciparum circumsporozoite (CS) protein in the CDR3 of the heavy (H) chain.…”

GD3‐replica peptides selected from a phage peptide library induce a GD3 ganglioside antibody response

“…Since Jerne advocated the idiotype network hypothesis [20], the fact that variable regions in some anti-Id antibodies include the internal images of the antigens has been documented [21][22][23]. Many anti-Id antibodies are used in place of the original antigens to induce antigen-specific immune responses.…”