From the Structure of Antibodies to the Diversification of the Immune Response

Abstract

Cuando se acerca elfin, escribió Cartaphilus, ya no quedan imágenes de1 recuerdo; sólo quedan palabras. Palabras, palabras desplazadas y mutiladas, palabras de otros, fué la pobre limosna que le dejaron las horas y los siglos. J. L. BorgesWhen an animal is infected, either naturally or by experimental injection, with a bacterium, virus, or other foreign body, the animal recognises this as an invader and acts in such a way as to remove or destroy it. There are millions of different chemical structures that the animal has never seen and yet which it is able to recognise in a specific manner. How is this achieved? Scientists have been fascinated by this question for most of this century, and we continue to be fascinated by the intricacies and complexities that still need to be clarified. Even so, looking back over the years since I myself became involved in this problem, progress in the understanding of the process has been phenomenal. Suffice it to remind our younger colleagues that 20 years ago we were still trying to demonstrate that each antibody differed in its primary amino acid sequence. What attracted me to immunology was that the whole thing seemed to revolve around a very simple experiment: take two different antibody molecules and compare their primary sequences. The secret of antibody diversity would emerge from that. Fortunately at the time I was sufficiently ignorant of the subject not to realise how naive I was being.Back in 1962, when I had by accident become the supervisor of Roberto Celis in Argentina, it occurred to me that antibody diversity might arise from the joining by disulphide bridges of a variety of small polypeptides in combinatorial patterns. I don't know whether anybody else had the same idea at that time, but of-all the prevailing theories about antibody diversity that I am aware of, this is one that was widest of the mark. I hold it to my credit that I never put it into print. But it was of great value to me as it provided an intellectual justification to work on disulphide bonds of antibodies. bonds. Each chain has two regions. The variable region differs in structure from one antibody to another and contains the combining site. The antibody combining site is located at the tips of a Yshaped three-dimensional structure. The constant region is invariant within a given class or subclass, and is responsible for effector functions (complement binding, attachment to and transport across membranes etc). The number and position of the interchain disulphide bonds is characteristic for the different classes and subclasses. In this figure, the structure depicted is the mouse myeloma protein MOPC 21 which was the subject of much research in our laboratory.chains joined by disulphide bonds (Fig. 1) had been established (l), and I was eager to accept Dr. Sanger's proposal that I should engage in studies of antibody combining sites. The nature of antibody diversityAt first I looked for differences in fingerprints of digests of iodinated antibodies directed against different antigens. The pattern...

Human lupus anti-DNA autoantibodies undergo essentially primary V kappa gene rearrangements.

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Immunogenetic Analysis of Variable Regions Encoding AB1 andγ-Type AB2 Antibodies from the NeuGc-Containing Ganglioside Family

“…Previous studies have shown that, in general, somatic mutations in H-and L-chain variable regions tend to occur concurrently. (29) Nevertheless, in some re- ports it is possible to find differences in the levels of mutations between the heavy and light chains. (30,31) This has been interpreted as an evidence of independent activity of the hypermutation machinery in each chain.…”

The structural basis of αβ T‐lineage immune recognition: TCR docking topologies, mechanotransduction, and co‐receptor function

“…Initial studies suggesting the existence of an ‘I‐J‐specific’ suppressor factor secreted by T cells and TCR specificity achieved through Ig genes were refuted. Rather, the discovery of how to expand T cells in vitro, via IL‐2‐dependent T‐cell cloning , in conjunction with monoclonal antibody and flow cytometry screening technologies plus in vitro functional analyses was decisive in molecular identification for the long sought‐after TCR. The key breakthroughs came in the early 1980s with the identification in human of a clonotypic disulfide‐linked heterodimer, the Ti αβ TCR heterodimer, which together with CD3 molecules, were essential for peptide/MHC complex recognition and cellular activation .…”