Structure and evolution of immunoglobulins

Milstein, C.; Pink, J. R. L.

doi:10.1016/0079-6107(70)90026-x

Cited by 194 publications

(96 citation statements)

References 152 publications

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“…Many studies on the structures of human and mouse myeloma immunoglobulins have been reported in recent years (1)(2)(3). These proteins possess a striking uniformity and show structural features common to the immunoglobulin molecules of several species, and their study has permitted the delineation of variable and constant regions of the immunoglobulins.…”

mentioning

confidence: 99%

Amino-Acid Sequences of Light Chains of a Rabbit Anti- p -Azobenzoate Antibody

Appella

Chersi

Roholt

et al. 1971

Proc. Natl. Acad. Sci. U.S.A.

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Half-cystine peptic peptides representing the intrachain disulfide bonds of the light chain from an apparently homogeneous rabbit anti-p-azobenzoate antibody were isolated in good yields after reduction and alkylation with ["C]iodoacetate, and their sequences were determined. The sequence of the first 21 amino-terminal residues was also determined. The good yields of these peptides, the fact that no variants of any of them were found, and the cleanness of the amino-terminal sequence determination confirm the high degree of homogeneity of this light-chain preparation. Previous Many studies on the structures of human and mouse myeloma immunoglobulins have been reported in recent years (1-3). These proteins possess a striking uniformity and show structural features common to the immunoglobulin molecules of several species, and their study has permitted the delineation of variable and constant regions of the immunoglobulins. These variable regions are primarily responsible for differences among individual myeloma proteins and for the different specificities among individual antibodies.The heterogeneity of most antibody preparations is well known, and because of this heterogeneity, amino-acid sequence determinations have not been possible. There are, however, reports of antibodies that appear to have restricted heterogeneity. Antihapten antibodies formed by certain individual rabbits against p-azobenzoate that is coupled to bovine gammaglobulin have been reported to be of very restricted heterogeneity (4, 5). Hyperimmunization of rabbits with streptococcal or pneumococcal vaccines has also resulted in a response of limited heterogeneity (6, 7).In this report, we present the sequences of the peptic peptides that contain half-cystines and the N-terminal aminoacid sequence of the light chain of a homogeneous antibenzoate antibody prepared in the rabbit. A major factor in the success of the determination was the homogeneity of the light chain. buffer (pH 3.1-5.0). The radioactive fractions were further purified by high-voltage paper electrophoresis at pH 6.5 and at pH 3.6. For light chains from rabbit 2717, the fractionation on the column was omitted and the peptides that contain half-cystine were purified directly by high voltage paper electrophoresis. Amino-acids were analyzed with a BeckmanSpinco model 644 amino-acid analyzer. Samples were hydrolyzed under reduced pressure in 6 N HC1 for 24 hr. Digestion with carboxypeptidases A and B was done as described elsewhere (10). Amino-terminal residues of peptic peptides were identified by the dansyl method of Gray and Hartley

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confidence: 99%

Amino-Acid Sequences of Light Chains of a Rabbit Anti- p -Azobenzoate Antibody

Appella

Chersi

Roholt

et al. 1971

Proc. Natl. Acad. Sci. U.S.A.

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“…Upon inspection of the amino acid sequences of the variable regions of heavy and light chains of immunoglobulin molecules, it became apparent that the positions at which variation occurs are dispersed throughout the variable regions. Certain portions showed a remarkable high degree of variability relative to the background [54] . Three hypervariable regions were found in the light chains [55,55a].…”

Section: S86mentioning

confidence: 99%

Selected highlights in immunological research in the last decade

Sela

1974

FEBS Letters

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This is an impressionistic and, therefore, undoubtedly subjective view of one immunologist on what seem to him the most interesting developments in the broad realm of immunology in the last ten years. Even to mention exclusively the titles of all those studies which deserve comment here would take up more than all the space allotted. I must thus start by pleading with all those friends and colleagues whose interesting work is not mentioned here to bear with me.The progress of immunology on the molecular level has been enormous, and it is not an exaggeration to state that the basic structure of antibody has been essentially formulated and solved within this decade. This success was symbolized in the joint award of the Nobel prize in Medicine and Physiology for 1972 to Rodney Porter [l] and Gerald Edelman [2] . On the antigen side, we have reached a much better understanding of the molecular basis of antigenicity (and of other immunological phenomena) largely due to the use of precisely designed immunogens. The synthetic approach has also been instrumental in the recent developments concerned with the genetic control of immune response.Lately we have begun to understand immunology at a cellular level. Certain crucial questions are still a matter of deep controversy, and the molecular approach to cellular immunological phenomena has not been yet used too extensively.

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“…By 1970 we became convinced that "the section of the genome involved in the coding of immunoglobulin chains undergoes an expansion-contraction evolution: that the number of individual genes coding for basic sequences is not large, and that it varies in different species and even within species at different stages of its own history. The task of providing for the endless variety of individual chains is left to somatic processes" (13).…”

Section: The Nature Of Antibody Diversitymentioning

confidence: 99%

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

Milstein¹

1993

Scand J Immunol

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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...

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Structure and evolution of immunoglobulins

Cited by 194 publications

References 152 publications

Amino-Acid Sequences of Light Chains of a Rabbit Anti- p -Azobenzoate Antibody

Amino-Acid Sequences of Light Chains of a Rabbit Anti- p -Azobenzoate Antibody

Selected highlights in immunological research in the last decade

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

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