Selection Theory Of Antibody Formation Research Articles

Molecular mimicry and clonal deletion: A fresh look

In this article, I trace the historic background of clonal deletion and molecular mimicry, two major pillars underlying our present understanding of autoimmunity and autoimmune disease. Clonal deletion originated as a critical element of the clonal selection theory of antibody formation in order to explain tolerance of self. If we did have complete clonal deletion, there would be major voids, the infamous “black holes”, in our immune repertoire. For comprehensive, protective adaptive immunity, full deletion is necessarily a rare event. Molecular mimicry, the sharing of epitopes among self and non-self antigens, is extraordinary common and provides the evidence that complete deletion of self-reactive clones is rare. If molecular mimicry were not common, protective adaptive immunity could not be all-encompassing. By taking a fresh look at these two processes together we can envision their evolutionary basis and understand the need for regulatory devices to prevent molecular mimicry from progressing to autoimmune disease.

Immunology (1955–1975): The Natural Selection Theory, the Two Signal Hypothesis and Positive Repertoire Selection

Observations suggesting the existence of natural antibody prior to exposure of an organism to the corresponding antigen, led to the natural selection theory of antibody formation of Jerne in 1955, and to the two signal hypothesis of Forsdyke in 1968. Aspects of these were not only first discoveries but also foundational discoveries in that they influenced contemporaries in a manner that, from our present vantage point, appears to have been constructive. Jerne's later hypothesis (1971, European Journal of Immunology 1: 1-9), that antibody-like receptors on lymphocytes were selected over evolutionary time for reactivity with the major histocompatibility complex (MHC) antigens of the species, was a first, but it was incorrect, and was foundational only to the extent that it emphasized the need to explain the Simonsen phenomenon. Although easily construed as derivative of Jerne (1971), the affinity/avidity model of Forsdyke (1975, Journal of Theoretical Biology 52: 187-198), which predicted that cell-surface components, including MHC antigens, would restrict antigen-reactivity by somatically shaping lymphocyte repertoires, was actually an extension of the two signal hypothesis. While presenting a mechanism for the positive selection of lymphocyte repertoires, and explaining the Simonsen phenomenon, the affinity/avidity model was not foundational in that it had to be independently rediscovered. For science to advance optimally we must seek to close temporal gaps so that first discoveries are also foundational. Listening to young scientists may be part of the solution.

Sir Frank Macfarlane Burnet and the clonal selection theory of antibody formation

Sir Macfarlane Burnet has been one of the twentieth century's outstanding biologists. In the years 1941-1956, Burnet focused his effort on the elaboration of a theory of antibody synthesis, the clonal selection theory, capable of bridging the gap between physiological findings, such as the kinetics of antibody production, self-tolerance and immunological memory on the one hand, and the newest ideas on synthesis of proteins, on the other. At the time of writing the clonal selection theory, Burnet was 57 years old and the Director of the Water and Eliza Hall Institute in Melbourne, Australia.

Biochemistry and the Sciences of Recognition

Biochemistry and the Sciences of Recognition

The Clonal Selection Theory: what it really is and why modern challenges are misplaced.

Historical insight: The clonal selection theory of antibody formation has recently been subjected to challenge from many quarters. A review of its history and that of scientific theories in general points to the importance of distinguishing between the central hypotheses of a theory and its subsidiary implications.

The life and work of Niels Kaj Jerne as a source of ethical reflection.

Niels Kaj Jerne, one of the leading theoreticians in 20th century immunology, was awarded the 1984 medical Nobel Prize for the natural selection theory of antibody formation, the haemolytic plaque technique, and the idiotypic network theory. A number of reasons for remembering Jerne are discussed, and three aspects of his life and work from three different life-phases are analysed. Drawing upon the classical tradition for writing biographies as 'ethical exemplars', the paper concludes that a major reason for remembering Jerne is that his life story addresses fundamental questions about how to live as a scientist in contemporary culture.

Paul Ehrlich's Passion: The Origins of His Receptor Immunology

In 1897, Paul Ehrlich published a selection theory of antibody formation that anticipated the theories of Jerne and Burnet by some 60 years. Ehrlich introduced into immunology the concept of the interaction of physiologically active substances with specific receptors, an idea that still dominates modern immunological thought. In this paper, we point out how Ehrlich's concept matured over 20 years, while it governed his studies in histological staining, in cell physiology, in hematology, and finally in his major contributions in experimental immunology.

A speculative view of immune recognition.

The speculation that immunologically reactive haptens must be those attached to carriers' immunodominant epitopes suggests a clearer mechanism by which the mysterious hapten-carrier phenomena are generated. This review focuses on the molecular biological nature of immune recognition of hapten-protein antigens both by the T-cell and the B-cell. T and B lymphocytes specifically recognize one determinant of the same antigen molecule in two different ways and in different circumstances. The B-cell recognizes an antigen by the preliminary antigen receptors on the cell's surface, at the time it is still intact, interiorizes it and presents the processed antigenic peptide after an antigen processing procedure. In contrast, the T-cell recognizes a hidden antigenic determinant, together with portions of the MHC on the presenting cell. The immune memory is mainly directed to the hidden internal determinant of an antigen. Some aspects of the clonal selection theory of antibody formation are also discussed at the modern molecular level.

Darwinian overtones: Niels K. Jerne and the origin of the selection theory of antibody formation

Comment sont produits les anticorps? Apres differentes theories proposees par de nombreux chercheurs, Jerne (N.K.) supposa que le plasma sanguin possedait des anticorps specifiques, diriges contre la plupart des substances etrangeres, et proposa un mecanisme de production et de selection de tels anticorps

Ontogeny of the clonal selection theory of antibody formation. Reflections on Darwin and Ehrlich.

This is an idiosyncratically personal account of the origins, about 30 years ago, of the clonal selection theory, a no longer controversial integrating theme of immunological research. As an interested participant, the perspectives I can offer are those within my own ken, inevitably an egocentric one. This will unfortunately understate the independent roles played by a host of others, including several in these proceedings. Other historical accounts’*2 may give a more objective view. However, some parts of my story have not been told before. It will be of particular interest to students of the philosophy and socioiogy of science to analyze the processes of resistance and acceptance of clonal selection theory after 1957, until its general acceptance around 1967.3m5 My personal mise-en-scene begins in 1955. I had been at the University of Wisconsin since 1947, having gone there directly from my work in Ed Tatum’s lab at Yale and Francis Ryan’s at Columbia. If I needed any reinforcement about the interest antigens and antibodies would have for general biological theory, I would have received this amply from M. R. Irwin. Ray Owen had left Wisconsin for Caltech just before I arrived, but his intellectual trace was everywhere. However, my own work was strictly confined to the genetics of Escherichia coli and of salmonella. The diversity of serotypes in salmonella had been one of the conceptual clues to genetic recombination in bacteria, and I had at least one experimental contact with immunology, namely, serology of tlagellar and somatic antigens.6 The principal antecedental threads of clonal selection, at least for this microbiologist, were: (1) physicochemical concepts of serological specificity, spanning from Paul Ehrlich to Karl Landsteiner and Linus Pauling; (2) the revalidation of Darwinian models (namely, prior spontaneous mutation and natural selection) in their application to adaptation in microorganisms, such as the development of specific resistance to antibiotics; (3) an emerging understanding of gene expression in protein synthesis, particularly in substrate-induced enzyme synthesis in bacteria; and (4) a developing conception of a genetics of somatic cells by analogy with the genetics of bacteria (Mendelian models). Karl Landsteiner’s “The Specificity of Serological Reactions” focused attention on antigen-antibody reaction as a prototype of biological specificity. Pauling’s chapter in the 1945 edition’ showed how “specificity can arise in the interaction of large molecules as a result of the spatial configuration of the molecules.” The seminal value of this stereochemical axiom was unfortunately not matched by well-founded speculations on the mechanism of antibody synthesis. In the early 1950s there was notably little serious discussion of the mechanism of antibody formation. The most prevalent

Auto-Immunity And Auto-Immune Disease.

To many a man, retirement means the end of his productive life. Not so for the academic physician like Sir Macfarlane Burnet. Relieved of the responsibility of running a world-famous medical research institute, the Walter and Eliza Hall Institute in Melbourne, he has already authored two important postretirement books in the field of cellular immunology. The first,Self and Not Self, updated his clonal selection theory of antibody formation. The second,Immunological Surveillance, concerned cancer immunity. In the present volume, Burnet reviews his thinking on a topic to which he made outstanding contributions during his days as a working scientist. To explain the exceptions to self-recognition, Burnet invokes two special extensions of the clonal concept. The first is the process of somatic mutation to explain the origin of those forbidden clones that should have been eliminated or arrested by self-antigens. The second is the application of statistical analyses in the

The Darwinian selection theory of antibody formation

A theory of antibody production is proposed in which (1) macrophages phagocytize the immunogen and transfer an immunogen-RNA complex to lymphocytes, (2) the RNA combines with the initiator locus of the lymphocyte and (3) a γ-globulin molecule with threshold avidity for the immunogen combines with it and, by allosteric changes, activates the initiator gene. Thus, it is seen that any cell making specific antibody will be selected for in the Darwinian sense and become more numerous in its kind. The mechanism is shown to explain the classical immunological phenomena of specificity, variety, tolerance, lymphoproliferation, spontaneous termination, anamnesia, recognition of self and increased affinity with the passage of time. An advantage to a system of antibody production involving two cell types is offered in the light of the proposed mechanism.

The rate of division of antibody-forming cells during the early primary immune response.

Mitotic blocking agents, colchicine or Velban, were used to estimate cycle times of spleen cells which release hemolysin for sheep erythrocytes (plaque-forming cells). The cells were obtained either from rats immunized with sheep erythrocytes or from cultures of mouse spleen cells immunized in vitro with the same antigen. 2, 3, or 4 days after immunization, animals or cell cultures were treated with mitotic blocking agents for periods of time ranging from 2.5 to 7 hr; plaque-forming cells were then enumerated. Decreased numbers of plaque-forming cells were found after such treatment. The extent of reduction was a function of duration of the drug treatment and the method of immunization, but was independent of the time after immunization. The evidence presented is consistent with premises that: (a) plaque-forming cells in mitosis do not release sufficient antibody to be detected, (b) mitotic blocking agents, by arresting plaque-forming cells in metaphase, prevent not only detection of these cells but also the increase in number of plaque-forming cells which would have resulted from cell division, (c) mitotic blocking agents do not affect release of antibody by cells in interphase. Cell cycle times, based on the extent of reduction of plaque-forming cells per unit time of drug treatment, were estimated using a mathematical model appropriate for an exponentially increasing population of cells. Cell cycle times estimated using the mitotic blocking agents agreed well with cell doubling times calculated from the increase in plaque-forming cells occurring 1-4 days after immunization. Increased responses produced by higher antigen doses or treatment of immunized animals with an adjuvant resulted from an increased rate of division of responding cells and their progeny. The results are consistent with a cell selection theory of antibody formation. Antigenic stimulation causes relatively few cells to proliferate and to synthesize antibody; apparently the magnitude of the response is dependent primarily on the rate of division of responding cells. It is suggested on the basis of observations of in vitro-immunized cell cultures that the rate of division of responding cells may be dependent on the rate of interaction between two cell types, both of which are essential for the in vitro plaque-forming cell response.