Searching for the antibody producers

Cellular Immunology, 1985

The Journal of Immunology

African Journal of Biological Sciences, 2021

The phenomenon of facilitation of viral infections by antibodies (ADE antibody dependent enhancement) as well as the resistance of agammaglobulinemia patients to certain viruses are in contradiction with the protective role of antibodies affirmed by classical immunology. This must be compared to the opsonizing antibodies that promote the specific phagocytosis of extra-cellular bacteria. However, questions about the role of antibodies have been raised since the beginning of the history of immunology. More recently, Pierre Sonigo has shed light on the contradictions between the finalist interpretation of the role of lymphocytes and the theory of evolution: how can it be explained that cells are selected to protect the organism they constitute? The role of anti-viral and antiintracellular bacteria antibodies could be to allow phagocytosis by the cells: either directly by the Fc fragment of immunoglobulins, or via the complement for many cell types. This makes it easy to understand the selection of antibodysecreting cells. Natural selection favors the cells that produce the most affine Ig and thus guides the maturation of the proB cell to the plasma cell. A review of recent publications in theoretical immunology is consistent with this hypothesis. The theory of evolution should be integrated at every level of research and teaching in immunology, as it is for biology as a whole.

Medical History, 1994

Such cultures could be valuable for medical and industrial use." Thus read the final sentence of an immunological paper published in Nature in 1975 by the Argentinian born Cesar Milstein, and his German post-doctoral fellow, Georges Kohler. Entitled

Nature Immunology, 2002

The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document and are linked to publications on ResearchGate, letting you access and read them immediately. http://immunol.nature.com • february 2002 • volume 3 no 2 • nature immunology 105

Cellular Immunology, 1992

During the period of 1895-19 10, immunology was preoccupied with defining the cellular (Elie Metchnikotf's phagocytosis theory) as opposed to the humoral basis of bactericidal defense. Although initial discovery of immunopathologic phenomena had been made (e.g., relating to transplantation, autoimmunity, allergy), focus on microbicidal therapy and diagnosis of infectious diseases remained the major stimuli of inquiry. The debate concerning the relative roles of phagocytes, complement, amboceptors (sensibilizing factors, antibody, antitoxins), various lysins (e.g., bacteriolysins, spermatolysins, hemolysins), agglutinins, stimulines, and then Almoth Wright's opsonins reflects the ambiguity of a scientific language being created in an era still struggling with a poorly defined experimental system, for the language, both its vocabulary (newly studied phenomena) and grammar (operational mechanisms) was yet to be codified. The joint award of the Nobel Prize to Metchnikoff and Paul Ehrlich in 1908 for their respective contributions to the "theory of immunity" appeared to proclaim a consensus, but the secret Nobel Committee reports that evaluated Metchnikoff's contributions reveal only a grudging acceptance of his position, and the award was clearly made on the basis of an apparent complementarity between the theoretical views of the humoralists and those elements of the phagocytosis theory that fit the then current discussion of immunity. In this regard, opsonins played an especially important role as both an experimental and conceptual bridge between the competing schools. What was no longer under consideration (and in fact never was explicitly debated) concerned the intellectual foundation of Metchnikolf's original concept of immunity as those activities that defined organismal identity, (developed from Metchnikoffs research in developmental biology) and which regarded host defense mechanisms as only subordinate to this primary function. Immunology in the first half of the 20th century pursued issues pertinent to chemically characterizing immune specificity and only later returned to the Metchnikovian question of how the immune identity was established. This latter venture has achieved molecular sophistication, but even such a formulation may be an inadequate answer to the Metchnikovian postulate. The theoretical discussion between cellularists and humoralists continues in new guises, for the essential debate remains unresolved. o 1992 Academic Press, Inc. I. ON PHAGOCYTES, HUMORAL FACTORS, AND OPSONINS The intellectual origins of immunology in large measure revolve around the phagocytosis theory presented by Elie Metchnikoff in 1883. The genesis of that hypothesis 505

Journal of Experimental Medicine

An increasing number of studies has accumulated during the past two decades implicating lymphoeytes and blast cells , as well as plasma cells, in the synthesis of antibody. Hayes, Dougherty, and Gebhardt offered the first evidence that lymphocytes might secrete antibody by demonstrating the specific binding of bacteria to the surfaces of a small number of lymphoid cells (15). Coons and his colleagues developed the fluorescent antibody technique and were able to detect, within the lymphoid tissues of immune animals, antibody in the cytoplasm of cells that resemble lymphocytes . In most of these reports, the antibody-forming elements have been classified according to criteria of fight and fluorescent microscopy, which are inadequate to define a substantial number of mononuclear cells. Harris et al. revealed the fine structure of a few cells that had formed hemolytic plaques and reemphasized the role of lymphocytes in antibody synthesis. Also using the electron microscope, Cunningham eta/. (20) and Storb et al. (21, have more recently demonstrated similar results. Our study has corroborated and extended their observations and has had a two-fold purpose: first, to classify quantitatively with the electxon microscope the cell types that were capable of antibody synthesis; and second, to develop an ultrastructural method with more versatility than the technique of fishing for hemolytic plaques or "rosettes." With the method applied in this investigation it was possible to use a wide variety of antigens, soluble or particulate, and to examine a reasonably large number of tagged cells in the electron microscope. * This is Publication No. 314 from

Journal of Immunology, 2009

1974

The generation of antibody diversity can be discussed at two levels: genotype and phenotype. The genetic question is, does the germ line genome contain all antibody genes, or are some created (by mutation) during the life of the individual? An equally important question at the level of phenotype is, when is immune competence expressed during development of an individual, and, particularly, does antigen stimulation increase the repertoire of competent cells? In this short article we will concentrate on the last question, after first listing reasons why we prefer somatic mutation to germ line theories at the genetic level. We will draw attention to some of the considerable body of indirect evidence that supports antigen-generated diversity and briefly discuss experiments that can directly test whether entirely new kinds of immunocompetent cells appear during the course of an immune response. GERM LINE VERSUS SOMATIC MUTATION Wigzell has recently, in this journal, stated the case for the germ line theory (38). Others have argued in detail for (6) or against (19) somatic mutation. The following points seem to us to make the gerrri line theory unlikely: 1. Although restricted and heritable antibody patterns are produced in some circumstances (23, 28, 37, for example), antibody responses are usually extremely heterogeneous and variable between individuals, even between members of the same inbred strain (4, 24). That is, variability seems to be the rule and homogeneity (which certainly implies some germ line gene control) the exception. 2. If all V genes exist in every cell, what determines which one the cell will express? This would seem to require a regulatory system as specific as antibody itself. 3. Why does a species retain a large number of genes that most individuals never use? 4. The existence of species-specific amino acids (11) and V-region aiiotypes (39) in Ig molecules implies few, rather than many, germ line genes. 5. Evidence for inheritance of idiotypes (13, 31) and other markers of antibody structure must be weighed against cases where such markers are not inherited (21, 29). Proof of somatic mutation would be a direct demonstration (for example, by RNA-DNA hybridization) that cells producing different antibodies have different genes. Suggestive evidence would be that lymphoid cells have some unique DNA. By contrast, the germ line theory will be harder to prove unequivocally: even a demonstration of several thousand different V genes in the DNA would not be enough, since the important question would still be whether these could be further amplified by mutation in somatic life. We would like to enter a plea, on behalf of Aj/^ermutation (1, for example) as a possible genetic mechanism at V-gene loci. If this occurs, then antibody molecules differing in framework as well as in contact residues (7) might come from the same initial gene. This would mean that V regions now assigned to different subgroups might evolve from the same gene.

Nature immunology, 2000

When we remember that immunology was barely a decade old and knowledge of circulating antibodies only two years old when Ehrlich performed the experiments described, we can appreciate the inventiveness of his experimental designs. With little wasted effort he planned simple and rapid experiments to answer crucial questions about the mechanism of passive transfer of antibody from mother to fetus to suckling young. Most remarkable and difficult were the foster mother experiments, as anyone who has tried these with mice will attest. But they were judged to be critical and thus were pursued with ultimate success. These experiments would not be improved upon for 60 years, when the identification of immunoglobulin classes made differential transplacental and transglandular passage of immunoglobulins an object of interest. To conceive of studying the kinetics of the immune response by measuring changes in antibody concentration in the milk of lactating animals was yet another demonstration...