A Few Key Historical Events in the Antibody Field: The Alacritous Antibody.

We have coined the term "alacrity" to describe the extraordinary diversity of B cell activation potentials, even among cells in a single B cell clone responding to a single antigen. The discovery of methodologies for B cell culture in limiting dilution allowed scientists to identify the source of cellular heterogeneity among cells of the immune system. Analyses of individual B cells set the stage for more detailed descriptions of the factors that diversify B cell functions, some of which will be expanded upon by partner articles in this B cell issue.

Remembering antibodies coming of age.

Fifty years ago, Norbert Hilschmann discovered that antibodies have variable immunoglobulin domains to bind antigens, and constant domains to carry out effector functions in the immune system. Just as this happened, the author of this perspective entered the field of immunology. Ten years later, the genetic basis of antibody variability was discovered by Susumu Tonegawa and his colleagues at the Basel Institute for Immunology, where the author had become a scientific member. At the same time, Georges Köhler, a former graduate student of the author's at the Basel Institute, invented with Cesar Milstein at the Laboratory of Molecular Biology in Cambridge, England, the method to produce monoclonal antibodies. The author describes here his memories connected to these three monumental, paradigm-changing discoveries, which he observed in close proximity.

Edelman's view on the discovery of antibodies.

Gerald M. Edelman began working to the structure of antibodies when joined as graduate student the laboratory of Henry Kunkel in 1958 at the "Rockefeller University" in New York, obtaining his doctorate in 1960. Edelman's focus on the structure of antibodies led to the 1972 Nobel Prize in Physiology or Medicine along with Rodney R. Porter. Edelman and Porter decided to approach the problem of antibodies structure by splitting. In 1959, Porter published a report in which he used the enzyme papain to cleave the antibody molecule into three pieces of about 50,000 Da, corresponding to the two Fab (antigen-binding) and constant Fc (crystallizable) fragments. In the same year, Edelman showed that reduction of the disulfide bonds of antibodies in the presence of denaturizing agents led to dissociation of the molecule into smaller pieces, now known to be the light (L) and heavy (H) chains.

A personal perspective: 100-year history of the humoral theory of transplantation.

The humoral theory states that antibodies cause the rejection of allografts. From 1917 to 1929, extensive efforts were made to produce antibodies against tumors. It was finally realized that the antibodies were produced against the transplant antigens present on transplantable tumors, not against the tumor-specific antigens. To get around this problem, inbred mouse strains were developed, leading to identification of the transplant antigens determined by the H-2 locus of mice. The antibodies were hemagglutinating and cytotoxic antibodies. The analogous human leukocyte antigen system was established by analysis of lymphocytotoxic alloantibodies that were made by pregnant women, directed against mismatched antigens of the fetus. The human leukocyte antigen antibodies were then found to cause hyperacute rejection, acute rejection, and chronic rejection of kidneys. Antibodies appeared in almost all patients after rejection of kidneys. With Luminex single antigen bead technology, donor-specific antibodies could be identified before rise in serum creatinine and graft failure. Antibodies were shown to be predictive of subsequent graft failure in kidney, heart, and lung transplants: patients without antibodies had superior 4-year graft survival compared with those who did have antibodies. New evidence that antibodies are also associated with chronic failure has appeared for liver and islet transplants. Four studies have now shown that removal or reduction of antibodies result in higher graft survival. If removal of antibodies prevents chronic graft failure, final validation of the humoral theory can be achieved.

The study of B cells and antibodies in Japan: a historical perspective.

Japanese scientists were involved in pioneering work on therapeutic antisera and have made huge contributions to the characterization of the antibody molecules that are responsible for this and many other biological activities, as well as working back to understand the B cells that produce these Igs. This review emphasizes the role of Japanese immunologists in this field, starting with their work in developing antisera and studying the structure of Igs. It describes the molecular mechanisms that generate the enormous antibody repertoire and regulate B-cell development and signaling. It also details the importance of the germinal center in generating B-cell memory and the terminal differentiation of B cells as antibody-secreting plasma cells.

[From the ancient serotherapy to naked antibodies: a century of successful targeted therapies]. / De la sérothérapie aux anticorps recombinants << nus >> : plus d'un siècle de succès en thérapie ciblée.

Monoclonal antibodies and molecular engineering have renewed the ancient serotherapy, multiplying the possibilities of therapeutic interventions and providing many new clinical successes! Standing back about this history allows us to better understand the evolution of concepts underlying the therapeutic use of antibodies, as well as the maturation of the tool itself. The different principles of therapeutic targeting will be successively tackled, from their sometimes hundred year-old conception until the most recent clinical developments: antibodies neutralizing toxins and soluble antigens, anti-microbial antibodies, cytotoxic antibodies, tumour-specific antibodies, cell function -modifying antibodies, etc. This overview will finally offer the opportunity to introduce a new pharmacological classification of the entire class of unconjugated -therapeutic antibodies.

Phages, antibodies and de-monstration.

Using examples from the field of molecular genetics and immunology, this paper examines the argumentative strategy underlying the use of electron micrographs as decisive evidence for previously uncertain or disputed claims. Scientists often resort to visual imagery in order to demonstrate the factual status of their claims and thus to compel assent from their peers, therefore bypassing other forms of argumentation such as propositional reasoning. The particular form of demonstration discussed in this article resorts to the use of photography rather than drawings and diagrams. While the mechanical objectivity of micrographs certainly adds to their evidential strength, the pictures we examine derive part of their power from their arrangement in a sequence that mimics experimental operations. The visual argument tracks the textual report of the steps in a biochemical or molecular genetic experiment, with which it becomes intimately associated. We conclude that much of the evidential strength conveyed by the articles we analyze is to be sought less in the extrinsic attributes of the instrumentation they mobilized than in the specific material and argumentative practices enacted by those particular uses of the instrument.

100 years of 'Allergy': can von Pirquet's word be rescued?

Summary It is 100 years since Clemens von Pirquet wrote his classic paper introducing the term 'allergy'. Although the word is no longer used in the way he intended, his concept of 'changed reactivity' laid the foundation for the modern science of immunology.

Labeled antigens and antibodies: the evolution of magic markers and magic bullets.

The ability to label antigens and antibodies with simple chemicals and even with whole proteins fostered new approaches to basic studies of the immune system as well as new methods of immunodiagnosis and immunotherapy. This was especially true following the introduction of monoclonal antibodies, which enhanced the specificity of many of these applications. The uses to which these labeled immunoreagents were put were legion, and those who employed them might come from any field of biology or medicine. Many of these technical elaborations were critical to progress in immunology and in many other biomedical sciences. They illustrate also the often complex interplay between technology and theory.