Immunology for Life Scientists, Second Edition
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In general, bibliographies of recent works are going to be much better linked than bibliographies of primary literature and older works. Entries with PhilPapers records have links on their titles. A green link indicates that the item is available online at least partially. This experiment has been authorized by the editors of the Stanford Encyclopedia of Philosophy. The original article and bibliography can be found here.
Sign in Create an account. This dichotomous view led to some confusion and controversy and it took some time until it transformed into a perspective of complementary binarity considering innate and acquired immunity as interactive partners. Today the two arms of antigen-specific acquired and antigen-nonspecific innate immunity are best viewed as a ying—yang concept, with highly intertwined, partly overlapping, and mutually beneficial activities.
Further highly valuable information on the highlights of immunology in its nascence can be found in the many publications of A.
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Silverstein of which I only cite his major treatise 3. From its birth, immunology was at the heart of biomedical research providing both crucial information on basic biological processes and on clinical application. Whilst Behring's discovery illustrates how medical application can stimulate basic research, the discoveries of Allison and Honjo epitomize clinical application as the result of in-depth understanding of basic biological mechanisms.
Immunology emerged as an academic discipline in its own right out of the fertile soil of medical microbiology 6. The discoveries of Louis Pasteur — , which confirmed and completed the germ theory of infectious diseases as well as Robert Koch's — meticulous studies on the etiology of infectious diseases, notably tuberculosis, raised a question of fundamental importance: Is the host a helpless prey of pathogenic microbes or is it equipped with an efficient defense mechanism to combat its invaders?
Both Pasteur and Koch favored the notion that the host was defenseless. However it was Metchnikoff, at the Pasteur Institute in Paris since , who earlier discovered the critical role of phagocytosis and intracellular killing in host defense 1 , and it was Behring and Ehrlich, young independent researchers at Koch's institute for Infectious Diseases in Berlin, who identified antibodies as crucial counterparts to the toxic activities of bacteria 1 , 2.
We now know that the outcome of infection depends on close interactions between pathogen and host factors, probably best described by the term infection biology. Virchow is the founder of cellular pathology, which assumes that all diseases are the result of malfunctioning of our body's cells 7. Hence, Koch's ideas on the etiology of infectious diseases seconded by the germ theory of Pasteur were highly criticized by Virchow. Ultimately, Koch's observations, well-supported by experimental evidence, became the accepted paradigm.
According to the American physicist and philosopher, Thomas Kuhn — , normal science progresses as long as available evidence can be accommodated in the existing paradigm 8. Once anomalies accumulate from scientific research that can no longer be integrated in an existing paradigm, the time is ripe for a paradigm shift 8.
Koch and Pasteur introduced a paradigm shift by demonstrating that exogenous invaders can cause certain diseases, beyond those diseases caused by dysfunctional cells. Yet, they both largely overlooked the role of host immunity as important defense mechanism. This paradigm shift was initiated by Metchnikoff, Behring, and Ehrlich.
Today we understand infectious diseases as the outcome of a crosstalk between host and pathogen. We also now know that immunology has more roles to play than only pathogen defense, such as surveillance of malignant cells. Moreover, a dysfunctional immune system results in allergy, autoimmunity or chronic inflammation thereby illustrating it as a double-edged sword.
Metchnikoff was born in in a part of Russia, which now belongs to the Ukraine 9. He studied zoology and soon became a traveling scientist.
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Notably, when working at the Zoological Station in Naples he studied simple organisms and identified specialized cells dedicated to nutrient uptake. These nutrients could be contained in particles and thus the concept of phagocytosis was conceived as a process of uptake of particles or microbes rich in food. Moreover, in his experiments with starfish larvae in Messina in , Metchnikoff found that phagocytic cells were highly motile and migrated to sites of foreign insult He later wrote about these groundbreaking observations:. I was too excited to sleep that night in the expectation of the result of my experiment and very early the next morning I ascertained that it had fully succeeded.
Indeed, Metchnikoff changed his scientific interests from zoology to pathology and in this way became one of the first immunologists. He discovered phagocytes in vertebrates and began analyzing phagocyte functions in infectious diseases, such as anthrax, sepsis, and tuberculosis Figure 2. Based on these studies, he distinguished macrophages from microphages which we now call neutrophils according to the form of their nucleus:. Figure 2. Metchnikoff's view on phagocytosis of different bacterial pathogens Behring was born in the German province of Prussia, now part of Poland, in He studied medicine at an army academy and soon became interested in studies on the curative activity of disinfectants in bacterial infections.
During his experiments on antiseptic activity of small molecules, together with the Japanese guest researcher Shibasaburo Kitasato — at the Institute for Infectious Diseases in Berlin, he discovered that serum from infected animals contained antibacterial activity that was specific for the infectious agent Essentially, the activity was directed against the bacterial toxin. Whilst the joint paper of Behring and Kitasato mostly focused on tetanus and its toxin, the single-authored paper by Behring published shortly thereafter, described protection against diphtheria and its toxin by antisera 15 , Soon these animal experiments were translated into a human study, which revealed that serum therapy protected against diphtheria when given during early stages of infection or even during disease.
Behring joined forces with industry to produce large doses of antisera for human use, thus embodying the translational immunologist with great interest in medical application Figure 3. His serum therapy was a breakthrough and honored by the first ever awarded Nobel Prize in Medicine in 4.
Serum therapy was more than just a curative method. It also provided supportive evidence for the idea that the cause of infectious disease is highly specific and that this specificity is linked to toxins produced by the etiologic pathogen.
As a corollary, the cure of the specific disease was accompanied by a specific poison-averting antitoxic agent, which circulates in blood and can offer specific protection against the toxin in other individuals 15 — Despite all the honors he received, Behring was not fully satisfied with passive vaccination. It took him some 20 years to solve the issue of active vaccination This agent was harnessed for treating individuals at risk prophylactically.
In order to neutralize the diphtheria toxin, Behring generated antigen-antibody complexes, which stimulated production of toxin-specific antibodies in the immunized host. This was an important, but still suboptimal start toward active vaccination against bacterial toxins. It was the French researcher, Gaston Ramon — , who ultimately introduced detoxification by formaldehyde for low-cost production of safe vaccines against diphtheria and tetanus, and aluminum hydroxide as adjuvant for potent immunization 19 , Whilst Behring was a translational immunologist, who contributed significantly to basic immunology, Ehrlich was most interested in the in-depth understanding of basic mechanisms underlying immunity, and contributed profoundly to the clinical development of serum therapy.
Indeed it was Ehrlich whose contribution made large-scale production of antisera of reproducible quality possible. Ehrlich was therefore the first to provide the basis for a quality control measure of a biological. At those times, this was urgently needed because of widespread state-controlled compulsory vaccination against smallpox. Yet, Ehrlich became most famous for basic research of, and stimulating ideas on, how the immune system works.
In his MD thesis, Ehrlich described mast cells which, as we now know, are critical effectors of allergy But his most important findings are related to antibodies. He foresaw that antigens, such as toxins, stimulate the production of specific antibodies. Interestingly, similar to Metchnikoff, Ehrlich assumed a nutritional point of view Different cells need different kinds of nutrients and hence Ehrlich postulated specific receptors as being responsible for nutrient uptake.
From this he concluded that the cell receptor specific for a given toxin should fulfill similar criteria. Because of the sheer abundance of toxins generated during infection, more specific receptors are produced and are ultimately secreted into the serum Figure 4. In the Croonian Lecture given in at the Royal Society, Ehrlich reflected on his ideas as follows:.
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Figure 4. Ehrlich's view on antibody secretion to different antigens Essentially this is the core message of the side chain theory for which Ehrlich is most renowned. But Ehrlich was far more productive. He showed that the milk of breastfeeding mothers carries antibodies beneficial to the suckling infant, thus providing the child with a high degree of immunity He revealed several biological features of complement, which was originally discovered by the German scientist, Hans Buchner — , and the Belgian researcher, Jules Bordet — , who termed it alexine Ultimately, however, the term complement created by Ehrlich prevailed.
Bordet and Buchner had already shown that alexine was heat-labile 25 — Buchner used serum from non-immunized animals, whereas Bordet included serum from immunized animals in his studies and so distinguished the heat-labile alexine from the heat-stable antibodies. Ehrlich, together with his colleague Richard Pfeiffer — , further defined the activities of antibodies and complement by mixing untreated and heat-inactivated serum. The interaction of complement and antibodies was the first dent in the dichotomous view of immunity Figure 1.
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Complement was part of the innate immune response and hence non-specific. But it was humoral.
Thus, the exclusive association of innate immunity with cells had become obsolete. More importantly, specific antibodies cooperated with non-specific complement. The dichotomous view of immunology was further softened by the experiments of the English scientist, Almroth Wright — , who showed that antibodies can specifically facilitate phagocytosis of bacteria 31 , This is of particular importance for efficient defense against bacterial pathogens which evade phagocytosis, such as encapsulated bacteria pneumococci, meningococci and gonococci.
His finding revealed that for some diseases, specific antibodies are needed to interact with phagocytes for optimal host defense 31 , For the first time therefore, specific humoral factors of the acquired immune response antibodies were shown to collaborate with non-specific cognates of the cellular innate immune response macrophage and neutrophils. This was another call for complementary dualism rather than dichotomy between innate and acquired immunity. The findings of Wright caught the interest of George Bernard Shaw — , who described the potential of phagocytes for cellular therapy of disease.
Have they not only eaten up the bacilli but attacked and destroyed the red corpuscles, as well? During the first half of the twentieth century, immunologists focused on clinical observations and even more on immunochemistry, which could build on a much broader armamentarium of technical tools. Immunochemistry found its culmination in the discovery of the chemical structure of antibodies Figure 4. This was accomplished independently by the British chemist, Rodney Porter — , and the US chemist, Gerald Edelman — , in the late s to early s 33 , Their work was honored by the Nobel Prize in The Austrian Karl Landsteiner — , first working in Europe and since in the US, developed the carrier hapten concept by coupling small aromatic molecules to proteins He showed that the small residue—the hapten—is recognized by antibodies, and therefore serves as epitope, and that the protein serves as carrier to provide the immunogenicity needed for successful stimulation of an antibody response 37 , Since the studies of Jacques Miller — , Henry Claman — and others, we know that the antibody response involves B lymphocytes for the recognition of the hapten and T lymphocytes for the recognition of the carrier.
Landsteiner is probably best known for the discovery of the ABO major blood group system Working at the time in Vienna, he found that mixing blood of two different individuals resulted in clumping of red blood cells. Based on this finding, he developed a technique for the serologic differentiation of erythrocytes, which allowed him to identify the different blood groups of the ABO system.
This discovery was honored by the Nobel Prize in Ten years later, and together with Alexander Wiener — , Landsteiner discovered a second important blood group, called Rhesus Rh , named after their original discovery with erythrocytes in Rhesus monkeys 41 , It became clear that antibodies do not only perform beneficial functions. That aberrant antibody responses could lead to hypersensitivity reactions was first shown by the French clinician Charles Richet — in 43 , who was awarded the Nobel Prize for his research on anaphylaxis in The term anaphylaxis was coined by Richet to describe harmful reactions, which were later shown by the Japanese immunologist Kimishigi Ishizaka — and his wife Teruko — , to be mediated by antibodies of the IgE isotype One year after Richet's discovery, the French researcher, Maurice Arthus — , described a similar yet distinct type of reaction which he induced experimentally by local injection of antigen into the skin of an individual previously immunized with the same antigen In contrast to the reaction described by Richet, this one was mediated by immune complexes and involved complement.
Immunology for Life Scientists, 2nd Edition
With serum therapy against diphtheria and tetanus broadly applied, numerous individuals received serum from horses in which the antiserum had been generated. This type of hypersensitivity is also the basis of erythrocyte damage after blood transfusion, e. At Rockefeller University, Karl Landsteiner together with the American researcher, Merrill Chase — , studied the tuberculin reaction first described by Robert Koch and demonstrated that this reaction can be adoptively transferred by cells of an immune animal but not by serum The four different types of hypersensitivity were categorized by the UK physicians, Philip Gell — , and Robin Coombs — , in In this categorization, type I hypersensitivity is the typical IgE-mediated allergy first described by Richet; type II is IgG plus complement-mediated destruction of host cells; type III is mediated by immune complexes such as the Arthus reaction; and type IV is the delayed-type hypersensitivity reaction, including the tuberculin reaction and contact dermatitis.
The s to s witnessed a marked shift in priorities from immunochemistry to immunobiology Figure 5. In fact, studies on transplant rejection preceded and prepared the ground for immunobiology. The US geneticist George Snell — , based on his studies with inbred mouse strains, elegantly demonstrated that distinct genes within the major histocompatibility complex MHC were responsible for transplant rejection A somewhat more direct link to immunobiology was provided by the Venezuelan-born US scientist, Baruj Benacerraf — , who identified the immune response genes within the MHC locus Later the Australian researcher, Peter Doherty — , and the Swiss researcher, Rolf Zinkernagel — , would broaden this perspective by showing that the MHC is crucial for antigen recognition by T lymphocytes, the cells that would become the dominant research target in the second half of the twentieth century.
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It was they who provided first evidence that the horror autotoxicus, envisaged by Paul Ehrlich, was not prefixed but a matter of education. Medawar had shown that transplant rejection could be prevented by transferring cells from an unrelated donor during neonatal life 54 , Although his concept remained speculative and was questioned because of the occurrence of autoimmune diseases, it proved to be a valid theory of immunobiology even though—as with many biological issues—it was not absolute.
Burnet's interests were much broader. Originally a virologist who became an immunologist, he readily used tools of virology to interrogate the immune system. Although Ehrlich's side chain theory held that antibody specificities of all kinds were present before antigen encounter, according to Ehrlich numerous specificities could be expressed by a single cell depending on its requirement for specific nutrients see Figure 4.
This assertion, however, was questioned during the area of immunochemistry when a chemical explanation was sought for a biological question. Several researchers including the US Nobel laureate of and , Linus Pauling — , claimed that the structure of the antigen would determine the specificity of its corresponding antibody With the understanding that the three-dimensional structure of a protein is strongly determined by its amino acid sequence, this became a matter of impossibility.
The Danish immunologist, Niels Jerne — , who received the Nobel Prize in 58 , postulated a more biologically oriented hypothesis, namely that various antibody specificities existed prior to antigen encounter This was then refined by Burnet and independently by the US immunologist David Talmage — , who both proposed a selection process for the specific antibody-producing cell 56 , Thus, Ehrlich was right in assuming the preexistence of antibody specificities before a foreign antibody arrived, but he was wrong in assuming that one cell would express numerous specificities.
Elegant studies by the Australian immunologist, Gustav Nossal — , partly together with US Nobel laureate of Joshua Lederberg — , provided strong evidence that a single cell produces an antibody of unique specificity 61 , Under the influence of the specific antigen, the antibody-producing cells expand numerically and produce more antibodies of the same specificity. Hence, interest in antibodies shifted from chemical structure to biological understanding of the generation of specificity, i.