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.
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.
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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.
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. The major cell type of the acquired immune response, however, was still missing Figure 5.
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It was the Australian immunologist, Jacques Miller — , who discovered the role of the thymus in the development of a specific lymphocyte population; this finding led to the identification of T lymphocytes as major regulators of the acquired immune response Independent from Miller, the US transplant immunologist Robert Good — characterized the role of the thymus and other lymphoid organs in the generation of different lymphocyte populations 64 , At about the same time, the UK immunologist, James Gowans — , had shown that the lymphocyte population was able to recirculate through the body and enter the different tissue sites—an important and necessary feature for T lymphocytes which mediate cellular immunity and hence depend on cell—cell contact The producers of antibodies had been identified earlier, namely in by the Swedish researcher, Astrid Fragaeus — , as plasma cells 67 , Her work as well as that of the US immunologist, Max Cooper — then led to the revelation that plasma cells are derived from B lymphocytes which develop in the Bursa fabricii in birds and in the bone marrow in mammals 64 , 65 , Now the major cells of the acquired immune response had been identified and immunologists increasingly focused on their biological functions Figure 5.
Henry Claman — was probably the first to provide compelling evidence that T lymphocytes and B lymphocytes collaborate in the generation of antigen-specific antibodies Av Mitchison — showed that antibodies were specific for the epitope Landsteiner's small residues—the haptens and T cells for the protein carrier The establishment of T lymphocytes and B lymphocytes as responsible cells of acquired cellular and humoral immunity, respectively, and their collaboration in shaping an optimal immune response laid the basis for the golden age of cellular immunity.
Following the footsteps of the founders of immunology, the Australian borne researcher working in the US, George Mackaness — , extensively studied immunity against intracellular bacteria. He discovered the cooperation between specific T lymphocytes and mononuclear phagocytes. In this setting, antigen specific T cells stimulate increased antibacterial activities in macrophages which thereby change from a habitat for the intracellular pathogens to the major effectors of cell-mediated immunity against the infection Transplantation biology and immunobiology converged when Peter Doherty and Rolf Zinkernagel demonstrated that MHC molecules were not only responsible for transplant rejection, but for T-cell recognition of any type of antigen.
Antigen recognition by T lymphocytes, therefore, was MHC-restricted and transplant rejection was just one special case Their breakthrough work, honored by the Nobel Prize in , was based on antigen recognition by cytolytic T lymphocytes, which kill virus-infected cells 73 , Activation of macrophages increases antibacterial activities, which in turn allows macrophages to control intracellular bacteria, such as the causative agent of tuberculosis. B cell activation leads to the production of antibodies of different isotypes.
The first molecularly defined T cell cytokine was interleukin-2 IL-2 , which was originally described by the US immunologist, Kendall Smith — His findings paved the way for the discovery of numerous humoral mediators of T cell immunity. With the identification of many other cytokines, the concept of T helper 1 TH1 vs. CD4 T cells of TH1 type contribute to the cellular immune response by activating killer T cells and macrophages. In contrast, TH2 cells produce IL-4 and other cytokines, which stimulate B lymphocytes to mature to antibody-producing plasma cells.
Early on it was recognized that the immune response is highly regulated and notably that a well-functioning immune response need not only be activated to combat an intruder, but also needs to be downregulated once the intruder had been eliminated. This led to the concept of a highly regulated immune response involving specific T cells with suppressive functions to avoid collateral damage.
Early attempts to explain this issue postulated suppressor T cells which, however, did not stand the test of time. The more refined concept of the better defined subsets of regulatory T cells, however, provided compelling evidence for specific T lymphocytes which not only control immune responses after elimination of invading pathogens, but also prevent autoimmunity and maintain homeostasis Although the biological functions of T lymphocytes were increasingly better understood, their antigen receptors remained elusive until the s.
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By using monoclonal antibodies, US immunologists, Pippa Marrack — and John Kappler — in the mouse system 78 , and Ellis Reinherz — and Stuart Schlossman — in the human system 79 , were able to phenotypically identify antigen-specific receptors on T lymphocytes. This was the first hint for the existence of the antigen-specific T cell receptor TCR. The T lymphocyte system can thus also be viewed as a binary system Figure 6. Again, support was withdrawn for a dichotomous view, in favor of a complementary dualism Figure 5.
These important findings were preceded by the breakthrough discovery of the Japanese researcher, Susumu Tonogawa — , then in Basel, Switzerland, who elucidated the mechanisms underlying the huge diversity of antibody specificities 82 , By then it was generally accepted: a single specific B cell was responsible for antibody production; diversity was generated prior to the first contact with antigen; a single B cell expresses a receptor with a unique specificity; contact with the homologous antigen stimulates selective expansion and differentiation of the specific B cell.
Yet, one critical issue remained unsolved, namely that the number of possible antibody specificities exceeded the number of genes present in our body.
The solution to this was identified by Tonegawa as the rearrangement of gene fragments. This recombination allows the generation of more than one million specificities which further increases numerically by additional mechanisms to up to some 10 9 specificities. Principally, antigen diversity of the T cell receptor is based on similar genetic mechanisms.
In any case, the specificity of the acquired immune response and the multiple roles played by T cells more or less dominated immunobiology in the s to s. An influential researcher in the field of T cell immunology was Charles Janeway — from the US 85 , who in a remarkable paper published in in the Proceedings of the Cold Spring Harbor Symposium, pointed to the widely underestimated role of the innate immune system Prevailing opinion was that innate immune cells, notably macrophages and neutrophils, play an important effector role in host defense, under the guidance of T lymphocytes and their soluble products.
Even though it was clear that T cells recognize antigens in the context of MHC presented on the surface of so-called antigen-presenting cells, these cells were viewed more as passive guides than active players. Janeway postulated the presence of pattern recognition receptors on antigen-presenting cells, which sense specific motifs of chemical products of bacteria and viruses and then instruct T cells about the different functions they should perform. Most compelling evidence for such an idea came from studies on the toll-like receptors TLR in mammals by the US geneticist Bruce Beutler — , and in insects by the biochemist Jules Hoffmann — in France 87 , This led to the concept that different types of pathogens are sensed by pattern recognition receptors with specificity for microbe-associated molecular patterns.
The concept of sensing of microbial motifs so-called pathogen-associated molecular patterns, PAMP by innate receptors was soon broadened when similar mechanisms were found to be induced by host motifs so-called danger associated molecular patterns, DAMP which arise from insult to the host In how far PAMP and DAMP influence immune tolerance by inducing danger associated non-self or self-signals to the induction of an acquired immune response remains a matter of controversial discussion 91 , As early as the s, the Canadian immunologist Ralph Steinman — at Rockefeller University, US, was engaged with defining the critical player in this concept: the dendritic cell He demonstrated that dendritic cells are much more potent antigen presenters than macrophages, and that they are the major instructors of T cells regarding the type of pathogen they will encounter.
Sadly he could not accept the award in person because he passed away shortly before the ceremony. In conclusion, innate immunity plays a crucial role, from the beginning to the end of an immune response. In the beginning it acts via antigen-presenting cells, which not only stimulate antigen-specific T cells but also serve as instructors for the biological functions T cells have to perform.
Toward the end, innate immunity takes care of effector functions, e. Instruction of T cell functions strongly depends on cytokines, i. In fact, the first chemically defined cytokine was described by the US immunologist, Charles Dinarello — as a macrophage-derived product, which accordingly was later named IL-1 IL-1 plays a role in the instruction of TH1 cells and serves as mediator of inflammation.
B cells stood in the shadow of T lymphocytes during the s. Obviously, this discovery had major implications. First, it allowed the ultimate proof for the production of an antibody with single specificity by a single plasma cell and second, it paved the way for a new era of immunotherapy.
As a short reminder, the concept of acquired immunity started with antibodies and was intrinsically intertwined with the concept of serum therapy, for which Behring received the Nobel Prize in Now the tools for more precise passive immunization had been put on the table. This led to the development of a number of monoclonal antibody-based therapies for infectious diseases; currently, the focus of monoclonal antibody therapy is on immunomodulation.
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Thus, cytokine-blocking monoclonal antibodies have been introduced in the treatment of chronic inflammatory diseases. A second important target of therapeutic monoclonal antibodies are surface-expressed molecules such as CD20 on B lymphocytes, which can be harnessed for treatment of non-Hodgkin's lymphoma such as Rituximab A major recent breakthrough has been the discovery of monoclonal antibodies which block checkpoint control. What does this mean? Regulation of T cell activity is not only a matter of cytokines but also of costimulatory molecules, which in addition to TCR recognition of antigen plus MHC as first signal, provide a second signal for T cells in stimulating their effector functions.