In this presentation I shall discuss 1) some historical highlights n the field of immunology; 2) the molecules of immunity, particularly the immunoglobulins; and 3) the cells of immunity, particularly the immunocytes. This presentation may provide a background for subsequent articles

Mullinax, Franklin

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Modern Immunology: Cells and Molecules* ** FRANKLIN MULLINAX, M. D. Associate Professor of Medicine, Division of Connective Tissue Diseases, Medical College of Virginia, Health Sciences Division of Virginia Commonwealth University, Richmond In this presentation I shall discuss 1) some historical highlights in the field of immunology; 2) the molecules of immunity, pa_rticularly the im-munoglo bulins; and 3) the cells of immunity, par-ticularly the immunocytes. This presentation may provide a background for subsequent articles. · Some Historical Highlights (Tables 1 and 2). From its origins, immunology has been closely asso-ciated with infectious diseases, a bias from which we are only now escaping. In the work of early investi-gators, we can see the clear demonstrations that 1) immunity is important in prevention of disease; 2) there are humoral and cellular phases of the immune response; and 3) immune reactions can themselves produce disease. Edward Jenner (1749-1823) and Vaccination. Systematic studies by this quiet scholarly country physician established that inoculation with cowpox pustules produced immunity to smallpox. The prac-tice of inoculation or variolation had existed in the Orient from early times. Material from the vesicle or pustule of an active case of smallpox was inocu-lated into the. skin in order to produce a mild and '· immunizing attack of smallpox. The value of this ' method was clearly documented in Benjamin Frank-lin's pamphlet of 1759, "Some account of the success of inoculation for the smallpox in England and America." Jenner proved that the much more innocent inoculation with cowpox pustules was also successful. During his studies he also discovered that viruses can be attenuated and that an accele-* Presented by Dr. Mullinax at the 45th Annual McGuire Lecture Series, November 8, 1973, at the Medical College of Virginia, Richmond. **This is publication No. 67 from the Charles W. Thomas Arthritis Fund. MCV QUARTERLY 10(1): 9-12, 1974 rated response occurs in previously immunized persons. His was the first account of an allergic reaction in the skin. Louis Pasteur (1822-1895) and the First Heroic Phase of Immunology. In his thinking, Louis Pas-teur was against the temper of his times. Anti-vitalism was dominant. Liebig and other prominent scientists had no use for the animalcules postulated to explain the origin of disease and fermentation. They were wrong, however, and the germ theory rose again with Pasteur's studies of the souring of milk. His work followed a natural path from studies of crystals to studies of diseases of wirte and silk-worms, to studies of diseases of man, culminating in immunization and prevention of disease. The studies of chicken cholera revealed that the microbe that kills is the one that immunizes and that the microbe may be attenuated. They suggested to him the possibility of attacking diseases of man. Finally, the renowned studies of rabies led to inoculation of young Joseph Meister on July 6, 1885 with the first and least virulent of his rabies vaccines. Joseph survived the series of injections and became the gatekeeper at the Pasteur Institute. Pasteur's experiments on immunization were followed by a great outpouring of studies of immu-nology with concurrent deveiopment of biologic and chemical concepts of immunity. On the biological side, Eli Metchnikoff, the wild Russian, migrated to Pasteur's laboratory and championed the non-specific and the cellular aspects of immunity. While looking through his microscope, Metchnikoff saw cells engulfing particles and became the primary discoverer of phagocytosis as a defense mechanism. Koch, also at the Pasteur Institute, showed that whereas the first intradermal injection of tubercle 9 10 MULLINAX: MODERN IMMUNOLOGY: CELLS AND MOLECULES TABLE 1 JMMUNOBIOLOGY May 14, 1796 Edward Jenner established vaccination. July 6, 1885 Louis Pasteur injected attenuated rabies virus into Joseph Meister. 1882 Eli Metchnikoff and phagocytosis. To 1905 Bordet,Arthus, vonPirquet, Schick, Ehrlich. 1953 Owen, Medawar and Burnet. Immunologic tolerance. bacilli evoked no response in guinea pigs, the sec-ond injection led to an inflammatory reaction, thus initiating the concept of delayed hypersensitivity or cellular immunity. The Pasteur Institute was also involved in chem-ical studies of immunity. After Pasteur's work on bacteria as the cause of diseases of wine, beer, and later, of man, attention turned to diphtheria. Roux expected that this devastating disease would be characterized by massive bacterial proliferation; but only a few bacilli could be isolated from the iocal lesion. Something else must be responsible for the toxicity of diphtheria. This line of investigation led to the isolation of bacterial toxins, the preparation of antitoxins, identification of the antitoxins as serum TABLE 2 IMMUNOCHEMISTRY October 30, 1845 William Macintyre examined the urine of his patient, Mr. Macbee, who had myelomatosis. 1890 1900 1920 1948 1%0's Roux and Behring identified toxiris and antitoxins. Landsteiner described blood group an-tigens and antibodies. Beginnings of quantitative immuno-chemistry with Heidelberger, and later, Kabat and Marrack. Hargraves described the LE cell. Fundamental discoveries of antibody structure: Putnam, Porter, Edelman, Hood, Dreyer. proteins, prophylactic use of antitoxin-containing sera, and description of serum sickness. This phase of research extended through 1905 with the publi-cation of Serum Sickness by von Pirquet and Schick. Forgetting many other important contributions, we may tum to 1953 and the development by Owen, Medawar, and Burnet of the concept of immuno-logic tolerance, another landmark in the biology of immunity. The Chemistry of Immunity. On October 30, 1845 a practicing physician, William Macintyre, examined the urine of his patient, Mr. Macbee, who had the disease now known as multiple mye-loma. The peculiar reactivity of . his urine-a pre-cipitate formed on warming and dissolved with boil-ing--led Dr. Macintyre to consult with Dr. Henry Bence Jones. More than a hundred years later, studies of the Bence Jones proteins ushered in a second heroic phase of immunology. Bence Jones proteins and serum monoclonal proteins have proved to be a Rosetta stone of immunology. In 1900 Karl Landsteiner discovered blood group antigens and their corresponding antibodies. His chemical studies, particularly with low molecular weight haptens, set the stage for quantitative im-munochemistry, developed by Heidelberger and Kabat, and by Marrack, from the 1920's through the 1950's. The discovery of the LE cell by Har-graves in 1948 was important because it led to detailed studies of the chemical basis of apparent autoimmune reactions. Early in the 1960's the work of Edelman, Porter, Putnam, and others gave the central focus of immunology on the now familiar four-chain structure of an antibody monomer. The Immunoglobulins. It is fortunate that the simple technique of paper or cellulose acetate elec-trophoresis provides a rather complete separation TABLE 3 THE IMMUNOGLOBULINS lgG-The main antibody class. lgA-Antibody, especially in secre!ions. IgM-Macroglobulins. JgD-? lgE-Skin sensitizing antibody. MULLINAX: MODERN IMMUNOLOGY: CELLS AND MOLECULES 11 of the antibodies. Most antibodies are in the y-globulin fraction and most y-globulins are antibodies. More sophisticated techniques, particularly immuno-electrophoresis, reveal that some antibodies are in other electrophoretic fractions and that there are at least five classes of antibodies. These are the immunoglobulins: IgG, lgA, IgM, lgD, and lgE (Table 3). IgG is the main circulating immuno-globulin; IgA is prominent in secretions (tears, saliva); lgM is generally a pentameric molecule, restricted to the intravascular space and particu-larly effective biologically; IgD is a minor com-ponent of uncertain function; and lgE is present in trace amounts but is extremely important because it mediates immediate ( anaphylactic) hypersensi-tivity. A diagrammatic representation (Fig. 1) of the IgG molecule reveals that it has four chains-two light chains and two heavy chains. The light chains (Bence Jones proteins) are often produced in ex-cess by plasma cells. Large amounts of these proteins are excreted by many patients with myelomatosis. Variations in amino acid sequences in the first part of the light and heavy chains provide variations in antibody specificity, that is, antibody diversity. Fur-ther structural studies reveal that the light chains have two and the heavy chains have four disulfide domains, homologous parts of the molecule which rotate almost independently. Another way to ex-amine the molecule is literally by looking at it. High-resolution electron micrographs reveal the lgG molecules to be Y-shaped with the two antigen binding sites on the forks. lgM molecules have five monomer Y's around a central core. {Light chain (Bence Jones protein) s Heavy chain s f s s s Antigen binding site Fig. I-Diagrammatic representation of an lgG molecule. Fig. 2-Electron micrograph of a plasma cell from a human kidney graft removed because of impending rejection. Note the prominent endoplasmic reticulum. (Courtesy of Dr. W. J. S. Still, Medical College of Virginia). These immunoglobulins are the mediators of humoral immunity and are produced by cells of the plasma cell series. These secretory cells (Fig. 2) have an elaborate endoplasmic reticulum which contains the organelles concerned with synthesis and secretion of plasma proteins. Cellular Immunity. A different group of cells, activated lymphocytes, mediate cellular immune re-actions. Such an activated lymphocyte is see·n in figure 3. Upon antigenic stimulation, lymphocytes mediating cellular immune reactions enlarge, divide, and provide mediators, lymphokines, which incite local inflammatory reactions. Cellular immunity is largely responsible for immunity against intracellular parasites, contact drug allergy, graft rejection, and tumor rejection. A typical reaction of cellular im-munity is the reaction of delayed hypersensitivity, such as the tuberculin reaction. Observations on patients with immunodeficiency 12 MULLINAX: MODERN IMMUNOLOGY: CELLS AND MOLECULES Fig. 3-Electron micrograph of a transformed lymphocyte in the splenic white pulp of a lethally x-irradiated mouse 36 hours after injection of rat small lymphocytes. Note the absence of endoplasmic reticulum. This rat lymphocyte became transformed after contact with immunologically foreign mouse tissue. It is now prepared to provide a line of cells mediating the graft-versus-host response. (Courtesy of Dr. J. L. Gowans, Oxford University, and publishers, S. Karger, Basel/New York).1 diseases and experiments in animals have given rise to the concept of two different systems that mediate humoral and cellular immunity (Fig. 4). According to this view, stem cells from the bone marrow migrate to breeding sites for the cells of the two types of immunity. In the chicken, plasma 1 Reprinted by permission from Gowans JL, McGregor DD : The immunological activities of lymphocytes. Progress in Allergy 9: 1, 1965. cell precursors (B cells) are produced in the bursa of Fabricius, an organ near the cloaca. In man, the - corresponding tissues are not clearly identified. The marrow itself or gut-associated lymphoid tissue may be involved. The second breeder site is the thymus. It provides T lymphocytes and cellular immunity. Interrelations of T and B cells are complicated and important, as some of the following presentations will indicate. In this brief overview, I have presented some historical highlights of chemical and biologic ap-proaches to immunology. The chemical approaches lead to our current detailed picture of immuno-globulin structure. The biologic studies lead to the concept of a two-component system, B and T cells, mediating humoral and cellular immunity. These chemical and biologic findings provide a framework for analyzing not only basic immunology but also clinical diseases. For completion, I should briefly mention the scavenger macrophages-probably im-portant in antigen processing; the complement sys-tem-important in amplifying the effects of an immune response; the kinins and other molecules of inflammation; and the polymorphonuclear leuko-cytes and other apparently nonspecific defenders. The Immunologic Mosaic. The outlines of mod-ern immunology are now discernible. The resultant picture is like a mosaic rather than a photograph. We are now at the exciting point where the form is emerging. BONE MARROW ! Stem4 Cells ~ ~URSA-LIK~ TISSUES! Thymic (T) tymphocytes i Bursa! (B) Lymphocytes Lymph nodes, spleen, Peyer's patches J, + Antig.en (Ag) Ag-specific transformed lymphocytes "'lJ .!~ Proliferation of thymic- dependent and antigen-sper '.fic lymphocytes in para-cortica l areas -+Ag- specific cellular immunity (delayed hype rsensitivity) (cell-bound antibody) and immunologic memory . Proliferation of bursal-dependent and antigen specific lymphocytes in germinal centers and develop-ment of plasma cells - Ag-specific humeral immunity (circulating antibodies) (lg's) and im munologic memory . Fig. 4-Bone marrow - thymus - bursa interrelations. The bursa-like tissues in man may be either the bone marrow itself or certain gut-associated lymphoid tissues (GALT). 

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Modern Immunology: Cells and Molecules

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