The discipline of immunology grew out of the observation that individuals who had recovered from certain infectious diseases were there after protected from the disease. Perhaps the earliest written reference to the phenomenon of immunity can be traced back to Thucydides, the greatest historian of the peloponnesian war. In describing a plague in Athens, he wrote in 430 BC that only those who had recovered from the plague could nurse the sick because they would not contract the disease a second time.
The first recorded crude attempts to induce immunity deliberately were performed by the Chinese and Turks in the 15th century. Various reports suggest that the dried crusts derived from smallpox pustules were either inhaled into the nostrils (or) inserted into small cuts in the skin (a technique called variolation). In 1718, Lady Mary Wortely Montagu, the wife of British ambassador to Constantinople observed the positive effects of variolation on the native population and had the techinque applied to her own children. The technique was significantly improved by the English physician Edward Jenner in 1798. Intrigued of the fact that milkmaids who had contracted cowpox (a mild disease) were subsequently immune to smallpox. Jenner reasoned that introducing fluid from a cowpox pustule into people might protect them from smallpox. To test this idea, he inoculated an 8-year-old boy with fluid from a cowpox pustule and later intentionally infected the child with smallpox. As predicted, the child did not develop smallpox. Jenner's technique of inoculating with cowpox to protect against smallpox spread quickly through Europe.
Even though the immunology was born in the 18th century with the practice of variolization and of Jenner's vaccination, it became a true science only in the 19th century. Beginning in 1880, the world witnessed a veritable torrent of progress, stimulated both by Pasteur and his students and by Robert Koch and his group. The magnificent contributions was done by Pasteur, Roux, Metchnikoff, and Bordet on the one hand and those of Koch, Pfeiffer and Ehrlich on the other. Louis Pasteur showed with his work on fowl cholera, on anthrax and on rabies that these organisms once attenuated, could be used specifically to protect the individual against the disease that they caused. From this extraordinary series of investigations were born the modern science of immunology. In 21885, Pasteur administered the first vaccine to a human, a young boy, who had been bitten repeatedly by a rabid dog (Figure 1.1).
Emil von Behring and Kitasato in 1890, inoculated toxins of diphtheria and tetanus to animals to produce neutralizing antitoxin serum. They introduced passive immunization in modern medicine for which von Behring was awarded Nobel prize in 1901.
The phagocytic theory was first to be conceptualized in 1880 by a Russian zoologist named Elie Metchnikoff. He hypothesized that the basis of inflammation was the cellular reaction. Vascular and nervous reactions were secondary. He further suggested that the elimination or destruction of invaders was the sole function of phagocytic cells. Subsequently many workers proposed the presence of soluble substances (humoral factors) which were bactericidal. Finally in 1903 Almroth Wright and Stewart Douglas discovered a humoral component known as opsonin which makes the target bacteria palatable for phagocytosis. In 1908 Metchnikoff and Ehrlich shared the Nobel prize for the respective studies of cellular and humoral factors in host defence. Ehrlich proposed side chain theory of antibody formation and antibody function.
In 1905 von Pirquet and Schick published a brilliant series of studies on children treated with horse diphtheria antiserum which led to untowards reaction. They then introduced the concept that all the events in immunological reactivity might not be beneficial to the host, and they named the disease caused by the immune response to horse protein “serum sickness” a term still in use. In the same decade Arthus, Proteir and Richet described the cutaneous vasculitis and anaphylaxis in animals. In 1913 Charles Richet received the Nobel prize in recognition to his work on anaphylaxis.
Pfeiffer discovered the phenomenon of in vivo cytolysis of Vibrio cholerae much earlier (1894–95) following intraperitonial inoculation of Vibrio cholerae in an immunized guinea pig. This early experiment led to the understanding of complement mediated cytolysis by Pfeiffer and later Buchner and Bordet. Jules Bordet was honoured with the Nobel prize in 1920 for his work on complement.
Being successful in passive immunization against diphtheria and tetanus von Behring applied this conception in tuberculosis and failed miserably. Robert koch also had to accept the failure in providing immunity 3against tuberculosis. Ultimately Albert Calmete and Camille Guerin, the French scientists found out an effective vaccine bacille Calmette-Guérin (BCG) for tuberculosis (1921). The vaccine had been prepared from the attenuated strain of Mycobacterium bovis.
Twentieth century witnessed a phenomenal advances in understanding the immunological concepts. As the subjects grew, a number of diseases were assigned to immunological causes (immunopathological disorders) and ultimately the subject was offered a separate status. The practice of transfusion of blood from man to man was risky and unpredictable until the discovery of blood groups by Carl Landsteiner. In recognition of his outstanding work of elucidating the blood groups and Rh factor, he was awarded Nobel prize in 1930.
The concept of immunocomplexes and their important contribution to immunopathology came with the development of radioactive tracers and immunofluorescent dyes. With these tracers and dyes foreign proteins were tagged and followed after they were injected into the body and their ultimate pathologic consequences were explored. It was impossible to understand the function of the cells in the immune response with the limited techniques available in the early part of the century. Lymphocytes were noted and their importance speculated, but these monotonously similar looking cells were difficult to study. The development of immunofluorescent techniques (Coon's and his colleagues, 1942) allowing for the localization of the unique products, the introduction of modern protein chemistry and the use of cell culture techniques helped, to a great extent, in understanding the vast complexity of the host defence system.
A succession of theories were put forwarded, from time to time, to explain the specificity, memory and other features of immune responses. Instructive theories such as direct template theory (Breinl and Haurowitz, 1930; Alexander, 1931; Mudd, 1932) and indirect theories (Burnet and Fenner, 1949) were the subject of criticism by Niels Jerne and Burnet. Burnet's proposition of clonal selection theory was universally accepted as this theory shifted the immunological specificity to the cellular level. The clonal selection theory also explained tolerance as the deletion or suppression of entire clone of cells occured before or soon after birth. Burnet was awarded Nobel prize in 1960 which he shared with Peter Medawar
Most credit went to Rodney R Porter and Gerald M Edelman in elucidating the structure of antibody. Edelman showed that the immunoglobulin molecule had polypeptide chains, two heavy and two light. For their outstanding contribution, they were awarded Nobel prize in 1972.
The existence of the markers of the biological individuality (histocompatibility antigens) was first suggested by Gorer in 1937. Snail, in 1948, showed that the mouse H-2 locus is genetically complex. Dauset identified the HLA (human leukocytic antigen) locus or MHC (major histocompatibility complex). Benarraf showed that genes of HLA determining loci may control immune response. In 1980 Snail, Dauset and Benarraf were awarded Nobel prize for their respective contribution in the field.
Niels Jerne was awarded Nobel prize in 1984, for his contributions in immunology, the most fundamental of his role in developing the concept of clonality and for his description of the idiotype network in the regulation of immune response.4
An ingenious method for large scale production of monoclonal (monospecific) antibody against any desired antigen was developed by George Kohler and Esar Milstein in 1975. They produced a hybrid cell by fusing antibody forming cell with a myeloma cell. The production of monoclonal antibody by hybridoma technique created a revolution in the field of immunology in opening up various research, diagnostic and therapeutic procedures. In recognition of their work they were awarded Nobel prize in 1984.
Another Stallwart (Susumu Tonegawa) was honoured by Nobel award in 1987 for his study on genetics of antibody production.
Murray and Thomas were awarded Nobel prize in the year 1990 for their work “use of immunosuppressive drugs in transplantation. For recognition of virus by immune system Doherty and Zinkernagel were also honoured by Nobel award in 1996.
The immunology as a subject has grown immensely in the last 100 years. Louis Pasteur, Metchnikoff, Ehrlich, Bordet and many others contributed importantly and critically to the birth and robust development of the science of immunology. The amount of detail knowledge that has been accumulated has already reached paroxysmic proportion, and the rate of accumulation, far from abating, is itself increasing. But the most discouraging fact is that the theoretical explosion of knowledge has not been able to make significant contribution to the management of situations as important as allergy, organ transplantation, autoimmune diseases and even, ironically, anti-infectious diseases.
If there has been some progress that results from the practical aspect of pure scientific knowledge, it is the domain of vacciniology. The control of number of diseases that cause significant mortality and morbidity has made outstanding progress, but there remains a crying need for vaccine against others. Every year millions of death, through out the world are caused by tuberculosis, malaria and AIDS, the diseases for which there are no effective vaccines.5
As it had happened, it is expected that the world would witness further explosion of knowledge in immunology in coming decades. Concerted efforts are needed to be directed in the subjects such as tumor immunology, autoimmunity and vacciniology to develop strategies for protection against many crippling diseases. Eventually what has evolved as a precise and powerful tool created by nature to ensue continued survival of the species, would perhaps be manipulated to yield a better quality of life (see Table 1.1).
BIBLIOGRAPHY
- Cazenave PA, Talwar GP. Pasteur's Heritage. Willy Eastern Limited 1991.
- Goldsby RA, et al. Immunology 4th edn., 2000.
- Ichhpujani RB. Essentials of medical microbiology, 3rd edn.
- Paniker A. Textbook of microbiology, 6th edn., 2000.
- Setty N. Immunology (introductory textbook). New Age International (P) Limited 1994.