Brief History of Immunology

Brief History of Immunology

The immune system comprises an enormous variety of cells and molecules capable of specifically recognizing and eliminating foreign molecules.  This versatile defense system protects animals from invading pathogenic microorganisms and cancer.

The immune system is highly specific, it can differentiate one foreign pathogen from another and discriminate between self and nonself (it recognize foreign molecules as nonself and own cells and proteins as self). Once a foreign invader organism is recognized, the immune system elicits an effector response by recruiting a variety of cells and molecules which eliminate or neutralize the organism and a later exposure to the same foreign organism induces a more rapid and enhanced immune reaction known as the memory response which eliminate the foreign organism.

History of Immunology

The term Immunology originated from the Latin term immunis, which mean “exempt”.  It means the state of protection from infectious disease.  The branch immunology started and grew from the observation that individuals who recovered from certain infectious diseases never developed the same disease.

The earliest written reference to immunity was by Thucydides, the great historian of the Peloponnesian War. In 430 BC while describing a plague in Athens, he wrote 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 attempts to induce immunity deliberately were performed by the Chinese and Turks in the fifteenth century. The dried crusts from smallpox pustules were either inhaled through

nostrils or inserted into small cuts in the skin, a technique called variolation to prevent the deadly and fatal Smallpox. In 1718, Lady Mary Wortley Montagu, the wife of the British ambassador to Constantinople, performed the technique of variolation on her own children.

This technique of variolation was significantly improved by the English physician Edward Jenner, in 1798. He observed that milkmaids who had the cowpox disease were immune to smallpox.  He reasoned that fluid from a cowpox pustule if introduced into people might protect them from smallpox and he inoculated an eight-year-old boy with fluid from a cowpox pustule and later intentionally infected the child with smallpox. As correctly predicted by Jenner, the child did not develop smallpox.  Thereafter this technique to protect against smallpox spread quickly throughout Europe.  Edward Jenner is honored as the father of immunology.

But this technique was not applied to other diseases for nearly a hundred years due to lack of obvious disease targets and knowledge.

Serendipity in combination with astute observation led to the next major advance in immunology. Louis Pasteur had succeeded in growing the bacterium responsible for fowl cholera in culture and showed that chickens injected with this culture developed cholera.   After a summer vacation during which the cultures were left in incubation for long intervals, Pasteur and Roux discovered the long incubation attenuated the bacteria, that is bacteria lost their ability to cause the disease.   Pasteur injected some chickens with this old culture, and to Pasteur’s surprise even though the chickens became ill, they recovered. Pasteur then used a fresh culture of the bacterium to inject into fresh chickens, but since his supply of chickens was limited, he had to use the previously injected chickens.  Now again to his surprise, the chickens were completely protected, they did not develop the disease. Pasteur hypothesized and proved that aging weakened the virulence of the pathogen and administering such an attenuated strain might protect against the disease. He called this attenuated strain a vaccine.  This name came from the Latin word ‘vacca’ which means “cow”.  He named it so in honor of Jenner’s technique of cowpox inoculation.

Pasteur extended this approach to other diseases and demonstrated that it is possible to attenuate, or weaken a pathogen and administer this attenuated strain as a vaccine.  He studied Bacillus anthracis, the causative agent of anthrax and was successful in attenuating the bacterium using heat.  Pasteur and Chamberland developed attenuation techniques to prepare anthrax vaccine in two ways: either by treating cultures with potassium bichromate or by incubating the bacteria at 42 to 43°C.In 1881, Pasteur vaccinated a group of sheep with heat-attenuated Bacillus anthracis and then infected the vaccinated sheep and some unvaccinated sheep with a virulent culture of the bacillus.  It was observed that all the vaccinated sheep lived, and all the unvaccinated animals died. These experiments marked the beginnings of the discipline of immunology.

Pasteur used a different approach to prepare rabies vaccine. The pathogen was attenuated by growing it in an abnormal host, the rabbit and after the death of the infected rabbits, their brains and spinal cords were removed and dried. In 1885, Pasteur administered his first vaccine to a human, a young boy, Joseph Meister, who had been bitten by a rabid dog and his death was certain. Joseph was injected 13 times over next 10 days with increasingly virulent preparations of the attenuated virus. He survived.

With contributions from all over the world, Pasteur Institute was constructed in Paris, France and the initial task of the Institute was vaccine production.

The German physician Robert Koch established the relationship between Bacillus anthracis and anthrax in 1876. Koch injected healthy mice with material from diseased animals, and the mice became ill. After transferring anthrax by inoculation and culturing of bacilli through a series of mice and beef serum, he proved the causal relationship between a microorganism and a specific disease.  He proposed the Koch’s postulates summarized as follows:

1. The microorganism must be present in every case of the disease but absent from healthy organisms.

2. The suspected microorganism must be isolated and grown in a pure culture.

3. The same disease must result when the isolated microorganism is inoculated into a healthy host.

4. The same microorganism must be isolated again from the diseased host.

In 1890 Emil von Behring and Shibasaburo Kitasato injected inactivated diphtheria toxin into rabbits, inducing them to produce an antitoxin to inactivate the toxin and protect against the disease. They demonstrated that serum from animals immunized to diphtheria could transfer the immune state to unimmunized animals. Their work gave insights into the mechanism of immunity.   von Behring earned the Nobel prize in medicine.  A tetanus antitoxin was also prepared.

Various researchers during the next decade demonstrated that an active component from the serum of immune animals could neutralize toxins, precipitate toxins, and agglutinate bacteria, and were termed as antitoxin, precipitin, and agglutinin, respectively.  During 1930s, Elvin Kabat showed that gamma-globulin present in serum is responsible for these activities. The active molecules in the gamma-globulin or immunoglobulin fraction are called antibodies. Since the immunity mediated by antibodies are present in body fluids or humors, it was called humoral immunity.

In 1883, Elie Metchnikoff observed that certain white blood cells, which he termed phagocytes, were able to ingest or phagocytose microorganisms and other foreign material. Metchnikoff hypothesized that these cells are the major effector of immunity and he introduced the concept of cell-mediated immunity

Further studies on serum and humoral immunity were possible due to the ready availability of blood and established biochemical techniques while studies on the activities of immune cells were done later only with the development of modern tissue culture techniques.  As a result, information about cellular immunity lagged behind.

In 1940s, Merrill Chase transferred immunity against tuberculosis by transferring white blood cells from immune guinea pigs. In 1950s, with the emergence of cell culture techniques, lymphocyte was identified as the cell responsible for both cellular and humoral immunity.

Bruce Glick with studies using chickens indicated that there are two types of lymphocytes: T lymphocytes derived from the thymus mediated cellular immunity, and B lymphocytes from the bursa of Fabricius mediated humoral immunity. It was understood that the two systems work in an intertwined manner for the immune response.

Around 1900, Jules Bordet demonstrated specific immune reactivity to nonpathogenic substances, such as red blood cells from different species.

The work of Karl Landsteiner showed that injecting an animal with almost any organic chemical could induce production of antibodies that would bind specifically to the chemical.  He received Nobel Prize for Physiology or Medicine in 1930.

In 1901 Karl Landsteiner demonstrated the human ABO blood group system. He identified the underlying mechanism by which clumping, or agglutination of red blood cells occur during mixing of blood from two individuals. It occurs due to an immunological reaction that occurs when antibodies are produced by the host against antigens located on the donated red blood cells. Landsteiner identified four such antigens, A, B, AB, and O.

Landsteiner’s work made it possible for blood transfusions to be carried out safely. Landsteiner also discovered other blood factors such as the M, N, and P factors and the Rhesus (Rh) system.

Landsteiner and Constantin Levaditi discovered the causative agent responsible for poliomyelitis and worked for the development of the polio vaccine.

Landsteiner worked to identify the microorganisms responsible for syphilis.

Landsteiner using small organic molecules called haptens, demonstrated how small variations in a molecule’s structure can cause great changes in antibody production.

These studies demonstrated that antibodies have almost unlimited range of reactivity, even to compounds never before existed in nature and were synthesized recently in a laboratory. Also highly structurally similar molecules could be recognized as different by antibodies. The selective theory and the instructional theory were proposed to explain these phenomena.

Selective theory was detailed by Paul Ehrlich in 1900. Ehrlich proposed that cells in the blood expressed a variety of receptors, which he called “side-chain receptors,” that could react and bind with infectious agents in a way similar to the fit between a lock and key. This interaction between an infectious agent and a cell receptor induce the cell to produce and release more receptors with the same specificity. As per this theory, the specificity of the receptor was determined before its exposure to antigen, and the antigen just selected the appropriate receptor.

In the 1930s and 1940s, the selective theory was challenged by instructional theories by Friedrich Breinl and Felix Haurowitz. According to the instructional theories, a particular antigen would serve as a template around which antibody would fold and the antibody molecule assume a complementary configuration. The instructional theories were disproved in the 1960s.

In the 1950s, selective theories were made resurface and refine by Niels Jerne, David Talmadge, and F. Macfarlane Burnet, as the clonal selection theory. According to this theory, an individual lymphocyte expresses membrane receptors that are specific for a distinct antigen even before the lymphocyte is exposed to the antigen. Binding of antigen to its specific receptor activates the cell, causing it to proliferate into a clone of cells that have the same immunologic specificity as the parent cell. The clonal selection theory is accepted as the underlying paradigm of modern immunology.