2 History of Immunology

Dr. M. N. Gupta

  1. Objectives
  •  To study the various milestones in the development of immunology
  •  To understand how the immune distinguishes between self and non-self
  •  To see the various Nobel Prizes awarded in this area over the years

 

2. Concept Map

  1. Description

 

Immunology is the science aiming to understand how vertebrates (credited with having an “immune system”) distinguish between „self‟ and „non-self‟!

 

In chemistry and life sciences, “molecular recognition” enables interactions between two chemical specie with a broad range of specificity.

 

How do immune system of the vertebrates fine tune a recognition mechanism which makes it possible for the system to detect that a particular protein is a „self‟ molecule and another protein is a „non-self‟ molecule?

 

Furthermore, the immune system is able to recall that a previous encounter with a particular microbe has taken place.

 

Without having any clue beforehand about the nature of an infection, the immune system is able to mount a very efficient response to this infection. Part of this response is fairly specific towards the invading pathogen. How does this „specific response‟ arise like a conjurer‟s trick?

 

History of immunology is the story of a scientist‟s search for answers to these and associated questions.

 

Like other traits of living organisms, immune system also has evolutionary history. Cells do recognize each other. Colonies of sponges when placed together either merge to form a larger colony or destroy each other upon contact. The first event happens if these cells are genetically related and the latter phenomenon takes place if these colonies are not genetically related.

 

We also know that during tissue/organ grafting, the grafted cells and the cells of the host have to be “matched”.

 

So, the capacity to distinguish between “self” and “non-self” is not limited to vertebrates.

 

What distinguishes the immune system of the vertebrates is the existence of large number of soluble factors and cells which act in a highly interdependent and synergistic fashion.

Immunology in the beginning overlapped with microbiology as it was concerned with understanding and preventing infectious diseases.

 

 

Girolamo Fracastoro, a contemporary of Copernicus at the University of Padua gave the concept of “contagion” in 1546. Contagion, according to the brilliant conclusion by him, were too small to be visible to the naked eye. It was later that the idea was taken up by others.

Notably:

 

Chinese were the first ones to adopt the practice of exposing infants to the scabs from the infected individual by rubbing it in (after scratching the skin) or through inhalation.

In 1718, Lady Mary Wortley Montague, wife of the English ambassador in Constantinople, Turkey, against the advice of the priest, tried this with her children and thereby saved them from small pox.

 

In 1774, an English farmer Benjamin Jesty used cowpox instead of small pox to “variolate” (“variola” in Latin means small pox) his children.

While Jesty did not publish his results formally, he is not generally credited for his discovery. In 1798, Edward Jenner, an English physician confirmed Jesty‟s observations, published them and is regarded as the father of vaccination (“vacca” in Latin means cow).

 

While Jenner’s interest in the protective effects of cowpox began during his apprenticeship with George Harwicke, it was 1796 before he made the first step in the long process whereby smallpox, the scourge of mankind, would be totally eradicated. For many years, he had heard the tales that dairymaids were protected from smallpox naturally after having suffered from cowpox. Pondering this, Jenner concluded that cowpox not only protected against smallpox but also could be transmitted from one person to another as a deliberate mechanism of protection. In May 1796, Edward Jenner found a young dairymaid, Sarah Nelms, who had fresh cowpox lesions on her hands and arms. On May 14, 1796, using matter from Nelms’ lesions, he inoculated an 8-year-old boy, James Phipps. Subsequently, the boy developed mild fever and discomfort in the axillae. Nine days after the procedure he felt cold and had lost his appetite, but on the next day he was much better. In July 1796, Jenner inoculated the boy again, this time with matter from a fresh smallpox lesion. No disease developed, and Jenner concluded that protection was complete.

In 1879, Louise Pasteur in France was investigating the bacteria responsible for fowl cholera. He asked his assistant to infect some fowls with the bacteria. The assistant instead went on vacation but did the experiment upon return after several weeks.

 

Chickens remained healthy so Pasteur decided to infect them again with fresh culture. The fowls still remained healthy. Pasteur brilliantly deducted that his “aged culture” worked just like Jenner‟s cowpox. The credit for extending this approach to other diseases like anthrax and rabies belongs to Pasteur. Till today, France honours Pasteur as Pasteur‟s Institute at Paris still focuses on developing vaccines.

We will, in a later module, resume the development of vaccines in later years after learning about some necessary fundamentals.

 

Part of the history of Immunology is best learnt through recalling some controversies which often continued for a considerable period and often resulted in bitter debates.

 

Humoral vs Cellular Immunity

 

In 1890, Emil von Behring and Shibasaburo Kitasato in Berlin proposed the idea of “factors” in the blood called “antibodies” were responsible for the effect of vaccination. In the next few years, three key discoveries were made:

  •   Paul Ehrlich, a German chemist, showed that antibodies couls protect animals against even non-bacterial “toxins”
  •   Richard Pfeiffer, another German showed that antibodies could clump and destroy vibrio cholera which causes cholera in humans
  •   In 1894, Emile Roux discovered “passive immunization” by transferring serum from an “immunized” horse against diphtheria and tetanus to protect respective patients against the two diseases.
  •   In 1893, a “heat labile component” was thought to be antibodies but (we will learn later about it) was a complement.

Hence the major thinking was that some soluble factors (Humor means were responsible for the defense mechanism.

In 1893, a Russian Elie Metchnikoff showed that white blood cells of vertebrates could cause phagocytosis of some fungal spores. This debate about humoral vs cellular agents involved in the defense against infections divided scientists into two groups.

 

Paul Ehrlich proposed a side chain theory which tried to combine the role of cells and soluble factors. The side chains were supposed to be present on cell surfaces and upon “blocking” of these side chains, the cells responded by secreting these side chains in large numbers.

 

Paul Ehrlich was a leading immunologist of that early era. He was one of the early people to speculate about the nature of substances in the body which neutralized toxins and was referred to as “antibody” [Ehrlich 1897].

 

In a presentation before The Royal Society of Chemistry in 1900, Erhlich proposed that cells have receptors which combine with the toxin (antigen). This binding released the receptor molecules and neutralization of the toxin continues. In his model, he also tried to explain the action of complement which in those days was called alexin.

 

In many ways Ehrlich‟s ideas were brilliantly precinct. The triggering of B-lymphocytes does involve “antigen” binding to Ig receptor leading to the release of Ig and making more of Ig receptors. Ehrlich also invoked cellular level picture in explaining immune response.

 

Instruction vs. Selection Theories

 

Around the same time, Hans Buchner postulated that combination of “antigens” with serum proteins led to a specific antibody structure. This later on developed into template theory which was part of the “instruction” school of thought.

 

Karl Landsteiner, using many haptens, showed that one could produce many antibodies against any given antigen. So how does one explain unlimited number of receptors? This period also coincided (1920s) with the rapid studies in our understanding of protein structure and protein chemistry. No antigens were detected in the blood. People still found merit in the template theory but were divided on whether the amino acid sequence or induced folding was responsible for the specific antibody formation.

 

In 1940, Linus Pauling joined the debate. Following up on the earlier ideas of Breinl and Haurowitz, Pauling proposed that terminal ends of “antibody” assumed specific and complementary shape to an antigen.

 

All the scientific contribution of Linus Pauling have one merit. A clear pictoral quality was inherent. So was the case in this particular area. Pauling implied that antibody has two combining sites for the antigen. As we will see later, he was right in this prediction but his prediction was based upon the wrong premise!

 

Burnet and Fenner (1949), having the emerging information about the protein biosynthesis at that time, enunciated the adaptive enzyme concept according to which an animal synthesized antibody de novo in response to an antigen.

 

The well known Monod‟s operon theory, however, stated that the organism synthesized a protein at the low level but could raise this level upon the addition of a substrate.

 

This led to Burnet (1963) revisiting his ideas and propose clonal selection theory which is a selection theory. According to the selection concept, antibody diversity pre exist, antigen merely selects.

The Contributions of Niels Jerne

 

  •  Niels Jerne was awarded the Nobel prize in 1984 for “theories concerning the specificity in development (lymphocyte clonality) and control of the immune system”.
  •  It was Jerne‟s overview of the understanding of the immune system at that time which sort of crystallized the concept of clonal selection theory.
  •  Jerne also initiated the concept of “epitope” and “idiotopes”.He envisaged a network of epitopes and idiotopes. That is why his theory is called network theory.

Serology

 

We have referred to Karl Landsteiner. Landsteiner can be called Father of Serology as he also discovered the blood group antigens and corresponding agglutinins. Blood transfusions are possible because of his pioneering work.

In 1901, Bordat and Gengou developed complement fixation test.

 

Cellular Immunology

 

Coons (1941-42) used immunofluorescence to show that both antigens and antibodies are present inside cells. Around the same time, Chase and Landsteiner showed that “delayed higher sensitivity” (a phenomenon which is a part of the immune response in some situations) was transferable via cells and not via serum.

 

Medawar‟s group in 1953 demonstrated acquired immunological tolerance. In the subsequent years, identification and characterization of many cells and proteins associated with the immune systems took place. In 1982-83, T-cell receptor isolation was reported and by then cell mediated immunity was firmly accepted as one arm of the immune response.

 

Perhaps no other area in biology has fetched so many nobel prizes. Below is the list of some names associated with the important developments of immunology in early years. The names with “*” were awarded Nobel Prize for their work in immunology.

 

Table 1:

Summary

 

We have looked at the several milestones in the development of immunology which help in understanding how the immune system

  • Distinguishes between self and non-self
  • Have Memory
  • Can react against unforeseen infectious agents!