Historical perspective of Immunology
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.
The Latin term immunis, meaning “exempt,” is the source of
the word immunity, a state of protection from infectious
disease.
Perhaps the earliest written reference to the phenomenon
of immunity can be traced back to Thucydides, the great
Greek historian when describing a plague in Athens during
Peloponnesian War in 430 BC, 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 deliberately induce
immunity were performed by the Chinese and Turks in
the 15th century and were attempting to prevent
smallpox, a disease that is fatal in about 30% of cases
and that leaves survivors disfigured for life.
•The dried crusts derived from smallpox pustules were
either inhaled or inserted into small cuts in the skin (a
technique called variolation) in order to prevent this
dreaded disease.
•In 1718, Lady Mary Wortley Montagu, the wife of the
British ambassador in Constantinople, observed the
positive effects of variolation on the native Turkish
population and had the technique performed on her
own children.
•In 1798, English physician Edward Jenner intrigued by the fact
that milk maids who had contracted the mild disease cowpox
were subsequently immune to the much more severe smallpox,
he reasoned that introducing fluid from a cowpox pustule into
people (i.e., inoculating them) might protect them from small
pox.
•To test this idea, he inoculated an eight-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 and Jenner’s
technique of inoculating with cowpox to protect against
smallpox spread quickly through Europe.
•Although this represented a major breakthrough, as one might
imagine, these sorts of human studies could not be conducted
under current standards of medical ethics.
Development of vaccine –
•In 1880, Louis Pasteur succeeded in growing the bacterium that
causes fowl cholera in culture, and confirmed this by injecting it
into chickens that then developed fatal cholera.
•After returning from a summer vacation, he and colleagues
resumed their experiments, injecting some chickens with an old
bacterial culture.
•The chickens became ill, but to Pasteur’s surprise, they
recovered. Interested, Pasteur then grew a fresh culture of the
bacterium with the intention of injecting this lethal brew into
some fresh, unexposed chickens.
•But his supply of fresh chickens was limited, and therefore he
used a mixture of previously injected chickens and unexposed
birds. Unexpectedly, only the fresh chickens died, while the
chickens previously exposed to the older bacterial culture were
completely protected from the disease.
•Pasteur hypothesized and later showed that aging had
weakened the virulence of the pathogen and that such a
weakened or attenuated strain could be administered to
provide immunity against the disease.
•He called this attenuated strain a vaccine (from the Latin
vacca, meaning “cow”), in honor of Jenner’s work with
cowpox inoculation.
•1881, Pasteur first vaccinated one group of sheep with
anthrax bacteria (Bacillus anthracis) attenuated by heat
treatment. He then challenged the vaccinated sheep, along
with some unvaccinated sheep, with a virulent culture of
the anthrax bacillus. All the vaccinated sheep lived and all
the unvaccinated animals died.
These experiments marked the beginnings of the discipline
of immunology.
•In 1885, Pasteur administered his
first vaccine to a human, a young
boy named Joseph Meister, who
had been bitten repeatedly by a
rabid dog.
•The boy was inoculated with a
series of attenuated rabies virus
preparations. The rabies vaccine is
one of very few that can be
successful when administered
shortly after exposure, as long as
the virus has not yet reached the
central nervous system and begun
to induce neurologic symptoms.
•Joseph survived, and later became
a caretaker at the Pasteur Institute, Fig: Wood engraving of Louis Pasteur
which was opened in 1887 to treat watching Joseph Meister receive the rabies
the many rabies victims. vaccine.
•In 1883, Elie Metchnikoff demonstrated that cells contribute to the
immune state of an animal. He observed that certain white blood
cells, which he termed phagocytes, ingested (phagocytosed)
microorganisms and other foreign material.
•These phagocytic cells are more active in animals that had been
immunized, he hypothesized that cells are the major effectors of
immunity.
Fig: Drawing by Elie Metchnikoff of phagocytic Fig: Modern image of a phagocyte
cells surrounding a foreign particle. engulfing the bacteria.
•In 1890, Emil Von Behring and Shibasaburo Kitasato
demonstrated that serum—the liquid, noncellular
component recovered from coagulated blood—from
animals previously immunized with diphtheria could
transfer the immune state to unimmunized animals.
(Emil Von Behring the Nobel Prize in Physiology
Medicine in 1901).
Selective theory
Paul Ehrlich in 1900 made the earliest conception of the selective
theory.
In an attempt to explain the origin of serum antibody, Ehrlich
proposed that cells in the blood expressed a variety of receptors,
which he called side-chain receptors, that could bind to infectious
agents and inactivate them.
The binding of the receptor to an infectious agent was like the fit
between a lock and key and the interaction would induce the cell
to produce and release more receptors with the same specificity.
According to Ehrlich’s theory, the cells were pluripotent,
expressing a number of different receptors, each of which could be
individually “selected.”
The specificity of the receptor was determined in the host before
its exposure to the foreign antigen, and therefore the antigen
selected the appropriate receptor.
Fig: Representation of Paul Ehrlich’s side chain theory to explain antibody formation
Instructional theory
This concept was first postulated by Friedrich Breinl
and Felix Haurowitz in about 1930 and redefined in
the 1940s in terms of protein folding by Linus Pauling.
The theory held that antigen played a central role in
determining the specificity of the antibody molecule.
According to the instructional theorists, a particular
antigen would serve as a template around which
antibody would fold—sort of like an impression mold.
The antibody molecule would thereby assume a
configuration complementary to that of the antigen
template.
The instructional theories were formally disproved in
the 1960s.
Clonal selection theory
•In 1950, F. Macfar lane Burnet, Niels Jerne, and
David Talmadge, refined the selective theories that
came to be known as the clonal selection theory.
•According to this theory, an individual B or T
lymphocyte expresses many copies of a membrane
receptor that is specific for a single, distinct antigen
and the unique receptor specificity is determined in
the lymphocyte before it is exposed to the antigen.
•Binding of antigen to its specific receptor activates
the cell, causing it to proliferate into a clone of
daughter cells that have the same receptor
specificity as the parent cell.
