History of immunology
Written records from over 2,500 years ago reveal an awareness that persons who recover
from certain diseases cannot contract them again. For example, one of the earliest
accounts of immunity comes from China, where they not only noticed that people who
recovered from smallpox were resistant to reinfection, but also that the various epidemics
varied in their severity - one year being usually fatal and other years being much milder.
Chinese physicians therefore deliberately infected healthy people with material (crusts or
fluid) taken from cases of mild smallpox, thus rendering them resistant during the serious
epidemics. Although this practice was introduced to Europe in the early 1700's it was at
best a risky procedure, since people occasionally died from these "mild" infections! It
was not until 1796 that Edward Jenner, an English country physician, put into practice a
well known countryside observation that the beauty of milk maids was often due to the
fact that they rarely contracted smallpox since they almost invariably caught cowpox
which made them immune to smallpox. This procedure was the first example of
vaccination (from Vacca which is the latin for cow), a term later coined by Louis Pasteur
in honor of Jenners contribution to include any procedure which induces immunity.
Nowadays vaccination is synonymous with immunization.
The next major step towards an understanding of immunology was not possible until the
late 1800's when Pasteur in France, and Koch in Germany demonstrated how microbes
cause disease. The initial studies on vaccination using a defined microbe were made in
Pasteur's laboratory where they were working on Chicken Cholera (Pasteurella
aviseptica). Pasteur, on returning from holiday, tried to use an old culture of the bacilli,
only to discover that it was apparently ineffective in producing the disease. Being a
careful person (or maybe mean!!) he tried to reuse the animals with a fresh isolate of the
microbe, and discovered that the old "attenuated" culture had induced immunity in the
chickens to challenge with the virulent organisms. This finding may have prompted
Pasteur to make his famous epigram that "chance favors only the prepared mind". Pasteur
later extended these findings to Anthrax and finally to Rabies, which after experiments in
animals was given to a small boy who survived and became the gate keeper of the Pasteur
Institute!
In 1883 a Russian, Eli Metchnikoff first demonstrated the role of phagocytic cells in the
immune process. Again like the discovery of Pasteur, it occurred while he was on holiday
(actually he was unemployed, since he had resigned from his job!) Metchnikoff was a
Zoologist, and since he was on holiday near the sea he decided to examine some starfish
larvae that he found. He pushed a splinter of wood into one of the animals and was
surprised to see that many phagocytic cells surrounded the "foreign object". His
subsequent investigations elucidated much of the basic role of phagocytic cells in dealing
with infections. Much of Metchnikoff`s work was carried out at the Pasteur Institute
where Roux and Yersin had isolated a toxin from diphtheria bacilli which was responsible
for many of the symptoms of this disease.
The next major step forward was in the discovery (initially by Von Behring in Robert
Kochs laboratory in Berlin) that immunity could be passively transferred using serum
taken from a previously immunized animal. This serum component became known as
antibodies. The next step was the discovery that antibodies could not only protect an
individual from infection, but could directly lyse (in vitro) bacteria cultures such as
cholera . Soon afterwards two other phenomena of antibacterial serum were
demonstrated, precipitation and agglutination. These discoveries soon lead to the
development of serotherapy where serum from horses immunized with organism such as
diphtheria and tetanus would cure people if administered soon after the infection
developed. In 1899 Bordet discovered that immune serum contained two components, a
heat stable one that had the activity of agglutination and precipitation (the antibody
activity), and a heat labile one that was responsible for bacterial lysis (later known as
complement). At the beginning of the 1900's Landsteiner demonstrated that antibodies
could not only be produced against complex organism and proteins but also against
simple organic chemical such as diamino benzene sulphonate.
The development of these two different approaches to immunity, the cells of Metchnikoff,
and the antibodies of the German investigators lead to considerable controversy as to
which was the most important in immunity. This question was largely settled in the early
1900's when it became clear that both cellular and humoral factors were involved in
immune protection, and that immune serum could also act together with phagocytic cells
to increase phagocytosis (opsonization).
Between 1903 and 1910 the role of histamine in the phenomena of anaphylaxis was
elucidated, initially by Riche and Portier, and later by Dale and his colleagues. Up until
the late 1940's the actual substance responsible for antibody activity was not known until
the development of electrophoretic protein separation techniques by Tiselius in 1939. He
demonstrated that the gamma globulin fraction of serum increased in concentration
following immunization and that antibody activity was confined to this fraction.
The next 50 years saw the development and expansion of immunology into the major
discipline it is today
Timeline of immunology:
1549 - The earliest account of inoculation of smallpox (variolation) occurs in Wan Quan's
(14991582) Douzhen Xinfa
1718 Lady Mary Wortley Montagu, the wife of the British ambassador to
Constantinople, observed the positive effects of variolation on the native population and
had the technique performed on her own children.
1796 First demonstration of vaccination smallpox vaccination (Edward Jenner)
1837 Description of the role of microbes in putrefaction and fermentation (Theodore
Schwann)
1838 Confirmation of the role of yeast in fermentation of sugar to alcohol (Charles
Cagniard-Latour)
When the antibodies, complement, and neutrophils are all functioning normally, this
process effectively kills the bacteria. However, when the number of bacteria is
overwhelming or there are defects in antibody production, complement, and/or
neutrophils, recurrent bacterial infections can occur.
Viruses
Most of us are exposed to viruses frequently. The way our bodies defend against viruses
is different than how we fight bacteria. Viruses can only survive and multiply inside our
cells. This allows them to hide from our immune system. When a virus infects a cell,
the cell releases cytokines to alert other cells to the infection. This alert generally
prevents other cells from becoming infected. Unfortunately, many viruses can outsmart
this protective strategy, and they continue to spread the infection.
Circulating T-cells and NK cells become alerted to a viral invasion and migrate to the site
where they kill the particular cells that are harboring the virus. This is a very destructive
mechanism to kill the virus because many of our own cells can be sacrificed in the
process. Nevertheless, it is an efficient process to eradicate the virus.
At the same time the T-lymphocytes are killing the virus, they are also instructing the Blymphocytes to make antibodies. When we are exposed to the same virus a second time,
the antibodies help prevent the infection. Memory T-cells are also produced and rapidly
respond to a second infection, which also leads to a milder course of the infection.
A. Neutrophil (Phagocytic Cell) Engages Bacteria (Microbe): The microbe is coated
with specific antibody and complement. The phagocytic cell then begins its attack on the
microbe by attaching to the antibody and complement molecules.
B. Phagocytosis of the Microbe: After attaching to the microbe, the phagocytic cell
begins to ingest the microbe by extending itself around the microbe and engulfing it.
C. Destruction of the Microbe: Once the microbe is ingested, bags of enzymes or
chemicals are discharged into the vacuole where they kill the microbe.
The Immune System and Primary Immunodeficiency Diseases
Immune deficiencies are categorized as primary immune deficiencies or secondary
immune deficiencies. Primary immune deficiencies are primary because the immune
system is the primary cause and most are genetic defects that may be inherited.
Secondary immune deficiencies are so called because they have been caused by other
conditions.
Secondary immune deficiencies are common and can occur as part of another disease or
as a consequence of certain medications. The most common secondary immune
deficiencies are caused by aging, malnutrition, certain medications and some infections,
such as HIV.
The most common medications associated with secondary immune deficiencies are
Examples of this are autoimmune lymphoproliferative syndrome (ALPS) and IPEX (an
X-linked syndrome of immunodeficiency, polyendocrinopathy and enteropathy).
Primary immunodeficiency diseases can occur in individuals of any age. The original
descriptions of these diseases were in children. However, as medical experience has
grown, many adolescents and adults have been diagnosed with primary
immunodeficiency diseases. This is partly due to the fact that some of the disorders, such
as CVID and Selective IgA Deficiency, may have their initial clinical presentation in
adult life. Effective therapy exists for several of the primary immunodeficiencies, and
many people with these disorders can live relatively normal lives.
Primary immunodeficiency diseases were initially felt to be very rare. However, recent
research has indicated that as a group they are more common than originally thought. It is
estimated that as many as 1 in every 1,2002,000 people may have some form of primary
immunodeficiency.
Vaccines:
A vaccine is a biological preparation that provides active acquired immunity to a
particular disease. A vaccine typically contains an agent that resembles a disease-causing
micro-organism and is often made from weakened or killed forms of the microbe, its
toxins or one of its surface proteins. The agent stimulates the body's immune system to
recognize the agent as a threat, destroy it, and keep a record of it, so that the immune
system can more easily recognize and destroy any of these micro-organisms that it later
encounters.
Vaccines are dead or inactivated organisms or purified products derived from them.
There are several types of vaccines in use. These represent different strategies used to try
to reduce risk of illness, while retaining the ability to induce a beneficial immune
response.
Inactivated
Some vaccines contain inactivated, but previously virulent, micro-organisms that have
been destroyed with chemicals, heat, radiation, or antibiotics. Examples are influenza,
cholera, bubonic plague, polio, hepatitis A, and rabies.
Attenuated
Some vaccines contain live, attenuated microorganisms. Many of these are active viruses
that have been cultivated under conditions that disable their virulent properties, or that
use closely related but less dangerous organisms to produce a broad immune response.
Although most attenuated vaccines are viral, some are bacterial in nature. Examples
include the viral diseases yellow fever, measles, rubella, and mumps, and the bacterial
disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette
and Gurin is not made of a contagious strain, but contains a virulently modified strain
called "BCG" used to elicit an immune response to the vaccine. The live attenuated
vaccine-containing strain Yersinia pestis EV is used for plague immunization. Attenuated
vaccines have some advantages and disadvantages. They typically provoke more durable
immunological responses and are the preferred type for healthy adults. But they may not
be safe for use in immunocompromised individuals, and may rarely mutate to a virulent
form and cause disease.
Toxoid
Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than
the micro-organism. Examples of toxoid-based vaccines include tetanus and diphtheria.
Toxoid vaccines are known for their efficacy. Not all toxoids are for micro-organisms; for
example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.
Subunit
Protein subunit rather than introducing an inactivated or attenuated micro-organism to
an immune system (which would constitute a "whole-agent" vaccine), a fragment of it
can create an immune response. Examples include the subunit vaccine against Hepatitis B
virus that is composed of only the surface proteins of the virus (previously extracted from
the blood serum of chronically infected patients, but now produced by recombination of
the viral genes into yeast), the virus-like particle (VLP) vaccine against human
papillomavirus (HPV) that is composed of the viral major capsid protein, and the
hemagglutinin and neuraminidase subunits of the influenza virus. Subunit vaccine is
being used for plague immunization.
Conjuga
Conjugate certain bacteria have polysaccharide outer coats that are poorly
immunogenic. By linking these outer coats to proteins (e.g., toxins), the immune system
can be led to recognize the polysaccharide as if it were a protein antigen. This approach is
used in the Haemophilus influenzae type B vaccine.
Experimental
Electroporation System for experimental "DNA vaccine" delivery
A number of innovative vaccines are also in development and in use:
Dendritic cell vaccines combine dendritic cells with antigens in order to present the
antigens to the body's white blood cells, thus stimulating an immune reaction. These
vaccines have shown some positive preliminary results for treating brain tumors and are
also tested in malignant melanoma.
Recombinant Vector by combining the physiology of one micro-organism and the DNA
of the other, immunity can be created against diseases that have complex infection
processes
DNA vaccination an alternative, experimental approach to vaccination called DNA
vaccination, created from an infectious agent's DNA, is under development. The
proposed mechanism is the insertion (and expression, enhanced by the use of
electroporation, triggering immune system recognition) of viral or bacterial DNA into
human or animal cells. Some cells of the immune system that recognize the proteins
expressed will mount an attack against these proteins and cells expressing them. Because
these cells live for a very long time, if the pathogen that normally expresses these
proteins is encountered at a later time, they will be attacked instantly by the immune
system. One potential advantage of DNA vaccines is that they are very easy to produce
and store. As of 2015, DNA vaccination is still experimental and is not approved for
human use.
T-cell receptor peptide vaccines are under development for several diseases using models
of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to
modulate cytokine production and improve cell mediated immunity.
Targeting of identified bacterial proteins that are involved in complement inhibition
would neutralize the key bacterial virulence mechanism.
While most vaccines are created using inactivated or attenuated compounds from microorganisms, synthetic vaccines are composed mainly or wholly of synthetic peptides,
carbohydrates, or antigens.
Valence
Vaccines may be monovalent (also called univalent) or multivalent (also called
polyvalent). A monovalent vaccine is designed to immunize against a single antigen or
single microorganism. A multivalent or polyvalent vaccine is designed to immunize
against two or more strai ns of the same microorganism, or against two or more
microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or
Latin prefix (e.g., tetravalent or quadrivalent). In certain cases a monovalent vaccine may
be preferable for rapidly developing a strong immune response.
Heterotypic
Also known as Heterologous or "Jennerian" vaccines these are vaccines that are
pathogens of other animals that either do not cause disease or cause mild disease in the
organism being treated. The classic example is Jenner's use of cowpox to protect against
smallpox. A current example is the use of BCG vaccine made from Mycobacterium bovis
to protect against human tuberculosis.