WORLD OF MICROBIOLOGY AND IMMUNOLOGY Immune system287•
tact with their target cells, their antigenreceptors, unlike anti-
bodies made by B cells, exist bound to the membrane only. In
the intercellular gap between the T cell and the antigen-pre-
senting cell, a special pattern of various receptors and com-
plementary ligands forms that is several microns in size. This
patterned collection of receptors is called the immune synapse.
The immune synapse can be compared to a molecular
machine that controls T cell activation. Physically it consists
of a group of T cell receptors surrounded by a ring of integrin-
like adhesion molecules as well as other accessory proteins
like the CD3 complex. Integrins are a family of cell-surface
proteins that are involved in binding to extracellular matrix
components. This specialized cell-cell junction was named the
immunological synapse because it is thought to be involved in
the transfer of information across the T cell-APC junction.
Specifically, the immune synapse appears to play an essential
role in organizing the immune response, the level of control,
and the nature of that response. The formation of the synapse
requires several minutes and it appears to be stable for several
hours. The structural protein actin seems to have an important
role in that stability as T-cell activation is blocked by disrup-
tion of actin filaments. There also appears to be a temporal
spatial component in that signals that modulate T-cell maturity
and functions are received in a serial manner as well as simul-
taneously. Further clarification of the structure of the immune
synapse will help develop further insights into T cell recogni-
tion as well as the mechanism of T cell receptor signaling -
how information transfer occurs across the synapse. The dura-
tion of signaling in immature T cells may control CD4 and
CD8 lineage decisions. This would be useful in determining
the degree to which different types and developmental stages
rely on alternative signaling mechanisms.See alsoAntibody and antigen; Antibody formation and kinet-
ics; Antibody-antigen, biochemical and molecular reactions; T
cells or T-lymphocytesIImmune systemMMUNE SYSTEM
The immune system is the body’s biological defense mecha-
nism that protects against foreign invaders. Only in the last
century have the components of that system and the ways in
which they work been discovered, and more remains to be
clarified.
The true roots of the study of the immune system date
from 1796 when an English physician, Edward Jenner, dis-
covered a method of smallpox vaccination. He noted that dairy
workers who contracted cowpoxfrom milking infected cows
were thereafter resistant to smallpox. In 1796, Jenner injected
a young boy with material from a milkmaid who had an active
case of cowpox. After the boy recovered from his own result-
ing cowpox, Jenner inoculated him with smallpox; the boy
was immune. After Jenner published the results of this and
other cases in 1798, the practice of Jennerian vaccination
spread rapidly.
It was Louis Pasteurwho established the cause of infec-
tious diseases and the medical basis for immunization. First,Pasteur formulated his germ theory of disease, the concept
that disease is caused by communicable microorganisms. In
1880, Pasteur discovered that aged cultures of fowl cholera
bacterialost their power to induce disease in chickens but still
conferred immunityto the disease when injected. He went on
to use attenuated (weakened) cultures of anthraxand rabiesto
vaccinate against those diseases. The American scientists
Theobald Smith (1859–1934) and Daniel Salmon
(1850–1914) showed in 1886 that bacteria killed by heat could
also confer immunity.
Why vaccination imparted immunity was not yet
known. In 1888, Pierre-Paul-Emile Roux (1853–1933) and
Alexandre Yersin (1863–1943) showed that diphtheriabacil-
lus produced a toxin that the body responded to by producing
an antitoxin. Emil von Behringand Shibasaburo Kitasato
found a similar toxin-antitoxin reaction in tetanusin 1890.
Von Behring discovered that small doses of tetanus or diph-
theria toxin produced immunity, and that this immunity could
be transferred from animal to animal via serum. Von Behring
concluded that the immunity was conferred by substances in
the blood, which he called antitoxins, or antibodies. In 1894,
Richard Pfeiffer (1858–1945) found that antibodies killed
cholera bacteria (bacterioloysis). Hans Buchner (1850–1902)
in 1893 discovered another important blood substance called
complement(Buchner’s term was alexin), and Jules Bordetin
1898 found that it enabled the antibodies to combine with anti-
gens (foreign substances) and destroy or eliminate them. It
became clear that each antibodyacted only against a specific
antigen. Karl Landsteinerwas able to use this specific antigen-
antibody reaction to distinguish the different blood groups.
A new element was introduced into the growing body of
immune system knowledge during the 1880s by the Russian
microbiologist Elie Metchnikoff. He discovered cell-based
immunity: white blood cells (leucocytes), which Metchnikoff
called phagocytes, ingested and destroyed foreign particles.
Considerable controversy flourished between the proponents
of cell-based and blood-based immunity until 1903, when
Almroth Edward Wrightbrought them together by showing that
certain blood substances were necessary for phagocytes to
function as bacteria destroyers. A unifying theory of immunity
was posited by Paul Ehrlichin the 1890s; his “side-chain” the-
ory explained that antigens and antibodies combine chemi-
cally in fixed ways, like a key fits into a lock. Until this time,
immune responses were seen as purely beneficial. In 1902,
however, Charles Richet and Paul Portier demonstrated
extreme immune reactions in test animals that had become
sensitive to antigens by previous exposure. This phenomenon
of hypersensitivity, called anaphylaxis, showed that immune
responses could cause the body to damage itself.
Hypersensitivity to antigens also explained allergies, a term
coined by Pirquet in 1906.
Much more was learned about antibodies in the mid-
twentieth century, including the fact that they are proteins of
the gamma globulin portion of plasma and are produced by
plasma cells; their molecular structure was also worked out.
An important advance in immunochemistrycame in 1935
when Michael Heidelberger and Edward Kendall (1886–1972)
developed a method to detect and measure amounts of differ-womi_I 5/6/03 3:23 PM Page 287