Milestone 2.1 Clonal Selection
Theory
Antibody production according to Ehrlich
In 1894, well in
advance of his time as usual, the remarkable Paul Ehrlich proposed the
side‐chain theory of antibody production. Each cell would make a large variety
of surface receptors that bound foreign antigens by complementary shape “lock
and key” fit. Exposure to antigen would provoke overproduction of receptors
(antibodies), which would then be shed into the circulation (Figure M2.1.1).
Template theories
Ehrlich’s hypothesis
implied that antibodies were preformed prior to antigen exposure. However, this
view was difficult to accept when later work showed that antibodies could be formed to
almost any organic structure synthesized in the chemist’s laboratory (e.g., m‐aminobenzene
sulfonate; Figure 5.6) despite the fact that such molecules would never be
encountered in the natural environment. Thus was born the idea that antibodies
were synthesized by using the antigen as a template. Twenty years passed before
this idea was “blown out of the water” by the observation that, after an
antibody molecule is unfolded by guanidinium salts in the absence of antigen,
it spontaneously refolds to regenerate its original specificity. It became
clear that each antibody has a different amino acid sequence that governs its
final folded shape and hence its ability to recognize antigen.
Selection theories
The wheel turns full
circle and we once more live with the idea that, as different antibodies must
be encoded by separate genes, the information for making these antibodies must
pre‐exist in the host DNA. In 1955, Nils Jerne perceived that this could form
the basis for a selective theory of antibody production. He suggested that the
complete antibody repertoire is expressed at a low level and that, when antigen
enters the body, it selects its complementary antibody to form a complex that
in some way provokes further synthesis of that particular antibody. But how?
Frank Macfarlane
Burnet now brilliantly conceived of a cellular basis for this selection
process. Let each lymphocyte be programmed to make its own singular antibody
that is inserted like an Ehrlich “side‐chain” into its surface membrane.
Antigen will now form the complex envisaged by Jerne, on the surface of the
lymphocyte, and by triggering its activation and clonal proliferation, large
amounts of the specific antibody will be synthesized (Figure 2.11). Bow
graciously to that soothsayer Ehrlich, he came so close in 1894!
