Introduction 
light chain. The random recombination of V, D, 
and J segments in the two chains can thus code for 
literally millions of different possible receptor 
structures. The receptors on B cells are formed in 
basically the same way, although the numbers 
of V, D, and J segments available for selection 
and recombination differ somewhat. Antibodies 
(which are secreted by plasma cells) are gener- 
ated in much the same way as their receptors, and 
have the same almost unlimited capacity for di- 
versity (Figure 16). 
At one time it was thought that antigens were 
capable of shaping the structure of lymphocyte 
receptors and antibodies so that the binding sites 
of receptors and antibodies would mold them- 
selves in some way to fit the shape of the antigen, 
much as a rubber glove molds itself to fit one's 
hand. We now know that this "instructional" hy- 
pothesis is wrong. Rather, as indicated above, the 
immune system produces very large numbers of 
different types of receptors and antibodies, and 
collectively these can "fit" essentially every pos- 
sible antigen (Figure 1 7) . Each T or B cell bears 
only one type of receptor on its surface (although 
there are thousands of receptor molecules of that 
given structure on each cell). In the same way, 
each B cell secretes antibodies of only a single, 
defined structure. Thus the capacity of the body 
to respond to an enormous variety of different 
antigens is due to the existence of an enormous 
number of different T or B cells, each able to rec- 
ognize a single antigen (or more commonly, a 
part of a complex antigen known as an antigenic 
determinant). And when the cell recognizes 
and binds to an antigen, it responds by proliferat- 
ing to form a large number of cells of the same 
type. Such a population of cells, all derived from 
a single progenitor, is known as a clone, and the 
hypothesis put forward to account for the selec- 
tive proliferation of lymphocytes of particular re- 
ceptor type in response to a specific antigen is 
known as the clonal selection hypothesis. This 
theory, first advanced by Sir F. Macfarlane Burnet, 
has withstood every test and is rightly viewed as 
one of the cornerstones of modern immunology. 
The intriguing question as to how the cells of 
the immune system distinguish foreign mole- 
cules from those on the surface of the cells of 
their own host was also addressed by Burnet. He 
suggested — and there is now a large body of evi- 
dence to support this view — that lymphocytes 
that recognize the body's own tissues (so-called 
self antigens) are selectively eliminated during 
early development — a process known as clonal 
deletion. The mechanisms responsible for clonal 
deletion of T and B cells are still under investiga- 
tion, but at least for the T cells it appears that 
during development the thymus may actively se- 
lect, for export to the rest of the immune system, 
only those T cells that are capable of functioning 
in the host (Figure 18). These "useful" T cells 
are allowed to survive and mature, while the po- 
tentially harmful cells die and are removed. This 
process results in the death of about 90 percent 
or more of the T cells that are initially formed. 
The bone marrow selection of B cells for survival 
may be equally stringent. Although this seems an 
astonishingly wasteful process, comparable cell 
deaths are known to be a rather common feature 
in the development of virtually all organs and of 
all multicellular organisms. 
For reasons that remain to be elucidated, in 
some conditions — commonly referred to as au- 
toimmune disorders — the immune system may 
mistakenly mount an attack on components of the 
host organism's own cells. For example, the neu- 
rological condition myasthenia gravis involves 
the production of circulating antibodies directed 
against the receptor molecules on the surfaces of 
muscle cells that normally enable them to re- 
spond to the release of the neural transmitter ace- 
tylcholine from the motor nerves. When the re- 
ceptor molecules are damaged or destroyed, 
there is a progressive loss of neuromuscular con- 
trol, and if the respiratory muscles are involved 
the condition may be fatal. Similarly, type I or 
juvenile-onset diabetes is now known to be due 
to the combined attack of T cells and antibodies 
directed against the jS-cells of the pancreas that 
normally produce insulin, the hormone that regu- 
lates sugar metabolism. 
Another topic of considerable current interest 
in immunology concerns antigen presenta- 
tion. We now know that this involves a complex 
set of genes called the major histocompatibil- 
ity complex (MHC). The membrane proteins 
encoded by these genes (of which there are two 
types called class I and class II) are able to selec- 
tively bind short segments of partially digested 
protein antigens, termed peptides. These pep- 
tides, arising from protein breakdown inside the 
cell, reach the surface of the cell together with 
the relevant MHC molecule. Recent x-ray crystal- 
lographic studies indicate that the peptide anti- 
gen is lodged within a distinctive groove on the 
outer surface of the MHC molecule, where it can 
be detected by a lymphocyte bearing the appro- 
priate receptor. The receptors on T cells are spe- 
xlvii 
