Introduction 
their potentially harmful effects. The task of ef- 
fecting both strategies falls to the immune 
system. 
Recognizing the strategic importance of the 
immune system in both health and disease, the 
Institute selected Immunology to be one of its 
earliest research programs. The wisdom of that 
decision has been amply borne out by the truly 
remarkable progress that has been made in immu- 
nology in the past two decades. With the notable 
exception of molecular genetics, no field of bio- 
medical research has witnessed such an astonish- 
ing series of successes at almost every level, from 
understanding the immune system's unique rec- 
ognition mechanisms to the elucidation of the 
cellular and chemical means used to destroy or 
neutralize invading organisms. 
The body's initial line of defense against inva- 
sion by foreign organisms is the continuously pa- 
trolling system of macrophages and other types 
of blood-borne phagocytic cells that act both as 
an early warning system and as a "first-strike" de- 
fense. These cells respond by ingesting and 
breaking up the invading organisms and by re- 
leasing soluble signaling molecules like inter- 
leukin-1 that serve, among other things, to mobi- 
lize the next line of defense, the immune 
response (Figure 14). This response involves 
two classes of lymphocytes, called T and B cells, 
reflecting their origin from the thymus and bone 
marrow, respectively. 
The first step in the immune response is the 
activation of a special subclass of T lympho- 
cytes called helper T cells. Macrophages pres- 
ent fragments of foreign proteins, or antigens, 
on their surfaces. Recognition of these antigens 
by specialized receptors found on helper T cells 
then initiates the two responses: a cell-mediated 
immune response and a humoral immune re- 
sponse. The cell-mediated response involves 
principally the stimulation of another subclass of 
T lymphocytes called cytotoxic T cells that rec- 
ognize and destroy infected cells. The humoral 
response, on the other hand, involves the activa- 
tion of the second major class of lymphocytes, the 
B cells, to produce circulating antibodies. Anti- 
bodies recognize and neutralize soluble antigens 
and mark cells or viruses bearing antigens for de- 
struction by phagocytic cells. 
One of the central problems in immunology 
concerns the way in which lymphocytes recog- 
nize antigens. The complexity of this problem 
may be gauged from the observation that humans 
and other higher vertebrates are capable of form- 
ing antibodies against virtually any molecule or 
part of a molecule (epitope), including even 
those that do not occur naturally but are chemi- 
cally synthesized in a laboratory. How does this 
occur? And how does the immune system distin- 
guish foreign molecules from those produced by 
its own cells? In a word, how do lymphocytes 
distinguish self from non-self? 
The key to the first issue, as we now know, is to 
be found in the almost unlimited variety of re- 
ceptors on the surfaces of lymphocytes. The dis- 
covery of how just a few hundred genes are capa- 
ble of producing such extraordinary receptor 
diversity is one of the great success stories of mod- 
ern immunology. The essential features of the im- 
mune system's capacity for generating molecular 
diversity can be summarized briefly by stating 
that lymphocyte receptors, like antibodies, are 
formed by pairs of protein chains that are chemi- 
cally linked to form a complex receptor struc- 
ture. Each chain of the pair has a constant domain 
and a variable domain. The variable domain of 
the two chains is responsible for antigen recogni- 
tion and the discrimination between self and 
non-self. The constant (invariant) domain is 
physically linked to other membrane proteins of 
the receptor complex that activates the lympho- 
cyte's internal signaling and effector mecha- 
nisms. T and B cells triggered via their antigen 
receptors respond to auxiliary signaling mole- 
cules by proliferating and differentiating to a ma- 
ture effector stage. In the case of B cells, the matu- 
ration process results in the generation of 
plasma cells that produce large amounts of anti- 
body for secretion into bodily fluids, chiefly the 
bloodstream. 
The complex structure of the variable parts of 
the receptors is due to several processes. First, 
and most important, the genes responsible for 
this portion of the receptor are assembled from a 
large number of different gene segments (Figure 
15). Each gene segment exists in several — and in 
some cases hundreds — of different copies. These 
segments randomly recombine to form new genes 
that encode the virtually limitless repertoire of 
recognition elements. To take just one example, 
T cells form their receptors by combining a num- 
ber of different gene sequences: V (variable), D 
(diversity), and J (joining) segments. From this 
array any given T cell derives 1 from about 100 
possible V segments, 1 from about 6 D segments, 
and 1 from about 50 J segments to form its so- 
called a- or heavy chain, and about 1 in 20 V, 
1 in 2 D, and 1 in 12 J segments to form its 
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