Introduction 
Immunology Program 
One of the most important developments that 
occurred during the evolution of vertebrates was 
the emergence of protective mechanisms that en- 
able animals to defend themselves against inva- 
sion by foreign organisms, especially viruses, bac- 
teria, and a number of disease-causing parasites. 
These defenses employ tw^o distinct but related 
strategies: the first detects, v^^ith exquisite sensi- 
tivity, the presence of foreign organisms, cells, or 
proteins; the second involves a series of mecha- 
nisms that act cooperatively to rid the body of the 
invading organisms or, at the least, to neutralize 
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 
releasing soluble signaling molecules like 
interleukin-1 that serve, among other things, to 
mobilize the next line of defense, the immune 
response (Figure 14). This response involves 
two classes of lymphocytes, called T and B ceils, 
reflecting their origin from the thymus and bone 
marrow, respectively. 
The first step jn the immune response is the 
activation of a special subclass of T lympho- 
cytes called helper T cells. Macrophages pre- 
sent 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 are formed by pairs 
of protein chains that are chemically linked to 
form a complex receptor structure. Each chain of 
the pair has a constant domain and a variable do- 
main. The variable domain of the two chains is 
responsible for antigen recognition and the dis- 
crimination between self and non-self. The con- 
stant (invariant) domain is physically linked to 
other membrane proteins of the receptor com- 
plex that activates the lymphocyte's internal sig- 
naling and effector mechanisms. T and B cells 
triggered via their antigen receptors respond to 
auxiliary signaling molecules by proliferating 
and differentiating to a mature effector stage. In 
the case of B cells, the maturation process ulti- 
mately results in the generation of plasma cells 
that produce large amounts of antibody for secre- 
tion 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 responsi- 
ble for this portion of the receptor are assembled 
from a large number of different gene segments 
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