Immunity and Pathogenesis of Third World 
Diseases: Leprosy and Tuberculosis 
Barry R. Bloom, Ph.D. — Investigator 
Dr. Bloom is also the Weinstock Professor of Microbiology and Immunology at the Albert Einstein College 
of Medicine. He received his B.A. degree and an honorary Sc.D. degree from Amherst College and his Ph.D. 
degree from the Rockefeller University. He is active as an advisor to the World Health Organization in the 
areas of tropical diseases and vaccine development. Dr. Bloom also serves on the Board of Science and 
Technology in Development of the U.S. National Research Council and the National Vaccine Advisory 
Board. He is a member of the National Academy of Sciences and the Institute of Medicine. 
THE commitment of our laboratory is to inves- 
tigate basic scientific problems that have par- 
ticular relevance for health in the Third World. 
Three-quarters of the world's population lives in 
the Third World, and one-fourth of that popula- 
tion suffers from malnutrition and disease. The 
premises of our research are that the advances in 
molecular biology and immunology have a great 
deal to offer for understanding infectious diseases 
afflicting people in developing countries and, re- 
ciprocally, that the study of some of those dis- 
eases can provide unique insights into fundamen- 
tal immunological and pathogenetic mechanisms 
of relevance to people in the industrialized 
world. 
The Importance of Mycobacterial Diseases 
Tuberculosis and leprosy are both caused by 
mycobacteria. Leprosy afflicts 10-12 million 
people in the world and produces deformity in 
30 percent if untreated. Throughout time and in 
all cultures, leprosy has engendered a unique fear 
and stigma. Although Mycobacterium leprae W2is 
the first major bacterial pathogen of humans ever 
described, it remains one of the very few that has 
never been cultivated in the test tube. Yet its anti- 
gens can be produced and studied vicariously in 
Escherichia coli by means of recombinant DNA 
technology. 
Tuberculosis is the major infectious cause of 
death in the world today. Each year there are 8 
million new cases of tuberculosis and 3 million 
deaths, afilicting primarily the most productive 
element of society — young adults. AIDS (ac- 
quired immune deficiency syndrome) causes a 
breakdown of resistance to tuberculosis and has 
produced a grave increase in the disease, both in 
the developing and the industrialized countries. 
Immunologic Unresponsiveness 
and Leprosy 
One of the fundamental issues in immunology 
is the nature of immunological tolerance — i.e., 
the mechanisms by which cells in the immune 
system discriminate between foreign antigens 
and self antigens, and prevent responses to self. A 
failure of tolerance to self antigens leads to au- 
toimmune diseases, such as rheumatoid arthritis, 
juvenile diabetes, and perhaps multiple sclerosis. 
The principal mechanism for developing toler- 
ance is thought to be deletion of clones of poten- 
tially autoreactive T cells in the thymus during 
neonatal life. It is becoming increasingly clear, 
however, that not all such clones can be deleted 
in the thymus and that there must be additional 
mechanisms by which self-reactive cells can be 
rendered unresponsive after birth. 
Leprosy provides a unique model with which 
to study immunoregulation and unresponsive- 
ness in humans. The disease comprises a spec- 
trum of clinical entities. In the tuberculoid form, 
strong cell-mediated immunity kills the organ- 
ism, but damages nerves in the process. In the 
lepromatous form, at the other end of the spec- 
trum, patients are unable to respond immunologi- 
cally to M. leprae antigens. Since infection oc- 
curs after birth, there is little evidence of clonal 
deletion of T cells capable of reacting to the or- 
ganism. Therefore, understanding the mecha- 
nisms of that unresponsiveness is relevant to pre- 
venting autoimmune disease and increasing 
transplant survival. 
We have learned that the unresponsiveness in 
leprosy is antigen-specific, in that lepromatous 
leprosy patients unable to respond to antigens of 
M. leprae usually respond to those of M. tubercu- 
losis, which is a very closely related mycobacte- 
rium. How is it possible for T cells to recognize 
antigens in the tubercle bacillus and yet be un- 
able to recognize the same or closely related anti- 
gens associated with the leprosy bacillus? We 
proposed that there might be one or a few unique 
antigens associated with M. leprae that induce 
active T cell suppression of potentially reactive T 
cell clones. Suppressor cells in immunology have 
been a very controversial subject, but the idea 
that some T cells can down-regulate immune re- 
sponses, particularly self-destructive ones, is 
compelling. 
Our studies in vitro have shown that about 85 
percent of responsive patients with lepromatous 
leprosy have a subset of T cells capable of being 
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