Immunity and Pathogenesis of Third World 
Diseases: Leprosy and Tuberculosis 
Barry R. Bloom, Ph.D. — Investigator 
Dr. Bloom is also Weinstock Professor of Microbiology and Immunology at 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 Committee. He is a member of the National Academy of Sciences, the Institute of Medicine, 
and the American Academy of Arts and Sciences. 
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 insights into fundamental im- 
munological 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 4-6 million peo- 
ple 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 /eprae was 
the first major human bacterial pathogen de- 
scribed, it remains one of the few that has never 
been cultivated in the test tube. However, its an- 
tigens can be produced and studied vicariously in 
Escherichia coli by means of recombinant DNA 
technology. 
Tuberculosis is the major cause of death from a 
single infectious disease in the world today. Each 
year there are 8 million new cases of tuberculosis 
and 3 million deaths, afflicting primarily the 
most productive element of society — young 
adults. Infection with HIV (human immunodefi- 
ciency virus) causes a breakdown of resistance to 
tuberculosis; this has produced a grave increase 
in the disease, in both the developing and the 
industrialized countries. In 1985, following a 
32-year decline in the number of cases, the inci- 
dence of tuberculosis in the Unites States began 
to increase, reaching 25,701 cases reported in 
1990. 
Resistance to M. tuberculosis 
The devastatingly heightened susceptibility of 
HIV-infected individuals to a galloping course of 
tuberculosis is compelling evidence that there 
are powerful mechanisms of immunity in im- 
munocompetent hosts. The cellular and molecu- 
lar mechanisms mediating that immunity remain 
enigmatic. We have, however, established that 
the most common microbicidal product of acti- 
vated macrophages, oxygen radicals, is ineffec- 
tive at killing virulent human tubercle bacilli, 
but reactive nitrogen intermediates (particularly 
nitric oxide) can inhibit growth and kill M. tu- 
berculosis in vitro. 
Immunologic Unresponsiveness 
and Leprosy 
One fundamental issue in immunology is the 
nature of immunological tolerance, i.e., the 
mechanisms by which cells in the immune sys- 
tem discriminate between foreign antigens and 
self-antigens and prevent responses to self. A 
breakdown of tolerance to self-antigens leads to 
autoimmune diseases, such as rheumatoid arthri- 
tis, juvenile diabetes, and perhaps multiple scle- 
rosis. The principal mechanism for developing 
tolerance is thought to be deletion of clones of 
potentially autoreactive T cells in the thymus 
during neonatal life. Clearly, however, not all 
such clones can be deleted in the thymus; 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. The disease comprises a spectrum of clini- 
cal entities. In the tuberculoid form, strong cell- 
mediated immunity kills the organism but 
damages nerves in the process. In the leproma- 
tous form, at the other end of the spectrum, pa- 
tients are unable to respond immunologically to 
M. leprae antigens. Because infection occurs 
after birth, there is little evidence of clonal dele- 
tion of T cells capable of reacting to this organ- 
ism. Therefore understanding the mechanisms of 
that unresponsiveness is relevant to preventing 
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