0022- 1767/86/137 1 -0OOiSO2.00/0 THEJOURNAL OF 1MMUNOLoGY Vol. 137. No. 1. July 1, I986 Copyright 0 1986 by The American Association of Immunol~lsts Prlnted In U.S.A. American Associationof Immunologists PRESIDENTIALADDRESS LEARNINGFROM LEPROSY:A PERSPECTIVE ONIMMUNOLOGY AND THE THIRDWORLD BARRY R. BLOOM From the Departmentsof Microbiology and Immunology. andCell Biology, Albert Einstein Collegeof Medicine. Bronx,NY 10461 "If we take the widest and wisest view of a Cause. there is no such thingas a Lost Cause, because there is no such thingas a Gained Cause. We fight for Lost Causes because we know that our defeat and dismay may be the preface to our successors' victory, although that victory itself will be temporary; we fi ht rather to keep somethning alive than in the expectation t fl at anything will triumph. "T.S. Eliot "A Map of the World Without Utopia on It Is not Worth Glancing At." "Oscar Wilde Let mebegin with a case history. notof an individual. tussis,tetanus, tuberculosis, polio, and measles, and but ratherof a country. any of the fortypoorest nations consequently 0.5%of them became lame from polio, 1% on earth. Let me ask you to try to imagine our qualityof died from neonatal tetanus. 2% succumbedto whooping life, if life expectancy at birth in this countrywere 42 yr. cough. and 3%died from measles. We would be living in if infant mortality at birth were 140 per thousand.if 40% a country whose average gross national product per cap- of our children suffered from malnutrition. and if only ita would be $310/yr: in which 37% of males, but only 10%of children were immunized against diphtheria, per-14% of females, would be literate. Access to waterwould i ii LEARNING FROM LEPROSY be enjoyed by 50%of the urbanpopulation, but only 15% monoclonal anti-interferon (IFN)-y antibodies. Recently, of the rural population.Government expenditures on Nathan et al.(6) have observed skin reactions, similar to health and education would represent only 3.9%of the those induced by MIF in guinea pigs, produced interest- central budget, and there would be 15,932 people per ingly in the skin of lepromatous leprosy patients after physician. This is the quality of life, differing only in inoculation of recombinant IFN-7. detail, endured by 200 to 300 million people in Africa, As the in vitro study of cellularimmune reactions Asia, and Latin America (1). This is the Third World, in became accepted as a legitimate immunological endeavor, which 75% of the planet’s population lives, where 86% I was invited by the World Health Organization to help of all children are born and 98% of all infant and child evaluatewhether these emerging in vitro techniques deaths occur, and where 10 kids die of vaccine-prevent- might have some conceptual or practical relevance to able illnessevery minute. understanding immunity to tropical diseases. One such This wasnot my world when I embarked ona career in meeting, held in India in 197 1,introduced me to the Third immunology. That world was the Rockefeller University World and the problem of leprosy, and was one from where I was trained in cellularimmunology by Dr. Merrill which I have never quite recovered. In the course of my Chase. Dr. Chase was one of the founders of cellular wanderings in immunology and around theglobe, I have immunology, who first established that delayed-type hy- been privileged to have been able to collaborate with a persensitivity (DTH) could be passively transferred by great many wonderful scientists andcolleagues, both in cells, not serum, andwhose example impressedupon me this country and abroad, and would like to express my the importance of discipline and commitment in science. sincere appreciation for all they have contributed. I am That too was not the world of St. Mary’s Medical School deeply grateful for the dedicated efforts and valuable in London where, as a postdoc, I learned something of advice provided me by many members of the Secretariat the structure of antibodies from Rodney Porter. I came, of the World Health Organization. in addition,to learn three important things from my Leprosy-the disease. From ancient times and inev- experience in Rod Porter’s lab: i) the active site of anti- ery culture,leprosy has evoked singular images of horror bodies was not on isolated heavy chains, ii) I was not and fascination. Many aspects of the diseaseremain destined to be a great chemist,and iii) most importantly, mysterious to this day. Although the leprosy bacillus was it was ultimately possible to do the highest quality of the first identified bacterial pathogen of man (7). it re- science with in no way compromising one’s dignity, gen- mains oneof the very few pathogens of man that cannot erosity, humor,or humanity. I cannot imagine being more yet be grown in culture. Thereis generally a long latency, privileged than to have had these two wonderful and perhaps 5 yr between presumed infection and manifes- inspiring teachers. tation of disease, and as a consequence the mode of To convey a sense of time in that “world,” the least transmissionremains largely unknown. Although 13 understood phenomenon in immunology was “delayed- million people are estimated to have leprosy around the type hypersensitivity,” not then even dignified by the world, the disease hasa relatively low prevalence, seldom term “cell-mediated immunity.” Pioneering studies in vi- exceeding 1 to 5 per 1000 in endemic areas. There is a troon lymphocytes and macrophages by Hirshhorn, unique fear and stigmaassociated with this disease, Bach, George, and Vaughan and John David were just partially deriving from the deformities that occur in ap- breaking new ground. The most burning question, in- proximately 30% of people afflicted by it. There is no credible as it may sound, that Boyce Bennett and I first other disease whosevictims were burned at the stakeby tried to address at Albert Einstein, was whether sensi- Henry I1 of England and Philip V of Spain, or buried alive tized lymphocytes or macrophages, or both, carried the by Henry’s grandson,Edward I, or given the last ritesof immunological specificity for DTH. We were able to show the dead by the Church in medieval Europe and turned in the macrophage migration inhibition reaction i) that outside the city walls (8). only immune lymphocytes had the ability to recognize The spectrum of leprosy. There has been a renais- specific antigen and inhibit macrophage migration: in- sance of scientific interest in leprosy, one reason being deed, as few as 0.6% of sensitized cells were sufficient: the extraordinary possibilities it offers for gaining insight and ii) that the in vitro reactionwas mediated by a into immunoregulatory mechanisms in man (9, 10). For nonantibody product of the antigen-activated lympho- leprosy is not a single clinical entity, but rathera spectral cytes (2). JohnDavid made the same observation essen- disease that presents a diversity of clinical manifesta- tially simultaneously (3). Migration inhibitoryfactor, tions (Fig. 2). At one pole of the spectrum, tuberculoid MIF, thus became the first of the lymphokines. Bennett leprosy, patients develop high levels of specific cell-me- and I really first began to believe in the lymphokines diated immunity that ultimately kills and clears the ba- when we found (Fig. 1) thatpartially purified MIF injected cilli in the tissues, although often with concomitant im- into normal guinea pig skin produced reactions as early munological damage to the nerves. At the lepromatous as 4 hr consisting of almost pure mononuclear cell infil- pole, patients exhibit a selective unresponsiveness to trates resembling DTH reactions (4).Although the chem- antigens of Mycobacterium leprae and the organisms ical nature ofMIF has been somewhat elusive and its ineluctably multiply in the skin, often to extraordinary biological effects on macrophages may well be mediated numbers-as many as 10’’ per gram of tissue. It remains by more than one molecular entity, it was gratifying to unclear why the vastmajority of peopleexposed to infec- learn only last year from the work of Thurman etal. (5) tion with M. leprae develop no clinical disease, and why that the in vitro activities of MIF were produced on hu- only a minority who do develop clinical disease become man monocytes by cloned human IFN-y, and conversely, lepromatous and remain immunologically unresponsive that MIF activityinduced by concanavalin A (Con A) to the antigensof the organism. activation of human lymphocytes was neutralized by Mechanism of nerve damage in leprosy. To a visitor LEARNING FROM LEPROSY FROM LEARNING iii L' L' r' Cy- s . Flgure I. Skin reactions produced in normal guinea pigs by MIF. Sephadex C-100 fractions of serum-free lymphocyte super- C. natants (approximate size range.40.000 to 65.000 daltons) from W control and Con A-stimulated lymphocytes wereinjected intrader- mally into normal guinea pig skin and werebiopsied 4 hr later. A. MIF fraction (x47.5). B. Control fraction (x47.5). C. MIF fraction (x 180).Fractions containing MIF induced mononuclear cell infil- tration and keratinocyte hyperplasia(4). THE SPECTRUM OF LEPROSY The resultsclearly demonstrated primaryfocal demyelin- ation of these myelinated fibers as innocent "bystanders" of a specificcellular immune reaction to the foreign antigen (Fig. 3). Togetherwith Celia Brosnan, Wendy Cammer, Gerry Stoner, SiamonGordon, and Bill Norton, we were able to demonstrate that activated macrophages secreted neutral proteinases that had the ability to de- grade purified myelin proteins in vitro(1 2). One of these was inhibitableby EDTA and wasprobably a collagenase: the other wasplasminogen activator, dependent on plas- minogen and blocked by inhibitors of plasminogen acti- vator and plasmin. Thissuggested that activated macro- phages could secrete small amountsof neutral proteases, one of which could act upon the very large reservoir of plasminogen (-1 mg/ml) found in serum and extravas- cular fluids.