Functional subsets of human T cells were delineated by analyzing patterns of lymphokines produced by clones from individuals with leprosy and by T cell clones of known function. CD4 clones from individuals with strong cell-mediated immunity produced predominantly interferon-gamma, whereas those clones that enhanced antibody formation produced interleukin-4. CD8 cytotoxic T cells secreted interferon-gamma. Interleukin-4 was produced by CD8 T suppressor clones from immunologically unresponsive individuals with leprosy and was found to be necessary for suppression in vitro. Both the classic reciprocal relation between antibody formation and cell-mediated immunity and resistance or susceptibility to certain infections may be explained by T cell subsets differing in patterns of lymphokine production.

Leprosy, a chronic human disease with potentially debilitating neurological consequences, results from infection with Mycobacterium leprae. This unculturable pathogen has undergone extensive reductive evolution, with half of its genome now occupied by pseudogenes. Using comparative genomics, we demonstrated that all extant cases of leprosy are attributable to a single clone whose dissemination worldwide can be retraced from analysis of very rare single-nucleotide polymorphisms. The disease seems to have originated in Eastern Africa or the Near East and spread with successive human migrations. Europeans or North Africans introduced leprosy into West Africa and the Americas within the past 500 years.

SummaryRecent studies have shown that mucocutaneous leishmaniasis (MCL), a severe and debilitating form of American cutaneous leishmaniasis (ACL) caused by Leishmania braziliensis infection, is accompanied by high circulating levels of tumor necrosis factor (TNF)-oL. Analysis of TNF polymorphisms in Venezuelan ACL patients and endemic unaffected controls demonstrates a high relative risk (RR) of 7.5 (P <0.001) of MCL disease in homozygotes for allele 2 of a polymorphism in intron 2 of the TNF-[3 gene, especially in females (RR = 9.5; P <0.001) compared with males (RR = 4; P <0.05). A significantly higher frequency (P <0.05) of allele 2 at the -308-basepair TNF-c~ gene polymorphism was also observed in MCL patients (0.18) compared with endemic control subjects (0.069), again associated with a high relative risk of disease (RR = 3.5; P <0.05) even in the heterozygous condition. Because both the TNF-c~ and TNF-[3 polymorphisms have previously been linked with functional differences in TNF-oL levels, these data suggest that susceptibility to the mucocutaneous form of disease may be directly associated with regulatory polymorphisms affecting TNF-~x production.

American cutaneous leishmaniasis is characterized by a spectrum of clinical manifestations. These include localized, often self-healing single lesions, intermediate forms which frequently produce mucosal lesions and often show exaggerated delayed-type hypersensitivity (DTH), and the rare diffuse cutaneous leishmaniasis in which no reaction of protective cell-mediated immunity or DTH can be demonstrated. Clinical, pathological and immunological studies have begun to unravel some of the mechanisms associated with different disease manifestations, dependent on complex interactions between the host immune response, measured in terms of indices including lymphocyte subsets and lymphokines in vitro and within active lesions, and different species of Leishmania.

Snmm~'ySeveral mycobacterial antigens, identified by monoclonal antibodies and patient sera, have been found to be homologous to stress or heat-shock proteins (hsp) defined in Escherichia coli and yeast. A major antigen recognized by most Mycobacterium leprae-reactive human T cell lines and cell wail-reactive T cell clones is a 10-kD protein that has now been cloned and sequenced. The predicted amino acid sequence of this protein is 44% homologous to the hsp 10 (GroES) of E. coll. The purified native and recombinant 10-kD protein was found to be a stronger stimulator of peripheral blood T cell proliferation than other native and recombinant M. l~rae proteins tested. The degree of reactivity parallded the response to intact M. leprae throughout the spectrum of leprosy. Limiting-dilution analysis of peripheral blood lymphocytes from a patient contact and a tuberculoid patient indicated that approximately one third ofM./e~e-reactive T cell precursors responded to the 10-kD antigen. T ceU lines derived from lepromin skin tests were strongly responsive to the 10-kD protein. T cell clones reactive to both the purified native and recombinant 10-kD antigens recognized M. l~rae-specific epitopes as well as epitopes crossreactive with the cognate antigen of M. tuberculosis. Further, the purified hsp 10 elicited strong ddayed-type hypersensitivity reactions in guinea pigs sensitized to M. leprae. The strong T ceil responses against the M. leprae 10-kD protein suggest a role for this heat-shock cognate protein in the protective/resistant responses to infection.

The clinical forms of leprosy constitute a spectrum that correlates closely with the degree of cellmediated immunity. Patients with tuberculoid leprosy develop strong cell-mediated responses and have only a few, localized lesions, whereas patients with multibacillary lepromatous leprosy are specifically unresponsive to antigens of Myobacterium leprae. T cells of the CD4+ subset predominate in tuberculoid lesions, whereas CD8+ cells predominate in lepromatous lesions. Monoclonal antibodies that distinguish subpopulations of CD4+ and CD8+ cells were used to analyze the distribution of T cells infiltrating lesions across the disease spectrum. In lepromatous lesions, T cells of T-suppressor phenotype (9.3-) were the predominant CD8+ cells and suppressor/inducer cells (2H4+, Leu-8+) represented half of the CD4+ subset. In tuberculoid lesions, helper T cells (CD4+4B4+) outnumbered suppressor/inducer T cells by 14:1, compared with a ratio of 1.2:1 in peripheral blood. Analysis of the precursor frequency of antigen-reactive T cells permitted us to estimate that there was a 100-fold enrichment of T cells able to proliferate in response to M. leprae antigens in tuberculoid lesions (2/100), when compared with blood from the same patients. The methods used here to characterize the T-lymphocyte subsets and frequency of antigen-reactive T cells in leprosy may be useful in analyzing imunological reactions occurring in lesions of other inflammatory and autoimmune diseases.There are at least two compelling reasons to study leprosy. The disease itself, affecting 10-15 million people worldwide, poses a significant health and economic burden on thirdworld countries. Second, because leprosy is a spectral disease in which pathology and immunology are inextricably related, it provides a unique critical model for investigating immunoregulatory mechanisms in humans.Leprosy is not a single critical entity but rather comprises a spectrum of clinical manifestations that correlate remarkably well with immunological responses to the organism (1). Patients with tuberculoid leprosy have a few localized lesions with rare organisms and a strong cell-mediated immune response directed against Myobacterium leprae antigens that ultimately kills and clears the bacilli, although often with concomitant injury to nerves. In contrast, lepromatous leprosy patients have numerous skin lesions containing extraordinarily high numbers of acid-fast bacilli and show specific immunological unresponsiveness to antigens of M. leprae in vivo and in vitro.The selective mechanisms of accumulation of lymphocytes, their antigen specificity, and immunological functions in inflammatory lesions of human infectious or autoimmune diseases remain largely unknown. Since the focal point of the immune response to M. leprae is the tissue granuloma, consisting of a collection of lymphocytes and macrophages, some of these questions can be approached directly through the study of cells infiltrating the lesions across the spectrum of leprosy.Immunohistological studies using m...

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Leprosy remains a significant medical and social problem in many developing countries. The varied forms of the disease form a spectrum. At one pole, tuberculoid leprosy, patients develop high levels of cell-mediated immunity which results in the killing and clearing of bacilli in the tissues. At the lepromatous pole, patients exhibit a selective immunological unresponsiveness to antigens of Mycobacterium leprae so that the organisms inexorably multiply in the skin. We have suggested that in lepromatous leprosy one or a small number of unique antigenic determinants present on M. leprae might induce specific suppressor cells that inhibit the reactivity of helper T-cell clones capable of recognizing other specific or cross reactive determinants. Although unique epitopes have been identified by monoclonal antibodies on a small number of M. leprae proteins, the only unique species of antigen present in M. leprae, and not on any other species of mycobacteria so far examined, is a phenolic glycolipid (gly-I). We show here that this unique antigen of M. leprae is capable of inducing suppression of mitogenic responses of lepromatous patients' lymphocytes in vitro and provide evidence that the suppressor T cells recognize the specific terminal trisaccharide moiety.