Lepromatous Form Research Articles

Complex segregation analysis of leprosy in southern Vietnam.

To investigate the nature of the genetic component controlling susceptibility to leprosy and its subtypes, 402 nuclear families were ascertained through a leprosy patient followed at the Dermatology Hospital in Ho Chi Minh City, Vietnam; 285 families were of Vietnamese origin and 117 were of Chinese origin with a higher proportion of lepromatous forms among Chinese patients. Segregation analyses were conducted using the model developed by Abel and Bonney [(1990) Genet Epidemiol 7:391-407], which accounted for variable age of onset and time-dependent covariates. Three phenotypes were considered: leprosy per se (all forms of leprosy together), nonlepromatous leprosy, and lepromatous leprosy. For each of this phenotype, analyses were performed on the whole sample and separately on the Vietnamese and the Chinese families. The results showed that a single Mendelian gene could not account for the familial distributions of leprosy per se and its two subtypes in the whole sample. However, these results were different according to the ethnic origin of the families. In the Vietnamese subsample, there was evidence for a codominant major gene with residual familial dependences for the leprosy per se phenotype, and borderline rejection of the Mendelian transmission hypothesis for the nonlepromatous phenotype. In Chinese families, strong rejection of Mendelian transmission was obtained in the analysis of leprosy per se, and no evidence for a familial component in the distribution of the nonlepromatous phenotype was observed. For the lepromatous phenotype, the discrimination between models was poor, and no definitive conclusion could be reached. Referring to immunological data, we suggest that these results could be explained by a heterogeneity in the definition of the lepromatous phenotype. It is likely that progress in the understanding of the genetic components involved in the expression of leprosy will come from a better definition of the phenotype under study, and immunological studies are ongoing in this population to investigate this hypothesis.

Chemotherapy of lepromatous leprosy: recent developments and prospects for the future.

Leprosy is a major debilitating infectious disease, primarily of the developing world. In this paper the current status and future prospects of antimicrobial therapy of the severe anergic lepromatous form of the disease are reviewed. Until the last few years only dapsone, rifampicin, clofazimine and ethionamide have had practical application in its therapy, and only rifampicin was bactericidal. Recently, antibiotics from three different classes have been found to be bactericidal in lepromatous patients: a tetracycline (minocycline), a macrolide (clarithromycin), and several fluoroquinolones (including pefloxacin, ofloxacin and sparfloxacin). Against a background of drug resistance and bacterial persistence, recommendations for multidrug therapy and the means to devise rationally based therapy for the future are discussed.

Coronary heart disease risk factors in hansen's disease sufferers

In the frame of an epidemiologic study of Hansen's disease (HD) sufferers, several risk factors have been investigated which might explain the high prevalence of coronary heart disease (CHD) among HD patients. The data analyzed in the present study are derived from 293 HD patients (157 men and 136 women). The patients, after having completed a WHO adopted questionnaire, were given a complete physical examination, a resting and an exercise electrocardiogram, and biochemical as well as hematological examinations. Coronary HD patients, when compared to noncoronary HD patients, showed statistically significant differences in the following parameters: (1) mean age, (2) mean concentration of the electrophoretic fraction of alpha-lipoproteins, (3) deviation from mean weight, (4) prevalence of hypertension, and (5) prevalence of the borderline lepromatous form of HD. However, the differences found when comparing other parameters, such as blood pressure, smoking, diabetes mellitus, total cholesterol, triglycerides, pre-beta and beta-lipoproteins, uric acid, erythrocyte sedimentation rate, ABO blood groups, etc., did not reach the level of significance. These findings suggest that HD sufferers are a special population subgroup with reference to CHD risk factors, differing in many ways from the general population.

Novel responses of human skin to intradermal recombinant granulocyte/macrophage-colony-stimulating factor: Langerhans cell recruitment, keratinocyte growth, and enhanced wound healing.

Recombinant granulocyte/macrophage-colony-stimulating factor (rGM-CSF), prepared from Chinese hamster ovary (CHO) cells and Escherichia coli, was administered to 35 patients with the borderline and polar lepromatous forms of leprosy by the intradermal and subcutaneous routes at doses of 7.5-45.0 micrograms/d for 10 d. With each of these doses and routes, increases in the number of circulating eosinophils were noted. After the intradermal injection, the local skin sites demonstrated zones of roughening and micronodularity that appeared within 24-48 h and persisted for more than 6 d. Reinjection of sites led to enhanced areas of epidermal reaction. GM-CSF prepared from CHO cells was a more potent inducer of this effect. GM-CSF given by the subcutaneous route, at higher doses, failed to initiate these changes. At the microscopic level, the epidermis became thickened (+75%) with increased numbers and layers of enlarged keratinocytes. These contained increased numbers of ribosomes and prominent nucleoli, and were imbedded in a looser meshwork of the zona Pellucida. The modified keratinocytes remained MHC class II antigen negative throughout the course of the response. A major change in the dermis was the progressive accumulation of CD1+, Birbeck granule-positive cells. These Langerhans were recognizable at 48 h after intradermal injection and reached maximum numbers by 4 d. During this period the number of epidermal Langerhans cells remained relatively constant. No increment in dermal Langerhans cells occurred when GLM-CSF was injected by the subcutaneous route. No appreciable increase in the numbers of T cells and monocytes was noted, and granulocytes and eosinophils were largely present within the dermal microvasculature. 4-mm punch biopsies taken from injected sites and adjacent controls were compared in terms of the rapidity of wound healing. 22 of 26 sites demonstrated more rapid filling and hemostasis, whereas four were equivalent to controls. We conclude that rGM-CSF, when introduced into the skin, leads to enhanced keratinocyte growth, the selective recruitment of Langerhans cells into the dermis, and enhanced wound healing of the prepared site. There was no evidence of an enhanced cell-mediated response to Mycobacterium leprae, and bacillary numbers remained unchanged.

Tumor necrosis factor production in patients with leprosy.

The spectrum of host responses to Mycobacterium leprae provides a model for investigating the role of cytokines in the pathogenesis of mycobacterial disease. Of particular interest is tumor necrosis factor (TNF), a cytokine which may have both antimycobacterial and immunopathologic effects. To evaluate the potential role of TNF in leprosy, we measured TNF production in response to M. leprae and its defined constituents by peripheral blood mononuclear cells from patients across the spectrum of disease. The levels of TNF induced through the stimulation of cells with M. leprae or its dominant "lipopolysaccharide," lipoarabinomannan, were higher in patients with the tuberculoid form of the disease than in those with the lepromatous form. In patients with erythema nodosum leprosum (ENL), a reactional state of lepromatous leprosy, the levels of TNF release by peripheral blood mononuclear cells were higher than in any other form of the disease. Treatment of ENL patients with thalidomide reduced TNF secretion by more than 90%. The mycolylarabinogalactan-peptidoglycan complex of Mycobacterium species, the protein-peptidoglycan complex, and muramyl dipeptide all elicited significant TNF release. Therefore, TNF release appears to be triggered by at least two major cell wall structural constituents of M. leprae, lipoarabinomannan and segments of the cell wall skeleton. The prominent TNF release in patients with the paucibacillary tuberculoid form of the disease compared with that in patients with the multibacillary lepromatous form suggests that this cytokine contributes to a resistant immune response to mycobacterial infection. However, the marked TNF release in patients with ENL indicates that TNF may also mediate immunopathologic effects, such as fever and tissue damage.

Leprosy in Bangladesh, 1984-88

A total of 2517 patients with leprosy were studied in Leprosy Control Institute and Hospital, Mohakhali, Dhaka, during the period 1984-1988. Among the total cases, 1891 (75.1%) were male and 626 (24.9%) were female. The male to female ratio was 3:1. The age groups comprised 185 (7.4%), below 15 years and 2332 (92.6%), 15 years and over. Most of the cases were diagnosed by clinical examination and classified as Indeterminate form (I), 52 (2.1%); tuberculoid form (T), 1326 (52.7%); borderline tuberculoid form (BT), 439 (17.4%); borderline lepromatous form (BL), 110 (4.4%); and lepromatous form (L), 590 (23.4%).

BCG gives protection against non-lepromatous leprosy but not against the lepromatous form

BCG gives protection against non-lepromatous leprosy but not against the lepromatous form

Human phagocytic cell responses to Mycobacterium leprae and Mycobacterium bovis Bacillus Calmette-Guérin. An in vitro comparison of leprosy vaccine components.

Components of current vaccines for Hansen's disease include Mycobacterium bovis Bacillus Calmette-Guérin (BCG) and killed Mycobacterium leprae. BCG infections in humans are rare and most often occur in immune-compromised individuals. M. leprae on the other hand, although not causing clinical disease in most exposed individuals, is capable of infecting and replicating within mononuclear phagocytes. Lymphocytes from patients with the lepromatous form of Hansen's disease exhibit defective lymphokine production when challenged in vitro with M. leprae. This may result in inefficient mononuclear phagocyte activation for oxidative killing. To study the ability of normal phagocytes to ingest and respond oxidatively to BCG and M. leprae, we measured phagocytic cell O2- release and fluorescent oxidative product formation and visually confirmed the ingestion of the organisms. BCG stimulated a vigorous O2- generation in neutrophils and monocytes and flow cytometric oxidative product generation by neutrophils occurred in the majority of cells. M. leprae, stimulated a weak but significant O2- release requiring a high concentration of organisms and long exposure. By flow cytometric analysis, most neutrophils were able to respond to both organisms with the generation of fluorescent oxidative products. Neutrophil oxidative responses to M. leprae were substantially less than responses seen from neutrophils exposed to BCG. By microscopic examination of neutrophils phagocytizing FITC-labeled bacteria, it was shown that both M. leprae and BCG were slowly ingested but that more BCG appeared to be associated with the cell membrane of more of the cells. When phagocytic cells were incubated with BCG and M. leprae for 30 min and subsequently examined by electron microscopy, few organisms were seen in either neutrophils or monocytes. This suggests that BCG are easily recognized and slowly ingested by normal phagocytic cells, the majority of which respond with a strong oxidative burst. M. leprae appeared to only weakly stimulate phagocyte oxidative responses and were also slowly phagocytized.

Efficacy of a cell-mediated reaction to the purified protein derivative of tuberculin in the disposal of Mycobacterium leprae from human skin.

The purpose of this study was to evaluate the effects of a delayed-type cell-mediated immune response to Mycobacterium tuberculosis antigen on the Mycobacterium leprae load in the skin of leprosy patients. Twelve patients with the lepromatous form of leprosy have been injected intradermally with 5 units of the purified protein derivative of tuberculin (PPD). Ten individuals responded with areas of induration ranging from 12 to 21 mm in diameter, and two were unresponsive (less than 10 mm). Twenty-one days thereafter, the injected and control sites were biopsied, and the histology, number of acid-fast bacilli, nature and phenotype of the emigrant cells, and ultrastructural characteristics of the lesions were evaluated. Eight of the 10 responding patients showed reductions in the number of acid-fast bacilli by factors ranging from 5 to 10,000. Two responders and both nonresponders exhibited no discernible decline in the number of organisms. The reduction in bacillary load was correlated with an intense mononuclear cell infiltrate, the maintenance of a high CD4+ T-cell/CD8+ T-cell ratio, the formation of granulomata, and the extensive destruction of previously parasitized macrophages.

Gamma interferon production induced by antigens in patients with leprosy and American cutaneous leishmaniasis.

In this study, we measured gamma interferon production in mononuclear cell cultures from patients with diverse forms of leprosy and American cutaneous leishmaniasis. We studied patients with lepromatous, borderline lepromatous, borderline, and borderline tuberculoid forms of leprosy, as well as a Mitsuda-negative contact. In leishmaniasis we studied patients with localized cutaneous, mucocutaneous, and diffuse cutaneous forms of the disease. High correlation was observed between gamma interferon production and lymphocyte proliferation assays in both diseases. Resistant forms of both diseases showed significant reactivity, while the severe progressive forms were characterized by insignificant responses in both assays. Localized cutaneous leishmaniasis is characterized by variability in gamma interferon production, which may be of prognostic value in longitudinal studies.

An analysis of in vitro T cell responsiveness in lepromatous leprosy.

In lepromatous leprosy, there is extensive replication of Mycobacterium leprae (M. leprae) within dermal macrophages. This lack of microbial resistance has been attributed to a defective cell-mediated immune response to M. leprae antigens. We have examined the in vitro response of T cells to M. leprae to determine if hyporesponsiveness could be reversed. The study included 40 unselected patients from New York and from Colombia, most with the severe lepromatous form of the disease. We first noted that lepromatous leprosy patients were of two types: those unable to respond, as assessed by T cell proliferation and immune (gamma) interferon (IFN-gamma) release, and a second group, exhibiting low but detectable responses relative to tuberculoid controls. When the effect of exogenous recombinant interleukin-2 (IL-2) on the response to M. leprae antigens was compared in the two groups, many of the low responders, but not the nonresponders, showed enhanced proliferation and IFN-gamma release. To evaluate a possible suppressive effect of monocytes, these cells were eliminated with a cell-specific monoclonal antibody and complement. Depletion of monocytes often expanded preexisting weak responses but did not reverse the anergy of the M. leprae nonresponders. The enhancement was not M. leprae-specific, since it was also observed when bacillus Calmette-Guerin was the antigenic stimulus for proliferation and IFN-gamma production. Removal of the suppressor T cell subset, with OKT8 antibody and complement, also did not restore responses in nonresponder patients. We conclude that a sizable number of lepromatous leprosy patients exhibit a low degree of responsiveness to M. leprae and that the responses can be enhanced in vitro with IL-2 or with monocyte depletion. Nonresponsiveness, however, cannot be reversed. Since currently available assays measure the function of previously sensitized T cells, suppressor mechanisms may yet contribute to defective cell-mediated immunity by impairing the initial sensitization to M. leprae antigens.

Interleukin 1 production by peripheral blood mononuclear cells from leprosy patients.

Quantitation of interleukin 1 production by adherent mononuclear cells from peripheral blood was performed in patients with tuberculoid and lepromatous forms of leprosy. Cells from patients with tuberculoid leprosy either secreted interleukin 1 spontaneously or produced amounts within the normal range in response to lipopolysaccharide stimulation. Conversely, stimulated cells from lepromatous patients failed to produce interleukin 1 in 5 of 13 (38.5%) cases.

Cancer Mortality Among Patients With Hansen's Disease

For the evaluation of cancer risks associated with immunodeficiencies experienced by patients with Hansen's disease (leprosy) and for the assessment of possible adverse effects of dapsone therapy, a follow-up study was conducted of 1,678 patients admitted to the National Hansen's Disease Center in Carville, La., between 1939 and 1977. Overall, no substantial cancer mortality was observed (standardized mortality ratio = 1.3), nor was there any excess among patients exhibiting defects in cellular immunity by virtue of lepromatous forms of the disease. Notable was the absence of any significant excess of lymphoma (5 observed vs. 2.3 expected), despite the predominance of this tumor in certain other immunodeficiency states. Several cancer sites (oral, bladder, and kidney) occurred excessively, but reasons for the elevations were obscure. Although dapsone has been implicated as a carcinogen in laboratory animals, the use of sulfones, including dapsone, did not appear to affect significantly the risk of any cancers in this population.

The cutaneous infiltrates of leprosy: cellular characteristics and the predominant T-cell phenotypes.

We report on the characteristics of cells in the cutaneous lesions and blood of 21 patients with lepromatous, tuberculoid, and intermediate forms of leprosy. A large proportion of the infiltrates in lepromatous lesions consist of macrophages heavily parasitized with Mycobacterium leprae. The T cells in the lesions are devoid of OKT4/Leu 3a-positive ("helper") cells and consist almost exclusively of OKT8/Leu 2a-positive ("suppressor") populations. In contrast, the tuberculoid infiltrates contain well-organized epithelioid and giant-cell granulomas and only remnants of bacilli, and the predominant T cell is from the OKT4/Leu 3a-positive subset. In both tuberculoid and lepromatous infiltrates, T cells and macrophages expressed HLA-DR antigen. No marked alteration in the distribution of blood T-cell phenotypes was noted. We conclude that there is a marked difference between T-cell subsets in lepromatous and tuberculoid infiltrates, which may influence the microbicidal activity of macrophages in the lesions.

Serum Macrophage Migration Inhibition Activity in Patients with Leprosy

We have found that 26 of 54 (48%) untreated patients with leprosy had serum migration inhibitory activity, and that this was present in tuberculoid, borderline, and lepromatous forms of the disease. Patients with active recreational states; i.e., reversal reactions, Lucio's reaction, or erythema nodosum leprosum, were particularly apt to have this inhibitory activity. The prevalence of inhibitory activity did not vary significantly with treatment, dinitrochlorobenzene responsiveness, tuberculin responsiveness, or serum lysozyme levels.

ANTIGEN-SPECIFIC SUPPRESSOR CELLS IN SUBCLINICAL LEPROSY INFECTION

A two-stage in-vitro culture system was used to assay cells which suppress the lymphoproliferative response to Mycobacterium leprae (ML). Responses to ML, purified protein derivative of tuberculin, and streptokinase-streptodornase were preferentially suppressed by mitomycin-treated cells which had been primed with the same antigen in a 7-day primary culture. Healthy subjects exposed to leprosy for more than 3 years showed strong suppression of the response to ML antigens (11 of 12 showed more than 40% suppression), whereas those exposed for 3 months to 3 years showed much less suppression (12 of 15 showed less than 40% suppression). The in-vitro generation of strong ML-specific suppression may reflect the maturation of a well-regulated and protective immune response. However, premature induction and in-vivo activation of these suppressor cells could predispose to disseminated (lepromatous) forms of leprosy. With this assay it would be possible to assess the ability of proposed leprosy vaccines to engage strongly the regulatory network controlling the immune response to ML in the same way as long-term exposure to the natural infection.

Lack of observed association between armadillo contact and leprosy in humans.

In 1971 it was discovered that the nine-banded armadillo (Dasypus novemcinctus) could be infected in the laboratory with Mycobacterium leprae, and would manifest disease similar to the lepromatous form of leprosy in man. In 1975 several wild armadillos captured in Louisiana were found to have a disease identical to the M. laprae infection in laboratory animals. To determine if there is a significant association between contact with armadillos and presence of leprosy in humans, the armadillo contact of persons with indigenous leprosy in Louisiana was compared to the contact of matched controls. No difference in the nature or frequency of contact was found. If this infection of wild armadillos is of recent onset, an association with human leprosy in enzootic areas may not be detectable for several years.

Clinical manifestation of leprous rhinitis.

Over 25 million people in the World have leprosy. In the lepromatous form of the illness the nose is involved at a very early stage and in this paper the clinical manifestations are described. The nasal discharge in early untreated lepromatous leprosy contains vast numbers of the causative bacillus (M. leprae) and the important implications of these observations are discussed.

Immunologic reactivity in patients with leprosy.

Alterations in some aspects of immunologic reactivity in a group of patients with leprosy were found primarily in patients with the lepromatous form of the disease. Such patients had impaired lymphocyte transformation to streptolysin 0 antigen. The ability to form circulating antibodies was preserved. Levels of IgG and IgA immunoglobulins were increased in lepromatous disease while IgM levels were normal in all groups. The concentration of serum complement was normal in all patients with uncomplicated disease but was elevated in those lepromaotus patients suffering erythema nodosum leprosum (ENL) reactions or amyloidosis. Reticuloendothelial system phagocytic function was increased in patients with lepromatous leprosy and especially in those with ENL reactions. Thus, the lepromatous form of leprosy is associated with a variety of abnormal immunologic responses.

Relapses in lepromatous leprosy

1. (1) West African lepromatous patients whom modern treatment has rendered bacteriologically negative are liable to develop relapses in the form of fresh outcrops of macules even in spite of continued treatment. 2. (2) These relapses show clinical and histopathological characteristics of the dimorphous (indeterminate) form of leprosy. 3. (3) The lepromin test in these patients, as in the great majority of subsided lepromatous cases, is negative or at most very weakly positive.Consequently they might probably revert easily to lepromatous type. 4. (4) It would seem, therefore, that in many lepromatous patients modern treatment, although able to render them bacteriologically negative by the standard method of examination, cannot eradicate completely the bacilli, and that only continuation of treatment for an indefinite length of time can prevent these patients from reverting to a severe lepromatous form of the disease.