In situ characterization of lymphocytic immunophenotypes and interleukin-2 receptors in cutaneous tuberculosis and leprosy--a comparative evaluation.

The granulomas of lupus vulgaris (LV) were characterized by preponderance of CD4+ lymphocytes and a raised CD4+/CD8+ ratio. In contrast, in scrofuloderma (SF) the CD8+ T-lymphocyte subpopulation predominated and the CD4+/CD8+ ratio was significantly decreased. A higher percentage of lymphocytes expressed interleukin-2 receptor (IL-2R) in LV as compared with SF, indicating an activated cellular immune response in the former. Immunophenotypic changes in tuberculosis verrucosa cutis (TBVC) were intermediate between LV and SF. CD4+ lymphocytes were the main infiltrating T-cell type in borderline tuberculoid leprosy (BT), while CD8+ lymphocytes predominated in the granuloma of lepromatous lepromatous (LL). The CD4+/CD8+ ratio and percentage of lymphocytes expressing IL-2R was significantly higher in BT as compared with LL. These immunophenotypic findings suggest that in both cutaneous tuberculosis and leprosy there is a continuous spectrum with regard to cell-mediated immunity depending on the clinical presentation.

Borderline tuberculoid Hansen's disease in AIDS.

We performed an immunohistochemical analysis of a skin lesion from a patient with AIDS who had borderline tuberculoid Hansen's disease. We also evaluated other laboratory features and performed peripheral blood flow cytometric analysis. The in situ immunologic response to Mycobacterium leprae was minimally affected by concomitant infection and immunosuppression by HIV. The skin demonstrated the typical characteristics of borderline tuberculoid lesions. These results indicate that although a patient with HIV infection may have laboratory evidence typical of the immunosuppression seen in AIDS, the immunologic response to M. leprae is essentially unchanged.

Studies of human leprosy lesions in situ using suction-induced blisters. 2. Cell changes and soluble interleukin 2 receptor (Tac peptide) in reversal reactions.

To examine the pathogenesis of type 1 (reversal) reactions in leprosy, we studied cellular and soluble immunologic components of skin lesions in 10 patients with reactions, 24 active patients without reactions, and 33 control patients whose leprosy had been treated and cured. Cells and Tac-peptide levels were obtained from fluid aspirated from blisters induced by suction directly over representative skin lesions. During reversal reactions: a) the lesions contained an increased number and percentage of CD4+ (T-helper) cells; b) Tac-peptide levels were elevated in half of the lesions; c) the increases in Tac peptide and CD4+ cells were directly correlated; and d) systemic administration of corticosteroids appeared to cause a reduction in the intralesional CD4+ cell population. These findings were localized to the skin, and do not represent simple filtration of these components from the peripheral blood. We conclude that spontaneous lymphocyte activation in situ, primarily of CD4+ cells, is an important feature of reversal reactions, and may be an intermittent or cyclic phenomenon during the reaction. Findings in active patients without reactions are consistent with the hypothesis that differing states of immunologic equilibrium have been established in different portions of the leprosy spectrum. In reversal reactions we may, therefore, be examining immunologic processes set in motion when a pre-existing equilibrium has been upset by spontaneous, natural events. The mechanism of such spontaneous changes in immunity in leprosy is of considerable interest, not only to understand the reaction, but also to examine the underlying determinants of delayed-type hypersensitivity and cell-mediated immunity in leprosy and the potential for artificially manipulating these responses, as proposed with vaccines or immunotherapy.

Cell changes and soluble interleukin-2 receptors (Tac peptide) in leprosy reversal reactions using suction-induced blisters.

The cellular contents and soluble interleukin-2 receptor (IL-2R) [Tac peptide] of skin blisters induced by suction over 7 reversal reaction (RR) patients were examined using immunoperoxidase and ELISA techniques respectively. The helper T activity (CD4+ cells) and helper:suppressor ratio were significantly greater in borderline lepromatous (BL) lesions with RR than in quiescent BL lesions. Interestingly, the intracutaneous levels of Tac peptide were elevated and directly correlated with the increases in CD4+ cells. The systemic administration of corticosteroids revealed a reduction in the numbers of CD4+ cells in the lesions. These results indicate that RRs are manifestations of a spontaneous increase in delayed type hypersensitivity (DTH) and possibly cell mediated immunity (CMI) in leprosy patients. The mechanism of such changes in immunity is of considerable value in understanding reversal reactions and the underlying determinants of DTH and CMI in leprosy and this in turn will have a bearing on the potential for proposed vaccines or immunotherapy.

Restoration of defective cytokine activity within lepromatous leprosy lesions.

Immunohistological studies of tuberculoid leprosy lesions (TT-lesions) showed a dense, well organized granuloma consisting of a central area with epitheloid and giant cells containing interferon-gamma (IFN-Gamma) and CD3+, CD4+ T helper/inducer (Th/i) cells, a considerable proportion of which expressed the interleukin-2-receptor (IL-2 R). This central area was surrounded by round cells which consisted mainly of CD3+/CD8+ T cytotoxic/suppressor (Tc/s) lymphocytes. The overlying keratinocytes (KC) were strongly positive for HLA-DR antigens on the surface, indicating high intralesional IFN-Gamma activity. In contrast, lepromatous leprosy lesions (LL-lesions) showed a disorganized infiltrate composed by foamy cells and round cells, the latter mainly expressing the CD3+/CD8+ phenotype. IFN-Gamma activity could not be detected within the lesions. The KC overlying the infiltrate were consistently negative for HLA/DR reactivity pointing to a defective intralesional IFN-Gamma production in LL patients. Two out of four patients with LL leprosy could be sensitized with dinitrochlorobenzene (DNCB). The eliciting of DNCB skin reactions within the LL-lesion led to the recruitment of new infiltrating cells; the resulting infiltrate resembled a local reversal towards the tuberculoid pole of leprosy.

Suppress of the increase in free cytosolic calcium during the inhibition of T-cell activation by an autoantibody present in the serum of leprosy patients.

A serum factor, believed to be an IgG autoantibody, in certain patients with lepromatous leprosy inhibits the proliferation of mitogen-stimulated lymphocytes. To investigate which stage of the cell cycle was inhibited, we examined the effect of these sera on the kinetics of lymphocyte activation induced by several mitogenic agents: phytohaemagglutinin (PHA), the calcium ionophore A23187, the phorbol ester phorbol myristate acetate (PMA) and purified protein derivative of BCG (PPD). Seven out of 54 sera tested were found to inhibit PHA-stimulated proliferation. Inhibitory sera and to a lesser extent serum IgG from leprosy patients were capable of suppressing the increase in free cytosolic calcium normally observed immediately after PHA stimulation. Subsequent stages of the cell cycle, increase in cell size, the expression of the IL-2 receptor and increase in DNA were also suppressed. The inhibitory sera was not toxic and, if addition of the sera was delayed, would not inhibit lymphocytes that had already entered the cell cycle. Using mitogenic agents which act intracellularly, the normal early increase in cell size with A23187- and PMA-stimulated lymphocytes was not affected by inhibitory leprosy sera or serum IgG, but all subsequent steps in the cell cycle were suppressed; although the inhibition of proliferation in PMA-stimulated cultures was incomplete. The mechanism of action of the inhibitory sera and derived IgG, although acting through a cell surface antigen, appears to interfere with a fundamental process in activation since the effect was seen with all of the diverse stimuli examined in this study.

Inmunosupresión en lepra / Immunosuppression in leprosy

Son varios los trabajos que tratan de demostrar que en la formal lepromatosa (LL) de la lepra, existirían mecanismos supresores de la respuesta inmune. Al emplear un método de inducción inespecífico, como el sistema de la Concavalina A (ConA), observamos que los pacientes LL tenían disminuida la función supresora, valorada sobre un sistema de proliferación celular T; dicha función tendía a normalizarse durante el episodio de eritema nudoso lepromatoso (ENL). En este sistema demonstramos además, que las células CD8+ (Leu 2a+) eram capaces de interferir en la generación de supresión. Observamos además, que un alto porcentaje de pacientes LL tenían una supresión espontánea elevada; en este tipo de supresión hallados. Por otra parte, hemos demostrado que en este sistema tendría un papel importante el sistema supresor de los monocitos, a través de la liberación de factores solubles (PGE2). Al evaluar la capacidad que tiene el M. leprae para inducir especificamente supresión in vitro la proliferación célular T, hallamos que en los pacientes LL el M. leprae no inducía supresión. Paralelamente, determinamos en sangre periférica, el número de células que tenían el antígeno Leu8+. Observamos que este antígeno estaba marcadamente disminuido, en la fracción de células T, en los pacientes LL y tendía a normalizarse durante el receptores para IL-2 (Tac) durante la etapa de inducción era similar tanto en los TT com LL. La capacidad de las células para proliferar frente a los mitógenos empleados...

Inmunosupresión en lepra / Immunosuppression in leprosy

Son varios los trabajos que tratan de demostrar que en la formal lepromatosa (LL) de la lepra, existirían mecanismos supresores de la respuesta inmune. Al emplear un método de inducción inespecífico, como el sistema de la Concavalina A (ConA), observamos que los pacientes LL tenían disminuida la función supresora, valorada sobre un sistema de proliferación celular T; dicha función tendía a normalizarse durante el episodio de eritema nudoso lepromatoso (ENL). En este sistema demonstramos además, que las células CD8+ (Leu 2a+) eram capaces de interferir en la generación de supresión. Observamos además, que un alto porcentaje de pacientes LL tenían una supresión espontánea elevada; en este tipo de supresión hallados. Por otra parte, hemos demostrado que en este sistema tendría un papel importante el sistema supresor de los monocitos, a través de la liberación de factores solubles (PGE2). Al evaluar la capacidad que tiene el M. leprae para inducir especificamente supresión in vitro la proliferación célular T, hallamos que en los pacientes LL el M. leprae no inducía supresión. Paralelamente, determinamos en sangre periférica, el número de células que tenían el antígeno Leu8+. Observamos que este antígeno estaba marcadamente disminuido, en la fracción de células T, en los pacientes LL y tendía a normalizarse durante el receptores para IL-2 (Tac) durante la etapa de inducción era similar tanto en los TT com LL. La capacidad de las células para proliferar frente a los mitógenos empleados... (AU)

[Immunosuppression in leprosy]. / Immunosupresión en lepra.

Many authors tried to show that in lepromatous leprosy (LL), suppressor mechanisms are involved in the immune response. We have previously shown that non-specific suppression (Con A induced) was impaired in LL patients and tends to normalize during the erythema nodosum leprosum episode (ENL). In this system we have shown that CD8+ cells (Leu 2a+) can interfere with the generation of Con A-induced suppression. We also observed that a high percentage of LL patients had an increased spontaneous suppression. In these patients, the number of Leu 2a+ cells added in the assay did not correlate with the suppression values. On the other hand, we had demonstrated that the monocyte suppressor system may have an important role, due to the release of soluble factors (PGE2). We evaluated M. leprae-induced suppressor cell function using a two step assay, on T cell proliferation. The results of this study indicate that the ability of M. leprae to induce suppressor activity was lower in LL patients than in tuberculoid (TT), intermediate clinical forms (BB, BL, BT) and BCG-immunized controls. On the other hand, we determined that the proportion of peripheral blood mononuclear cells (PBMC) bearing the Leu 8+ antigen (associated to suppressor inducer cells) was low in LL and tends to normalize during the ENL episode. Suppression of proliferation could not be overcome with exogenous IL-2 and was not related to the induction of Tac antigen. The ability of LL, TT, ENL and normal cells to proliferate upon PHA or Con A stimulus was similar.(ABSTRACT TRUNCATED AT 250 WORDS)