In vitro and skin lesion cytokine profile in Brazilian patients with borderline tuberculoid and borderline lepromatous leprosy

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Lepromatous leprosy and perianal tuberculosis: a case report and literature review

Leprosy is a chronic infectious disease caused by Mycobacterium leprae, a microorganism that usually affects skin and nerves. Although it is usually well-controlled by multidrug therapy (MDT), the disease may be aggravated by acute inflammatory reaction episodes that cause permanent tissue damage particularly to peripheral nerves. Tuberculosis is predominantly a disease of the lungs; however, it may spread to other organs and cause an extrapulmonary infection. Both mycobacterial infections are endemic in developing countries including Brazil, and cases of coinfection have been reported in the last decade. Nevertheless, simultaneous occurrence of perianal cutaneous tuberculosis and erythema nodosum leprosum is very rare, even in countries where both mycobacterial infections are endemic.

Increased Expression of Regulatory T Cells and Down-Regulatory Molecules in Lepromatous Leprosy

T regulatory cells (Tregs) play an important role in the mechanism of host's failure to control pathogen dissemination in severe forms of different chronic granulomatous diseases, but their role in leprosy has not yet been elucidated; 28 newly diagnosed patients (16 patients with lepromatous leprosy and 12 patients with tuberculoid leprosy) and 6 healthy Mycobacterium leprae-exposed individuals (contacts) were studied. Tregs were quantified by flow cytometry (CD4+ CD25+ Foxp3+) in peripheral blood mononuclear cells stimulated in vitro with a M. leprae antigenic preparation and phytohemagglutinin as well as in skin lesions by immunohistochemistry. The lymphoproliferative (LPR), interleukin-10 (IL-10), and interferon-gamma (IFN-gamma) responses of the in vitro-stimulated peripheral blood mononuclear cells and the in situ expression of IL-10, transforming growth factor-beta (TGF-beta), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) were also determined. We show that M. leprae antigens induced significantly lower LPR but significantly higher Treg numbers in lepromatous than tuberculoid patients and contacts. Mitogen-induced LPR and Treg frequencies were not significantly different among the three groups. Tregs were also more frequent in situ in lepromatous patients, and this finding was paralleled by increased expression of the antiinflammatory molecules IL-10 and CTLA-4 but not TGF-beta. In lepromatous patients, Tregs were intermingled with vacuolized hystiocyte infiltrates all over the lesion, whereas in tuberculoid patients, Tregs were rare. Our results suggest that Tregs are present in increased numbers, and they may have a pathogenic role in leprosy patients harboring uncontrolled bacillary multiplication but not in those individuals capable of limiting M. leprae growth.

WHO disability grade does not influence physical activity in Brazilian leprosy patients

Disability caused by leprosy may be associated with stigma. The aim of this work is to describe the degree of disability, quality of life and level of physical activity of individuals with leprosy and to identify possible correlations between these factors. Ninety-seven patients from two referral centres were studied. A complete medical history was taken and the World Health Organization degree of physical disability classification (WHO-DG), the International Physical Activity Questionnaire (IPAQ) and the Medical Outcome Study 36-item Short-form health Survey (SF36) were applied. The mean age of patients was 51 +/- 14.9 years old; participants were predominantly men, married, unemployed, had concluded treatment and had had lepromatous leprosy. The WHO-DG and the level of physical activity (P-value = 0.36) were not correlated. The WHO-DG showed that 72.2% of patients had disabilities, 37-1% of whom performed vigorous physical activities. No significant association was observed between the WHO-DG and the domains of the QoL SF-36 except for functional capacity (P-value = 0.02); the physical capacity is generally 'very good' when individuals have no disabilities and 'bad' with severe disabilities. In conclusion, the WHO-DG of leprosy patients does not affect the level of physical activities or quality of life except functional capacity. There is no significant association between physical activities and quality of life in these individuals.

Anti-neutrophil cytoplasmic antibodies (ANCA) in the clinical forms of leprosy

Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies against enzymes present in primary granules of neutrophils and lysosomes of monocytes detected in systemic vasculitis and in other diseases, including infections, ANCA are markers of active Wegener granulomatosis, which presents some anatomo-pathologic and immune response features similar to those of leprosy. Thus, we raised the hypothesis that ANCA may be present in leprosy as markers specifically linked to the presence of vasculitis. The aim of this study was to determine the presence of ANCA in leprosy and its correlation with the clinical forms of the disease. Sera from 60 normal individuals and from 59 patients with different clinical forms of leprosy were studied. The patients were also allocated into reactional and nonreactional groups. By indirect immunofluorescence, ANCA were positive, an atypical pattern A-ANCA, in 28.8% of the patient sera. A-ANCA predominated, although not significantly (p >0,05), in the reactional groups (37.9% vs 20.0%), and in those at the lepromatous pole (41.6% vs 20.0%). There was no correlation between ANCA positivity and either disease duration, disease activity, or therapeutic regimen (p >0.05), An interesting finding was the correlation between ANCA and gender: 94.1% of ANCA-positive patients were males (p <0.01), a feature that so far has not been reported in ANCA-related diseases and for which there is no explanation at the moment. By ELISA, the sera of the lepromatous leprosy patients did not show activity against either PR3, MPO, HLE, the most common ANCA antigens. Because A-ANCA are nonspecific, this finding requires further investigation for the determination of the responsible antigen(s), in conclusion, A-ANCA are present in 28.8% of leprosy patients but are not related to vasculitis in the erythema nodosum leprosum reaction and are not a marker of a specific clinical form.

Renal lesions in leprosy: A retrospective study of 199 autopsies

In the present work, 199 patients with leprosy who underwent autopsy between 1970 and 1986 were retrospectively studied to determine the prevalence, types, clinical characteristics, and etiologic factors of renal lesions (RLs) in leprosy. Patients were divided into two groups: 144 patients with RLs (RL+) and 55 patients without RLs (RL-), RLs observed in 72% of the autopsied patients were amyloidosis (AMY) in 61 patients (31%), glomerulonephritis (GN) in 29 patients (14%), nephrosclerosis (NPS) in 22 patients (11%), tubulointerstitial nephritis (TIN) in 18 patients (9%), granuloma in 2 patients (1%), and other lesions in 12 patients (6%), AMY occurred most frequently in patients with lepromatous leprosy (36%; nonlepromatous leprosy, 5%; P < 0.01), recurrent erythema nodosum leprosum (33%; P < 0.02), and trophic ulcers (27%; 0.05 < P < 0.10), Ninety-seven percent of AMY was found in patients with lepromatous leprosy, 88% showed recurrent trophic ulcers, and 76% presented with erythema nodosum leprosum, NPS was found in older patients with arterial hypertension, neoplastic diseases, infectious diseases, and vasculitis associated with GN, Most patients with AMY presented with proteinuria (95%) and renal failure (88%), the most frequent causes of death were renal failure in patients with AMY (57%), infectious diseases in patients with GN (41%) and TIN (45%), and cardiovascular diseases in patients with NPS (41%), No difference in survival rates was observed among RL- patients and those with AMY, GN, NPS, or TIN. (C) 2001 by the National Kidney Foundation, Inc.

Leprosy, a neglected disease that causes a wide variety of clinical conditions in tropical countries

Leprosy is an ancient disease that remains endemic and continues to be a major public health problem in some tropical countries, where it has been internationally recognized as being linked to the underdevelopment conditions. The natural course of the disease covers a wide variety of clinical conditions with systemic involvement. In this paper, we review the findings obtained in studies of the pathological mechanisms of leprosy, including a survey of the literature and of our own work. The understanding and control of the wide variety of clinical conditions should help improve patient care and thus prevent the onset of physical impairment and the stigma of the disease.

Differential expression of the costimulatory molecules CD86, CD28, CD152 and PD-1 correlates with the host-parasite outcome in leprosy

Leprosy is a spectral disease exhibiting two polar sides, namely, lepromatous leprosy (LL) characterised by impaired T-cell responses and tuberculoid leprosy in which T-cell responses are strong. Proper T-cell activation requires signalling through costimulatory molecules expressed by antigen presenting cells and their ligands on T-cells. We studied the influence of costimulatory molecules on the immune responses of subjects along the leprosy spectrum. The expression of the costimulatory molecules was evaluated in in vitro-stimulated peripheral blood mononuclear cells of lepromatous and tuberculoid patients and healthy exposed individuals (contacts). We show that LL patients have defective monocyte CD86 expression, which likely contributes to the impairment of the antigen presentation process and to patients anergy. Accordingly, CD86 but not CD80 blockade inhibited the lymphoproliferative response to Mycobacterium leprae. Consistent with the LL anergy, there was reduced expression of the positive signalling costimulatory molecules CD28 and CD86 on the T-cells in these patients. In contrast, tuberculoid leprosy patients displayed increased expression of the negative signalling molecules CD152 and programmed death-1 (PD-1), which represents a probable means of modulating an exacerbated immune response and avoiding immunopathology. Notably, the contacts exhibited proper CD86 and CD28 expression but not exacerbated CD152 or PD-1 expression, suggesting that they tend to develop a balanced immunity without requiring immunosuppressive costimulatory signalling.

Evidencia actual sobre características demográficas en mastitis granulomatosa idiopática

Introducción: La mastitis granulomatosa idiopática es una enfermedad crónica benigna, rara y de etiología desconocida; tiende a confundirse con otras enfermedades debido a síntomas similares. Este estudio pretende identificar y cuantificar las características demográficas, los antecedentes ginecoobstétricos relevantes y las manifestaciones clínicas prediagnósticas de esta enfermedad Metodología: Se realizó una revisión sistemática con análisis agrupado de datos tipo meta análisis. Se utilizó una estrategia de búsqueda en PubMed. Todos los estudios relacionados con la definición, manifestaciones clínicas, diagnóstico, tratamiento y pronóstico de la mastitis granulomatosa idiopática fueron elegibles. Las variables de interés fueron edad, país, antecedente de contracepción hormonal, tiempo de evolución, tiempo desde el último embarazo, diagnóstico inicial, y manifestaciones clínicas previas a la consulta. No hubo restricción en fechas de publicación. Resultados: Fueron incluidas 641 mujeres con diagnóstico de MGI reportadas en 68 publicaciones que cumplieron los criterios de selección. La edad media fue 35.9 años, 14.1% de ellas estaba embarazada o lactando, el antecedente de consumo de anticonceptivos hormonales fue 21% y el tiempo promedio desde el último parto fue de 3.9 años. La afectación ocurre principalmente en mama izquierda y en cuadrante superoexterno. El cáncer de mama y el absceso mamario son diagnósticos diferenciales en la consulta. Discusión: El diagnóstico de MGI es un reto para el ginecólogo desde la consulta inicial. Debido a que sus manifestaciones clínicas no son específicas, su diagnóstico parece apuntar a la necesidad de un proceso de descarte de otras patologías más frecuentes e incluso de peor pronóstico. Palabras clave mastitis granulomatosa idiopática

AVALIACAO DA REACAO DE MITSUDA EM PACIENTES VIRCHOVIANOS INATIVOS ANTES E APOS IMUNOTERAPIA

In this study the immunopotentiator levamisole as well as a mixture of BCG/Mycobacterium leprae were investigated in inactive lepromatous leprosy patients by using the Mitsuda reaction as a parameter. Twenty lepromatous patients ten years ago classified as histologically negative for Mitsuda's test were divided into three groups: five patients that were only retested with Mitsuda antigen; eight patients that received oral levamisol and seven patients that received a mixture of alive BCG plus autoclaved M. leprae. The results indicated that: 1) the levamisole did not alter the reactivity to lepromin in any of the patients studied; 2) neither the changes in the reactivity to lepromin by using the mixture (3 cases) nor those that occurred spontaneously (3 cases) were clear. They properly reflected the natural variation of patients with some degree of resistance to Mycobacterium leprae.

Estudo terapêntico comparando a associação de rifampicina, ofloxacina e minociclina com a associação rifampicina, clofazimina e dapsona em pacientes multibacilar

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Ciclosporina A no eritema nodoso hansênico com manifestações sistêmicas: avaliação clínica, laboratorial e histopatológica

O ENH é séria intercorrência aguda ou subaguda que acomete pacientes das formas dimorfa-virchowiana e virchowiana da classificação de Ridley e Jopling. Neste estudo, foi utilizada uma droga imunorreguladora, a ciclosporina A, com o propósito de avaliar a eficácia nesta reação, cujo tratamento depende de medicamentos como a talidomida, que tem contra-indicações formais e corticóides, que provocam dependência, entre outros danos. Foram selecionados dez doentes de ENH com sintomas sistêmicos; todos haviam passado por vários episódios desta reação e faziam uso contínuo e prolongado de prednisona em doses elevadas e ocasionalmente, de talidomida. Os pacientes tomaram ciclosporina A em doses de 3-5 mg/kg/dia durante um período de 90 dias. Realizaram exames laboratoriais nos dias zero, 150 e 600 de uso da ciclosporina A e também o histopatológico das lesões de ENH (antes do tratamento e com 60 dias). Os exames laboratoriais solicitados foram: hemograma e leucograma; TGO; TGP: uréia e creatinina. Detectou-se leucocitose em graus entre moderado e elevado em 70% dos casos, mas evoluiu para leucocitose leve até o término do acompanhamento na mesma percentagem dos doentes. O exame bioquímico não mostrou alterações significantes, com exceção da elevação da TGO em um caso, da TGP em outro, além de dois pacientes que mostraram aumento da uréia e creatinina, mas que posteriormente, normalizaram sem precisar de medidas adicionais. Os achados histológicos encontrados no primeiro exame foram representados em 40% dos doentes, por dermatite granulomatosa e em 30%, por dermatite nodular. Na segunda análise, houve mudança para dermatite perivascular superficial e profunda em 50% dos casos e para paniculite septal em 20%; isto denota melhora histológica compatível com a melhora dos sintomas verificada nos primeiros quinze dias de terapêutica. A ação da ciclosporina A se revelou benéfica, principalmente na sintomatologia sistêmica, com exceção dos casos que se acompanhavam de neurite; desta forma, a ciclosporina A pode ser uma opção para a melhoria clínica das reações hansênicas tipo 11.

Avaliação da função macrofágica na hanseníase virchowiana: marcadores de superfície, receptores TLR e NLR e mediadores inflamatórios

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Borderline leprosy: in situ and cytokine profile in supernatant of mononuclear of cell culture

In order to contribute to a better understanding of cytokine participation in borderline leprosy, in the present study we determined - by in vitro and in situ examinations - the production of these cytokine mediation in non-treated borderline tuberculoid (BT) patients and borderline lepromatous (BL) patients. Seven non-treated BT patients, 12 non-treated BL patients, besides 19 healthy individuals (control group), were evaluated. Peripheral blood mononuclear cells (PBMC) were stimulated or not with specific-M. leprae stimulus (whole and sonicated M. leprae antigens) and a non-specific stimulus. After 48 hours, supernatant was collected for TNF-alpha, IFN-gamma, IL-10 and TGF-beta1 cytokine determination by ELISA. Biopsies from cutaneous lesions were submitted to histological analysis and hematoxylin-eosin and Fite-Faraco stainings; the sections then underwent iNOS, IL-10 and TGF-beta1 in situ detection by immunohistochemistry. Cytokine quantification in PBMC supernatants from patients showed that BT patients produced higher levels of IFN-gamma. Compared to healthy individuals, both borderline patient groups produced lower levels of TGF-beta1 while BL patients generated lower IL-10 levels. The in situ iNOS expression was higher in BT patients compared to BL individuals. on the order hand, TGF-beta1 cytokine revealed a higher proportion of immunostained cells in BL patients. There was no significant difference in IL-10 level between BT and BL patients. Regarding cutaneous lesions, in BL patients there was a negative correlation between TGF-beta1 tissue expression and IL-10. Independently of the clinical form, we observed a positive correlation between TGF-beta1 and bacterial index as well as a negative correlation between the TGF-beta1 tissue expression and iNOS. The results even showed a positive correlation between iNOS tissue expression and production of IFN-gamma by PBMC stimulated with M. leprae antigens. Taken together, the histopathological and immunological observations reinforce the notion of immunological instability in borderline leprosy patients and indicating the participation of mixed cytokines profiles in these individuals, specifically a Th1 profile in BT patients and Th2 profile in BL patients, with a possible participation of T-regulatory lymphocytes.

Oral distribution of Candida species and presence of oral lesions in Brazilian leprosy patients under multidrug therapy

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)