New insights in the pathogenesis of type 1 and type 2 lepra reaction.

In the current scenario of leprosy elimination, lepra reactions (LRs) remain a major persistent problem. Type 1 LR (T1LR) and type 2 LR (T2LR) are the major causes of nerve damage and permanent disabilities. The immunopathogenesis of LR have recently become an important fi eld of research, since it may provide the relevant targets for the early detection and control of these episodes. Presently, there are no uniformly acceptable laboratory markers for LR. Genetic and serum markers in human host may predict susceptibility to reactions as well as progression of nerve damage in leprosy. Therefore, a deeper understanding of the molecular mechanisms involved in LR may provide a rational strategy for early diagnosis and prevention of the catastrophic consequences of LR.

Mycobacterial laminin-binding histone-like protein mediates collagen-dependent cytoadherence

When grown in the presence of exogenous collagen I, Mycobacterium bovis BCG was shown to form clumps. Scanning electron microscopy examination of these clumps revealed the presence of collagen fibres cross-linking the bacilli. Since collagen is a major constituent of the eukaryotic extracellular matrices, we assayed BCG cytoadherence in the presence of exogenous collagen I. Collagen increased the interaction of the bacilli with A549 type II pneumocytes or U937 macrophages, suggesting that BCG is able to recruit collagen to facilitate its attachment to host cells. Using an affinity chromatography approach, we have isolated a BCG collagen-binding protein corresponding to the previously described mycobacterial laminin-binding histone-like protein (LBP/Hlp), a highly conserved protein associated with the mycobacterial cell wall. Moreover, Mycobacterium leprae LBP/Hlp, a well-characterized adhesin, was also able to bind collagen I. Finally, using recombinant fragments of M. leprae LBP/Hlp, we mapped the collagen-binding activity within the C-terminal domain of the adhesin. Since this protein was already shown to be involved in the recognition of laminin and heparan sulphate-containing proteoglycans, the present observations reinforce the adhesive activities of LBP/Hlp, which can be therefore considered as a multifaceted mycobacterial adhesin, playing an important role in both leprosy and tuberculosis pathogenesis.

Ligand-binding prediction for ErbB2, a key molecule in the pathogenesis of leprosy.

BACKGROUND AND AIMS: Mycobacterium leprae is an obligate intracellular pathogen. Ligand-binding is an important factor in the success of chemoprevention and chemotherapy. A new drug that can inhibit M. leprae binding to and activation of, ErbB2 and Erk1/2 in primary Schwann cells is the new therapeutic option. However, the ligand-binding pattern of ErbB2 has never been clarified. METHODS: In this work, the author performed a ligand-binding prediction for ErbB2 using a new bioinformatics tool. RESULTS: According to this study, nine strong possible ligands can be identified. CONCLUSION: These sites can be useful for further drug-development studies.

Further biochemical characterization of Mycobacterium leprae laminin-binding proteins

It has been demonstrated that the alpha2 chain of laminin-2 present on the surface of Schwann cells is involved in the process of attachment of Mycobacterium leprae to these cells. Searching for M. leprae laminin-binding molecules, in a previous study we isolated and characterized the cationic proteins histone-like protein (Hlp) and ribosomal proteins S4 and S5 as potential adhesins involved in M. leprae-Schwann cell interaction. Hlp was shown to bind alpha2-laminins and to greatly enhance the attachment of mycobacteria to ST88-14 Schwann cells. In the present study, we investigated the laminin-binding capacity of the ribosomal proteins S4 and S5. The genes coding for these proteins were PCR amplified and their recombinant products were shown to bind alpha2-laminins in overlay assays. However, when tested in ELISA-based assays and in adhesion assays with ST88-14 cells, in contrast to Hlp, S4 and S5 failed to bind laminin and act as adhesins. The laminin-binding property and adhesin capacity of two basic host-derived proteins were also tested, and only histones, but not cytochrome c, were able to increase bacterial attachment to ST88-14 cells. Our data suggest that the alanine/lysine-rich sequences shared by Hlp and eukaryotic H1 histones might be involved in the binding of these cationic proteins to laminin

Substrato anatômico da sensibilidade tátil na hanseníase / anatomic substratum of tactile sensibility in hanseniasis

Proposta de uma melhor avaliaçäo, com bases anatômicas e métodos clínicos de fácil execuçäo, da sensibilidade tátil na hanseníase

Interleukin-1 beta production by monocytes from leprosy patients

The cause responsible for the lack of an efficient cell-mediated immunity or a delayed type hypersensitivity to M. leprae in lepromatous patients is poorly understood. But the resistance to M. leprae infection in humans is likely mediated by the activated macrophages to present M. leprae antigen to T cells for cell-mediated immunity. Phenolic glycolipid-I (PGL-I) is a M. leprae-specific antigen and is supposed to play a significant role in the long lasting unresponsiveness in lepromatous leprosy. In this study, IL-1 activities were tested among leprosy patients to evaluate monocyte function and the role of IL-1 in the immunosuppression in leprosy. We found that peripheral blood mononuclear cells (PBMCs) from tuberculoid patients were strongly reactive to M. leprae (mean cpm; 28,853 +/- 28,916), but the proliferative responses of PBMCs from lepromatous patients (mean cpm; 6,051 +/- 803) were significantly lower. IL-1 concentration in culture supernatant of monocytes from lepromatous patients was similar to that from tuberculoid patients with stimulation of M. leprae (lepromatous: 1,014 +/- 637 pg/ml, tuberculoid: 1,012 +/- 167 pg/ml) or lipopolysaccharides (IPS) (lepromatous: 3,479 +/- 2,188 pg/ml, tuberculoid: 4,246 +/- 2,432 pg/ml). The IL-1 concentration is sera from lepromatous patients (42 +/- 30 pg/ml) tended to be higher than those from tuberculoid patients (28 +/- 69 pg/ml). And there was no significant difference in IL-1 production between peritoneal macrophages from mice sensitized with PGL-1 and those from nonsensitized mice. In conclusion, this study suggests that the immunosuppression in lepromatous patients may not be due to the decreased production of IL-1. And the increased IL-1 activity in sera may affect the inflammatory response of lepromatous patients.

Influencia del tratamiento con Mycobacterium leprae sobre la respuesta inmune en ratas: su evaluacion en un modelo de artritis experimental / The influence of treatment with Mycobacterium leprae on immune response in rats: its evaluation in a model of experimental arthritis

Ratas endocriadas de línea "m" machos adultos, fueron tratadas con Mycobacterium leprae (Ml) muerto por calor (4 x 10**7 bacilos/ml, extraído de lepromas humanos) de acuerdo con el siguiente esquema: una inyección intraperitoneal -ip- o subcutánea -sc- de 2 ml de Ml dos días anters de la inducción artrítica; una inyección ip o sc de 0.5 ml de Ml 2 veces por semana, durante 15 días previos a la inducción. La artritis por adyuvante (AA) fue provocada 48 horas después, inoculando 0.1 ml de Adyuvante Completo de Freund (ACF) en la almohadilla plantar de la pata trasera derecha. Se constató una significativa reducción del proceso artrítico, a los 15 días de la inducción, en las ratas tratados con 4 inyecciones ip de 0.5 ml de Ml. Un efecto depresivo similar también se obtuvo en ratas singeneicas que recibieron 1 x 10**8 células esplénicas de animales tratados con el mismo protocolo. En otra serie de experimentos, 48 horas antes de la inducción de la AA, 2 grupos de ratas recibieron 1 x 10**8 totales, o 1 x 10**7 células esplénicas no adherentes de animales tratados con Ml. Se pudo constatar que la población de células no adherentes también fue capaz de producir una notable reducción del proceso artrítico. A su vez, esta población no modificó la AA en el receptor cuando la transferencia se efectuó 48 horas después de la inducción. Sobre la base de nuestros resultados, concluimos que la exposición reiterada al Ml induciría células supresoras con actividad regulatoria sobre la AA que operaría...