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1.
PLoS One ; 8(6): e64748, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23798993

RESUMO

Herein, we performed microarray experiments in Schwann cells infected with live M. leprae and identified novel differentially expressed genes (DEG) in M. leprae infected cells. Also, we selected candidate genes associated or implicated with leprosy in genetic studies and biological experiments. Forty-seven genes were selected for validation in two independent types of samples by multiplex qPCR. First, an in vitro model using THP-1 cells was infected with live Mycobacterium leprae and M. bovis bacillus Calmette-Guérin (BCG). In a second situation, mRNA obtained from nerve biopsies from patients with leprosy or other peripheral neuropathies was tested. We detected DEGs that discriminate M. bovis BCG from M. leprae infection. Specific signatures of susceptible responses after M. leprae infection when compared to BCG lead to repression of genes, including CCL2, CCL3, IL8 and SOD2. The same 47-gene set was screened in nerve biopsies, which corroborated the down-regulation of CCL2 and CCL3 in leprosy, but also evidenced the down-regulation of genes involved in mitochondrial metabolism, and the up-regulation of genes involved in lipid metabolism and ubiquitination. Finally, a gene expression signature from DEG was identified in patients confirmed of having leprosy. A classification tree was able to ascertain 80% of the cases as leprosy or non-leprous peripheral neuropathy based on the expression of only LDLR and CCL4. A general immune and mitochondrial hypo-responsive state occurs in response to M. leprae infection. Also, the most important genes and pathways have been highlighted providing new tools for early diagnosis and treatment of leprosy.


Assuntos
Quimiocinas/metabolismo , Hanseníase/metabolismo , Metabolismo dos Lipídeos , Mitocôndrias/metabolismo , Transcriptoma , Células Cultivadas , Quimiocinas/genética , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Patógeno , Humanos , Hanseníase/imunologia , Hanseníase/microbiologia , Masculino , Mitocôndrias/microbiologia , Mycobacterium bovis/imunologia , Mycobacterium leprae/imunologia , Análise de Sequência com Séries de Oligonucleotídeos , Nervos Periféricos/metabolismo , Células de Schwann/imunologia , Células de Schwann/metabolismo , Células de Schwann/microbiologia
2.
J Drugs Dermatol ; 10(3): 274-8, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21369644

RESUMO

Erythema nodosum leprosum (ENL) is an inflammatory reaction that may occur in multibacillary leprosy patients, and thalidomide is the treatment of choice. Its cause and the mechanism by which thalidomide suppresses ENL are not known. In the skin lesions, im- mune complexes and split products of complement are found. The activation of complement could precipitate ENL, and thalidomide could suppress the inflammation by inhibiting the activation of complement. To determine if thalidomide could suppress the activation of complement, we first incubated normal serum with thalidomide and with M. leprae or zymosan. The amount of residual functional complement was then assessed by determining the dilution of serum required to lyses sheep erythrocytes sensitized by rabbit antibodies (CH50 Assay). M. leprae and zymosan activated complement. The residual complement activity in the serum incubated with M. leprae or with zymosan was equivalent to that incubated with M. leprae or zymosan in the presence of thalidomide, hydrolyzed thalidomide and metabolites of thalidomide. Thalidomide did not inhibit the activation of complement by zymosan, a known initiator of complement activation by the alternative pathway, or by M. leprae.


Assuntos
Ativação do Complemento/efeitos dos fármacos , Eritema Nodoso/tratamento farmacológico , Hansenostáticos/farmacologia , Hanseníase Virchowiana/tratamento farmacológico , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/imunologia , Talidomida/farmacologia , Animais , Proteínas do Sistema Complemento/análise , Eritema Nodoso/imunologia , Eritema Nodoso/fisiopatologia , Humanos , Hanseníase Virchowiana/imunologia , Hanseníase Virchowiana/fisiopatologia , Fígado/enzimologia , Camundongos , Mycobacterium leprae/metabolismo , Coelhos , Ovinos
3.
J Drugs Dermatol ; 9(7): 814-26, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20677538

RESUMO

Thalidomide and analogues are a class of immunomodulatory drugs or IMiDS. Thalidomide was initially approved by the U.S. Food and Drug Administation for treatment of erythema nodosum in leprosy and is now approved for multiple myeloma as well. A second generation IMiD, lenalidomide, is also approved for multiple myeloma and refractory myelodysplastic syndrome. Discovery of this class of drugs has been serendipitous and empirical, as the drug targets have been unknown. In this review, the authors integrate recent identification of drug targets of IMiDS, which include the inducible form of nitric oxide synthase (iNOS), Rho GTPase and caspase-1, with the developments in the understanding of the molecular biology of human inflammatory, infectious and neoplastic skin disorders. Because thalidomide reemerged through leprosy, the original disease classified by the T cell, the authors have also emphasized advances in the understanding of T-cell subsets in human skin disorders.


Assuntos
Dermatite/tratamento farmacológico , Imunomodulação , Neoplasias Cutâneas/tratamento farmacológico , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Síndrome de Behçet/tratamento farmacológico , Dermatite/imunologia , Eritema Nodoso/tratamento farmacológico , Eritema Nodoso/imunologia , Humanos , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/imunologia , Sarcoidose/tratamento farmacológico , Sarcoidose/imunologia , Neoplasias Cutâneas/imunologia , Talidomida/farmacologia
4.
Lepr Rev ; 79(3): 311-4, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19009980

RESUMO

OBJECTIVE: The immune-mediated events that precipitate erythema nodosum leprosum (ENL) are not well understood. One component may be the complexing of antibody with antigens released from infected macrophages, the activation of complement and the subsequent local inflammation. We assess here the ability of highly-purified, disrupted M. leprae, to activate complement. RESULTS: Intact and sonically-disrupted crude and alkali-purified nu/nu mouse-derived M. leprae suspensions were incubated with normal serum and a hemolytic titer (CH50) was determined as a measure of complement fixation. Crude M. leprae consumed complement, and disrupted preparations more than the intact. Purified M. leprae preparations did not consume complement unless disrupted. CONCLUSION: M. leprae, if disrupted, can activate complement. This supports a hypothesis that links released antigens with ENL, and may explain the increased probability of an occurrence of ENL following chemotherapy.


Assuntos
Ativação do Complemento , Eritema Nodoso/imunologia , Hanseníase Virchowiana/imunologia , Mycobacterium leprae/imunologia , Animais , Eritema Nodoso/fisiopatologia , Humanos , Camundongos , Camundongos Nus , Mycobacterium leprae/fisiologia , Sonicação
5.
In. International Leprosy Congress, 12. International Leprosy Congress, 12/Proceedings. New Delhi, s.n, 1984. p.185-186.
Não convencional em Inglês | LILACS-Express | SES-SP, HANSEN, SESSP-ILSLACERVO, SES-SP | ID: biblio-1246388
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