RESUMO
BACKGROUND: Individual differences in T cell responsiveness to interleukin 12 (IL-12), resulting from inherited factors, may be responsible for differences in the intensity of cell mediated immune (CMI) responses in patients with leprosy, a disease with a wide clinical spectrum. AIM: Polymorphisms in the 5' flanking region of the IL12RB2 gene were analysed to determine potential immunogenetic factors affecting CMI responses, using leprosy as a model. METHODS: Polymorphisms in the 5' flanking region of IL12RB2 were examined using direct sequencing techniques, and allele frequencies between patients with lepromatous leprosy and patients with tuberculoid leprosy were compared. The effect of these single nucleotide polymorphisms (SNPs) on IL12RB2 expression was estimated using the dual luciferase reporter gene assay in Jurkat T cells. RESULTS: Several SNPs, including -1035A>G, -1023A>G, -650delG, and -465A>G, were detected within the 5' flanking region of IL12RB2. The frequency of haplotype 1 (-1035A, -1023A, -650G, -464A) was high in the general Japanese population, but was significantly lower in lepromatous patients compared with tuberculoid patients and healthy controls. Reporter gene assays using Jurkat T cells revealed that all haplotypes carrying one or more SNP exhibited a lower transcriptional activity compared with haplotype 1. CONCLUSION: SNPs within the 5' flanking region of IL12RB2 affect the degree of expression of this gene and may be implicated in individual differences in CMI responsiveness to mycobacterial antigens, leading to lepromatous or tuberculoid leprosy.
Assuntos
Hanseníase Virchowiana/genética , Hanseníase Tuberculoide/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética , Transcrição Gênica/imunologia , Região 5'-Flanqueadora/genética , Região 5'-Flanqueadora/imunologia , Frequência do Gene , Predisposição Genética para Doença , Haplótipos , Humanos , Imunidade Celular/genética , Interleucina-12/metabolismo , Hanseníase Virchowiana/imunologia , Hanseníase Tuberculoide/imunologia , Receptores de Interleucina-12RESUMO
Sequences of the folP1, rpoB, and gyrA genes were analyzed for 88 isolates of Mycobacterium leprae from leprosy patients in Japan, Haiti, Indonesia, Pakistan, and the Philippines. Thirteen isolates (14.8%) showed representative mutations in more than two genes, suggesting the emergence of multidrug-resistant M. leprae.
Assuntos
Hansenostáticos/farmacologia , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Hanseníase/microbiologia , Mycobacterium leprae/efeitos dos fármacos , Animais , Anti-Infecciosos/farmacologia , Anti-Infecciosos/uso terapêutico , Antibióticos Antituberculose/farmacologia , Antibióticos Antituberculose/uso terapêutico , Sequência de Bases , Primers do DNA , DNA Bacteriano/efeitos dos fármacos , DNA Bacteriano/genética , Resistência Microbiana a Medicamentos , Resistência a Múltiplos Medicamentos , Genes Bacterianos/efeitos dos fármacos , Genes Bacterianos/genética , Humanos , Camundongos , Dados de Sequência Molecular , Mycobacterium leprae/genética , Ofloxacino/farmacologia , Ofloxacino/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Rifampina/farmacologia , Rifampina/uso terapêuticoRESUMO
The nucleotide sequence analysis of the dihydropteroate synthase (DHPS) gene of six diaminodiphenylsulfone-resistant Mycobacterium leprae strains revealed that the mutation was limited at highly conserved amino acid residues 53 or 55. Though the mutation at amino acid residue 55 or its homologous site has been reported in other bacteria, the mutation at residue 53 is the first case in bacteria. This is the first paper which links the mutations in DHPS and sulfonamide resistance in M. leprae. This finding is medically and socially relevant, since leprosy is still a big problem in certain regions.