RESUMO
The clinical manifestations of the leprosy depend on host immune response and the macrophages are the primary cells involved in this process. M1 and M2 cells exhibited distinct morphology, distinct surface marker profiles, as well as different cytokine and chemokine secretion. Macrophages express receptors such as CD163, CD68, CD206, and costimulatory molecules such as CD80 and CD86, and cytokines that trigger a suppressive or inflammatory response. Thirty-three untreated patients were selected, 17 patients had the tuberculoid leprosy (TT) and 16 had the lepromatous leprosy (LL). We performed immunohistochemistry to detect IL-13, IL-10, TGF-ß, FGF-ß, CD163, CD68, arginase 1. M2 macrophages showed significant differences between the groups studied with increase in the expression of costimulatory molecules (CD68 and CD163), arginase 1 and cytokines (IL-10, IL-13, TGF-ß and FGF-b) in the LL form. Response of M2 macrophages emerge as an alternative for a better understanding of the innate immunity in the polar forms of leprosy, highlighting the role of cytokines, arginase 1 and costimulatory molecules in the repair and suppressive responses in the lepromatous form of the disease.
Assuntos
Biomarcadores/análise , Citocinas/análise , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/imunologia , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/imunologia , Macrófagos/imunologia , HumanosRESUMO
Leprosy remains prevalent in Brazil. ErbB2 is a receptor for leprosy bacilli entering Schwann cells, which mediates Mycobacterium leprae-induced demyelination and the ERBB2 gene lies within a leprosy susceptibility locus on chromosome 17q11-q21. To determine whether polymorphisms at the ERBB2 locus contribute to this linkage peak, three haplotype tagging single nucleotide polymorphisms (tag-SNPs) (rs2517956, rs2952156, rs1058808) were genotyped in 72 families (208 cases; 372 individuals) from the state of Pará (PA). All three tag-SNPs were associated with leprosy per se [best SNP rs2517959 odds ratio (OR) = 2.22; 95% confidence interval (CI) 1.37-3.59; p = 0.001]. Lepromatous (LL) (OR = 3.25; 95% CI 1.37-7.70; p = 0.007) and tuberculoid (TT) (OR = 1.79; 95% CI 1.04-3.05; p = 0.034) leprosy both contributed to the association, which is consistent with the previous linkage to chromosome 17q11-q21 in the population from PA and supports the functional role of ErbB2 in disease pathogenesis. To attempt to replicate these findings, six SNPs (rs2517955, rs2517956, rs1810132, rs2952156, rs1801200, rs1058808) were genotyped in a population-based sample of 570 leprosy cases and 370 controls from the state of Rio Grande do Norte (RN) and the results were analysed using logistic regression analysis. However, none of the associations were replicated in the RN sample, whether analysed for leprosy per se, LL leprosy, TT leprosy, erythema nodosum leprosum or reversal reaction conditions. The role of polymorphisms at ERBB2 in controlling susceptibility to leprosy in Brazil therefore remains unclear.
Assuntos
Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Eritema Nodoso/genética , /genética , Predisposição Genética para Doença/epidemiologia , Hanseníase Virchowiana/genética , Hanseníase Tuberculoide/genética , Brasil/epidemiologia , Estudos de Casos e Controles , /metabolismo , Eritema Nodoso/epidemiologia , Estudos de Associação Genética , Técnicas de Genotipagem , Haplótipos , Hanseníase Virchowiana/epidemiologia , Hanseníase Tuberculoide/epidemiologia , Polimorfismo de Nucleotídeo Único/genética , Fatores SocioeconômicosRESUMO
Leprosy remains prevalent in Brazil. ErbB2 is a receptor for leprosy bacilli entering Schwann cells, which mediates Mycobacterium leprae-induced demyelination and the ERBB2 gene lies within a leprosy susceptibility locus on chromosome 17q11-q21. To determine whether polymorphisms at the ERBB2 locus contribute to this linkage peak, three haplotype tagging single nucleotide polymorphisms (tag-SNPs) (rs2517956, rs2952156, rs1058808) were genotyped in 72 families (208 cases; 372 individuals) from the state of Pará (PA). All three tag-SNPs were associated with leprosy per se [best SNP rs2517959 odds ratio (OR) = 2.22; 95% confidence interval (CI) 1.37-3.59; p = 0.001]. Lepromatous (LL) (OR = 3.25; 95% CI 1.37-7.70; p = 0.007) and tuberculoid (TT) (OR = 1.79; 95% CI 1.04-3.05; p = 0.034) leprosy both contributed to the association, which is consistent with the previous linkage to chromosome 17q11-q21 in the population from PA and supports the functional role of ErbB2 in disease pathogenesis. To attempt to replicate these findings, six SNPs (rs2517955, rs2517956, rs1810132, rs2952156, rs1801200, rs1058808) were genotyped in a population-based sample of 570 leprosy cases and 370 controls from the state of Rio Grande do Norte (RN) and the results were analysed using logistic regression analysis. However, none of the associations were replicated in the RN sample, whether analysed for leprosy per se, LL leprosy, TT leprosy, erythema nodosum leprosum or reversal reaction conditions. The role of polymorphisms at ERBB2 in controlling susceptibility to leprosy in Brazil therefore remains unclear.
Assuntos
Eritema Nodoso/genética , Genes erbB-2/genética , Predisposição Genética para Doença/epidemiologia , Hanseníase Virchowiana/genética , Hanseníase Tuberculoide/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Estudos de Casos e Controles , Criança , Cromossomos Humanos Par 17/metabolismo , Eritema Nodoso/epidemiologia , Feminino , Estudos de Associação Genética , Técnicas de Genotipagem , Haplótipos , Humanos , Hanseníase Virchowiana/epidemiologia , Hanseníase Tuberculoide/epidemiologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Fatores Socioeconômicos , Adulto JovemRESUMO
BACKGROUND: Many epidemiological studies have shown that the genetic factors of the host play a role in the variability of clinical response to infection caused by M. leprae. With the purpose of identifying genes of susceptibility, the present study investigated the possible role of HLA-DRB1 and DQA1/DQB1 alleles in susceptibility to leprosy, and whether they account for the heterogeneity in immune responses observed following infection in a Southern Brazilian population. METHODS: One hundred and sixty-nine leprosy patients and 217 healthy controls were analyzed by polymerase chain reaction amplification and reverse hybridization with sequence-specific oligonucleotide probes and sequence-specific primers (One Lambda, CA, USA). RESULTS: There was a positive association of HLA-DRB1*16 (*1601 and *1602) with leprosy per se (7.3% vs. 3.2%, P = 0.01, OR = 2.52, CI = 1.26-5.01), in accord with previous serological studies, which showed DR2 as a marker of leprosy. Although, HLA-DQA1*05 frequency (29.8% vs. 20.9%, P = 0.0424, OR = 1.61, CI = 1.09-2.39) was higher in patients, and HLA-DQA1*02 (3.0% vs. 7.5%, P = 0.0392, OR = 0.39, CI = 0.16 - 0.95) and HLA-DQA1*04 (4.0% vs. 9.1%, P = 0.0314, OR = 0.42, CI = 0.19 - 0.93) frequencies lower, P-values were not significant after the Bonferroni's correction. Furthermore, HLA-DRB1*1601 (9.0% vs. 1.8%; P = 0.0016; OR = 5.81; CI = 2.05-16.46) was associated with susceptibility to borderline leprosy compared to control group, and while HLA-DRB1*08 (11.2% vs. 1.2%; P = 0.0037; OR = 12.00; CI = 1.51 - 95.12) was associated with susceptibility to lepromatous leprosy, when compared to tuberculoid leprosy, DRB1*04 was associated to protection. CONCLUSION: These data confirm the positive association of HLA-DR2 (DRB1*16) with leprosy per se, and the protector effect of DRB1*04 against lepromatous leprosy in Brazilian patients.
Assuntos
Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Hanseníase Virchowiana/genética , Hanseníase Tuberculoide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Brasil , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genes MHC da Classe II , Antígenos HLA-DQ/imunologia , Cadeias alfa de HLA-DQ , Antígenos HLA-DR/imunologia , Cadeias HLA-DRB1 , Humanos , Hanseníase Virchowiana/imunologia , Hanseníase Tuberculoide/imunologia , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto JovemRESUMO
Pure neural leprosy (PNL) is often difficult to diagnose when acid-fast bacilli (AFB) cannot be detected. We undertook the present study to evaluate use of the polymerase chain reaction (PCR) in diagnosing PNL. Fifty-eight patients (41 men and 17 women) suspected of pure neural leprosy (PNL) were examined. Patients were classified as borderline tuberculoid (BT, 40 cases) and polar tuberculoid (TT, 18 cases) types. Nerve biopsy was performed and was positive for AFB in 20 patients (all BT patients), i.e., 34.5% of total cases. DNA was extracted from the nerve biopsy samples and amplified using PCR for a specific repeated sequence of DNA from Mycobacterium leprae. PCR analysis was positive in the nerve samples from 29 patients (50%), 27 of the BT type, and 2 of the TT type patients. Further, PCR analysis was positive in 14 of 38 cases that were negative for AFB by nerve biopsy, of which 12 were of the BT type and 2 the TT type. PCR analysis proved to be a useful method to investigate pure neural leprosy, enabling confirmation of the diagnosis in more than a third of the cases that were negative for AFB by nerve biopsy.
Assuntos
DNA Bacteriano/genética , Hanseníase Tuberculoide/diagnóstico , Hanseníase Tuberculoide/genética , Mycobacterium leprae/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Adulto , Idoso , Biópsia , Eletroforese em Gel de Poliacrilamida , Feminino , Fibrose , Humanos , Hanseníase Tuberculoide/patologia , Masculino , Pessoa de Meia-Idade , Infecções por Mycobacterium não Tuberculosas/diagnóstico , Infecções por Mycobacterium não Tuberculosas/genética , Infecções por Mycobacterium não Tuberculosas/patologiaRESUMO
Leprosy presents as a clinical and immunological spectrum of disease. With the use of gene expression profiling, we observed that a distinction in gene expression correlates with and accurately classifies the clinical form of the disease. Genes belonging to the leukocyte immunoglobulin-like receptor (LIR) family were significantly up-regulated in lesions of lepromatous patients suffering from the disseminated form of the infection. In functional studies, LIR-7 suppressed innate host defense mechanisms by shifting monocyte production from interleukin-12 toward interleukin-10 and by blocking antimicrobial activity triggered by Toll-like receptors. Gene expression profiles may be useful in defining clinical forms of disease and providing insights into the regulation of immune responses to pathogens.
Assuntos
Humanos , Análise por Conglomerados , Citocinas/genética , Citocinas/metabolismo , Contagem de Colônia Microbiana , Glicoproteínas de Membrana/imunologia , Hanseníase Tuberculoide/classificação , Hanseníase Tuberculoide/fisiopatologia , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/imunologia , Hanseníase Virchowiana/classificação , Hanseníase Virchowiana/fisiopatologia , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/imunologia , Imunidade Celular , Imunidade Inata , Macrófagos Alveolares/microbiologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/imunologia , Perfilação da Expressão Gênica , Reação em Cadeia da Polimerase , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores de Superfície Celular/imunologia , Regulação da Expressão Gênica , Algoritmos , Análise de Componente Principal , Análise de Sequência com Séries de Oligonucleotídeos , Genes de Imunoglobulinas , Regulação para CimaAssuntos
Hanseníase Tuberculoide/imunologia , Mycobacterium leprae/imunologia , Fator de Necrose Tumoral alfa/imunologia , Alelos , Brasil , DNA Bacteriano/química , DNA Bacteriano/isolamento & purificação , Desoxirribonucleases de Sítio Específico do Tipo II/química , Humanos , Hanseníase Tuberculoide/genética , Mycobacterium leprae/genética , Projetos Piloto , Reação em Cadeia da Polimerase , Polimorfismo Genético/genética , Polimorfismo Genético/imunologia , Fator de Necrose Tumoral alfa/genéticaRESUMO
The diagnosis of primary neuritic leprosy (PNL) and its differentiation from other causes of peripheral neuropathy is difficult since acid-fast bacilli (AFB) smears and skin biopsy are negative from anesthetic areas. A biopsy of the involved nerve is the only conclusive method of diagnosis. Such a biopsy may not necessarily be free of complications when a large nerve is involved. However, fine needle aspiration has in this study proved to be a simple technique to demonstrate inflammation granulomas and AFB from these involved nerves in 18 of the 27 cases suspected to have PNL. The validity of the cytological classification into morphological subtypes may have to be supplemented by a large series of studies.
Assuntos
Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/patologia , Hanseníase/genética , Hanseníase/patologiaAssuntos
Alelos , Deleção de Sequência , Estudos de Casos e Controles , Frequência do Gene , Genótipo , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/imunologia , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/imunologia , Hanseníase/genética , Hanseníase/imunologia , Imunogenética , Polimorfismo Genético , Primers do DNA/genética , Proteínas Precoces de Adenovirus , Proteínas de Membrana/genética , Proteínas de Transporte/genética , Receptores de Calcitriol/genética , Receptores de Calcitriol/imunologia , Sequência de Bases , Variação Genética , ÍndiaAssuntos
DNA , Apresentação de Antígeno/genética , Cadeias alfa de Imunoglobulina/genética , Chaperoninas/imunologia , Células Clonais , Dados de Sequência Molecular , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/imunologia , Homologia de Sequência de Aminoácidos , Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Sequência de Aminoácidos , Sequência de BasesAssuntos
Antígenos HLA-D , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , /imunologia , Epitopos , Exposição Ocupacional , Fragmentos de Peptídeos/imunologia , Genes MHC da Classe II , Hanseníase Tuberculoide/genética , Hanseníase Tuberculoide/imunologia , Hanseníase Virchowiana/genética , Hanseníase Virchowiana/imunologia , Hanseníase/genética , Hanseníase/imunologia , Linfócitos T/imunologia , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/imunologia , Mycobacterium/imunologia , Sequência de AminoácidosRESUMO
To investigate whether the susceptibility to leprosy (type), subclinical infection with Mycobacterium leprae and the antibody response against M. leprae-specific antigens are associated with HLA-DR phenotypes sequence-specific oligonucleotide HLA-DRB1 and DQA1 typing and antibody assays have been performed in 79 leprosy patients (41 TT/BT and 38 LL/BL) and 50 healthy controls from a Javanese population in Yogyakarta, Indonesia. DRB1*02 was associated with LL/BL [odds ratio (OR) 2.54, 95% confidence interval (CI) 0.97-9.78, p = 0.037 and attributable risk (AR) 41.5%] but not with TT/BT leprosy (p > 0.05). HLA-DRB1*12 was negatively associated with leprosy (either LL/BL or TT/BT [OR 0.33-0.35, p < 0.05, prevented fraction (PF) 58.8%-65.3%]. No significant association was found between HLA-DRB1 or DQA1 type, anti-M. leprae antibody level and subclinical infection with M. leprae. These data indicate that in this population susceptibility to lepromatous leprosy is associated with HLA-DRB1*02, while resistance to leprosy is associated with HLA-DRB1*12. These associations are not paralleled with associations of the same HLA types with anti-M. leprae antibody level. Finally, the results of this study also support the notion that infection with M. leprae per se is not associated with HLA-DRB1 or DQA1 alleles.