RESUMO
An overview of investigations indicating an important role of host genetics, both major histocompatibility complex (MHC) and non-MHC, in leprosy.
Assuntos
Predisposição Genética para Doença , Hanseníase/genética , Chaperonas Moleculares/genética , Infecções por Mycobacterium/genética , Ubiquitina-Proteína Ligases/genética , Humanos , Proteínas dos Microfilamentos , Mycobacterium/genética , Infecções por Mycobacterium/imunologiaRESUMO
The host genetic background has been considered one of the factors that influence leprosy outcome, a chronic infectious disease caused by Mycobacterium leprae. Genome scans demonstrated that the 6p21 region is associated with leprosy and a substantial number of population-based studies analyzing human leukocyte antigen (HLA) class II loci suggested association of HLA-DR with leprosy. However, some studies lacked robustness as they had limited power. Indeed, experimental designs require increased sample size to achieve adequate power, as well as replication studies with independent samples for confirmation of previous findings. In this work, we analyzed the influence of the HLA-DRB1 locus on leprosy susceptibility per se and disease type using a case-control design carried out in Brazilians (578 cases and 691 controls) and a replication study based on a family design in a Vietnamese population (n=194 families). The results showed that HLA-DRB1*10 is associated with susceptibility to leprosy and HLA-DRB1*04 is associated with resistance, both in the Brazilian and Vietnamese populations suggesting that these alleles play an important role in the activation of cellular immune responses against M. leprae.
Assuntos
Predisposição Genética para Doença , Antígenos HLA-DR/genética , Hanseníase/genética , Hanseníase/imunologia , Alelos , Brasil , Cadeias HLA-DRB1 , Humanos , Imunidade Inata , VietnãRESUMO
Each year an estimated 600000 new leprosy cases are diagnosed worldwide. The spectrum of the disease varies widely from limited tuberculoid forms to extensive lepromatous forms. A measure of the risk to develop lepromatous forms of leprosy is provided by the extent of skin reactivity to lepromin (Mitsuda reaction). To address a postulated oligogenic control of leprosy pathogenesis, we investigated in the present study linkage of leprosy susceptibility, leprosy clinical subtypes, and extent of the Mitsuda reaction to six chromosomal regions carrying known or suspected leprosy susceptibility loci. The only significant result obtained was linkage of leprosy clinical subtype to the HLA/TNF region on human chromosome 6p21 (P(corrected)=0.00126). In addition, we established that within the same family different HLA/TNF haplotypes segregate into patients with different leprosy subtypes directly demonstrating the importance of this genome region for the control of clinical leprosy presentation.
Assuntos
Ligação Genética/genética , Antígenos HLA/genética , Hanseníase/genética , Fator de Necrose Tumoral alfa/genética , Cromossomos Humanos Par 6/genética , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Hanseníase/classificação , Masculino , Linhagem , FenótipoRESUMO
Each year an estimated 600000 new leprosy cases are diagnosed worldwide. The spectrum of the disease varies widely from limited tuberculoid forms to extensive lepromatous forms. A measure of the risk to develop lepromatous forms of leprosy is provided by the extent of skin reactivity to lepromin (Mitsuda reaction). To address a postulated oligogenic control of leprosy pathogenesis, we investigated in the present study linkage of leprosy susceptibility, leprosy clinical subtypes, and extent of the Mitsuda reaction to six chromosomal regions carrying known or suspected leprosy susceptibility loci. The only significant result obtained was linkage of leprosy clinical subtype to the HLA/TNF region on human chromosome 6p21 (P(corrected)=0.00126). In addition, we established that within the same family different HLA/TNF haplotypes segregate into patients with different leprosy subtypes directly demonstrating the importance of this genome region for the control of clinical leprosy presentation.
Assuntos
Masculino , Feminino , Humanos , Antígenos HLA/genética , /genética , Fator de Necrose Tumoral alfa/genética , Genótipo , Hanseníase/classificação , Hanseníase/genética , Ligação Genética/genética , Predisposição Genética para Doença , Fenótipo , LinhagemRESUMO
In the mouse, resistance and susceptibility to intracellular growth of mycobacteria in macrophages is controlled by the Bcg (Nramp1) gene, which has been cloned and shown to encode a macrophage phagosomal membrane protein with a putative transporter function. In the homologous human NRAMP1 gene, a total of 11 polymorphisms have been identified, which are being used to test for the linkage of NRAMP1 alleles with human responses to mycobacteria, including susceptibility to tuberculosis and leprosy, as well as BCG immunotherapy in bladder cancer.
Assuntos
Vacina BCG/uso terapêutico , Proteínas de Transporte/genética , Proteínas de Transporte de Cátions , Hanseníase/genética , Proteínas de Membrana/genética , Tuberculose Pulmonar/genética , Neoplasias da Bexiga Urinária/terapia , Animais , Proteínas de Transporte/fisiologia , Ligação Genética , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Imunidade Inata/genética , Hanseníase/imunologia , Proteínas de Membrana/fisiologia , Camundongos , Tuberculose Pulmonar/imunologia , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologiaRESUMO
The Mitsuda test, which measures the specific immune response against intradermally injected lepromin, has a high prognostic value for susceptibility or resistance to the lepromatous form of leprosy. A sib-pair linkage analysis between the Mitsuda response and the NRAMP1 gene was done among 20 nuclear families with leprosy (totaling 118 sibs) from Ho Chi Minh City, Vietnam. All family subjects were genotyped for several intragenic and flanking NRAMP1 markers, leading to the definition of a fully informative NRAMP1 haplotype. Significant linkage was observed between NRAMP1 and Mitsuda reaction when considered either as a quantitative (P<.002) or as a categorical (P=.001) trait. Separate analyses among healthy and affected sibs showed evidence for linkage in both subsamples, indicating that linkage between the Mitsuda reaction and NRAMP1 is independent of leprosy status. These results support the view that NRAMP1 plays a regulatory role for the development of acquired antimycobacterial immune responses as determined by in vivo Mitsuda test reaction.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte de Cátions , Predisposição Genética para Doença , Antígeno de Mitsuda/imunologia , Hanseníase/imunologia , Proteínas de Membrana/genética , Pele/imunologia , China/etnologia , Feminino , Ligação Genética , Granuloma , Haplótipos , Humanos , Imunidade Inata , Injeções Intradérmicas , Hanseníase Virchowiana/imunologia , Hanseníase Tuberculoide/imunologia , Masculino , Núcleo Familiar , Linhagem , Fenótipo , Linfócitos T Auxiliares-Indutores , VietnãRESUMO
The Mitsuda test, which measures the specific immune response against intradermally injected lepromin, has a high prognostic value for susceptibility or resistance to the lepromatous form of leprosy. A sib-pair linkage analysis between the Mitsuda response and the NRAMP1 gene was done among 20 nuclear families with leprosy (totaling 118 sibs) from Ho Chi Minh City, Vietnam. All family subjects were genotyped for several intragenic and flanking NRAMP1 markers, leading to the definition of a fully informative NRAMP1 haplotype. Significant linkage was observed between NRAMP1 and Mitsuda reaction when considered either as a quantitative (P<.002) or as a categorical (P=.001) trait. Separate analyses among healthy and affected sibs showed evidence for linkage in both subsamples, indicating that linkage between the Mitsuda reaction and NRAMP1 is independent of leprosy status. These results support the view that NRAMP1 plays a regulatory role for the development of acquired antimycobacterial immune responses as determined by in vivo Mitsuda test reaction.
Assuntos
Masculino , Feminino , Humanos , Antígeno de Mitsuda/imunologia , China/etnologia , Granuloma , Hanseníase Tuberculoide/imunologia , Hanseníase Virchowiana/imunologia , Hanseníase/imunologia , Pele/imunologia , Vietnã , Fenótipo , Haplótipos , Imunidade Inata , Injeções Intradérmicas , Linfócitos T Auxiliares-Indutores , Linhagem , Núcleo FamiliarAssuntos
Animais , Camundongos , Hanseníase/genética , Hanseníase/imunologia , Imunidade Inata/genética , Ligação Genética , Marcadores Genéticos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/terapia , Predisposição Genética para Doença , Proteínas de Membrana/fisiologia , Proteínas de Membrana/genética , Proteínas de Transporte/fisiologia , Proteínas de Transporte/genética , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/imunologia , Vacina BCG/uso terapêuticoRESUMO
The human NRAMP1 gene located on Chromosome (Chr) region 2q35 is a candidate gene for increased risk of infection by several intracellular macrophage parasites, including M. tuberculosis and M. leprae. In search for a possible mutational hot spot, we have analyzed a 3.5-kb region 5' to NRAMP1 that is highly enriched for DNA repeat sequences. The repeat sequences could be grouped into one Mer element and six Alu elements, representing five Alu subfamilies, that had integrated in the same DNA region during successive rounds of Alu retropositional activity. Comparative sequence analysis of the Alu cluster region in humans, chimpanzee (Pan paniscus), and gorilla (Gorilla gorilla) revealed only modest sequence variability and failed to detect any evidence for genomic instability of the highly repetitive DNA region. These results show that sequence length variants in the Alu-flanking regions as well as nucleotide substitutions are the most common genomic variations even in a region of extreme Alu-clustering. Moreover, the high degree of sequence conservation among three primate species argues against the Alu cluster being the site of frequent genomic rearrangements or other frequent genetic events that might influence NRAMP1 expression.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte de Cátions , Cromossomos Humanos Par 2 , Proteínas de Membrana/genética , Sequências Repetitivas de Ácido Nucleico , Animais , Sequência de Bases , Gorilla gorilla , Humanos , Imunidade Inata/genética , Dados de Sequência Molecular , Pan paniscus , Reação em Cadeia da Polimerase , Análise de Sequência de DNARESUMO
The scope of the tuberculosis (TB) epidemic in the world today is enormous, with about 30 million active cases. Current research into preventing the spread of TB is focused on development of new drugs to inactivate Mycobacterium tuberculosis, the causative agent of TB, as well as on identifying the critical steps of host defense to infection with Mycobacteria, which might also yield therapeutic targets. Our infection genomics approach toward the latter strategy has been to isolate and characterize a mouse gene, Bcg (Nramp1), which controls natural susceptibility to infection with Mycobacteria, as well as Salmonella and Leishmania. Through comparative genomics, we have identified the homologous human NRAMP1 gene, alleles of which are now being used for tests of linkage with TB and leprosy.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte de Cátions , Imunidade Inata/genética , Hanseníase/genética , Macrófagos/imunologia , Proteínas de Membrana/genética , Tuberculose/genética , Alelos , Animais , Antituberculosos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/genética , Infecções Bacterianas/imunologia , Infecções Bacterianas/prevenção & controle , Surtos de Doenças , Suscetibilidade a Doenças/imunologia , Ligação Genética , Predisposição Genética para Doença , Genoma Bacteriano , Genoma Humano , Genoma de Protozoário , Saúde Global , Humanos , Leishmaniose/genética , Leishmaniose/imunologia , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Hanseníase/imunologia , Hanseníase/prevenção & controle , Camundongos , Mycobacterium leprae/efeitos dos fármacos , Mycobacterium leprae/imunologia , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Infecções por Salmonella/genética , Infecções por Salmonella/imunologia , Tuberculose/tratamento farmacológico , Tuberculose/imunologia , Tuberculose/prevenção & controleRESUMO
Leprosy is a debilitating infectious disease of human skin and nerves. Genetic factors of the host play an important role in the manifestation of disease susceptibility. The human NRAMP1 gene is a leprosy susceptibility candidate locus since its murine homologue Nramp1 (formerly Lsh/Ity/Bcg) controls innate resistance to Mycobacterium lepraemurium. In this study, 168 members of 20 multiplex leprosy families were genotyped for NRAMP1 alleles and 4 closely linked polymorphic markers. Highly informative haplotypes overlapping the NRAMP1 gene were constructed, and the haplotype segregation into leprosy-affected offspring was analyzed. It was observed that the segregation of NRAMP1 haplotypes into affected siblings was significantly nonrandom. This finding is consistent with the hypothesis that NRAMP1 itself is a leprosy susceptibility locus.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte de Cátions , Predisposição Genética para Doença , Hanseníase/genética , Proteínas de Membrana/genética , Alelos , Marcadores Genéticos , Haplótipos/genética , Interações Hospedeiro-Parasita/genética , Humanos , Linhagem , Polimorfismo GenéticoRESUMO
In order to determine whether a human homolog (NRAMP1) to a murine candidate gene for resistance to mycobacteria influences susceptibility to human disease, we analyzed data from seven multicase leprosy families (84 individuals) from French Polynesia for linkage markers within the NRAMP1 gene and leprosy per se. Individual family members were typed at nine polymorphic loci within NRAMP1. In addition, three physically linked, polymorphic microsatellite markers-D2S104, D2S173 and D2S1471-were also typed. Linkage analyses were done using affected sibpair and LOD score methods employing different modes of inheritance with full and reduced penetrance. The results of this study strongly suggest that NRAMP1 is not linked to leprosy susceptibility in the French Polynesian families tested.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte de Cátions , Hanseníase/genética , Proteínas de Membrana/genética , Alelos , Feminino , Ligação Genética , Predisposição Genética para Doença , Humanos , Hanseníase/epidemiologia , Escore Lod , Masculino , Repetições de Microssatélites , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polinésia/epidemiologiaRESUMO
In order to determine the genetic components of susceptibility to leprosy in 6 multiplex French Polynesian families, linkage analysis was carried out between a putative disease gene and 6 polymorphic loci: G1M, G2M, KM, IL-1 beta, TNF-alpha (1, 2) and TNF-alpha (A, G) using the lod score method. The three modes of inheritance, assuming a full penetrance value or reduced penetrance values (80 and 40%) for the susceptible allele, as well as with affected ones only, were tested. The results of this study provide no evidence for linkage between leprosy and the markers tested.
Assuntos
Alótipos Gm de Imunoglobulina/genética , Interleucina-1/genética , Hanseníase/genética , Fator de Necrose Tumoral alfa/genética , Suscetibilidade a Doenças , Ligação Genética , Humanos , Alótipos de Imunoglobulina/genética , Hanseníase/imunologiaRESUMO
To investigate the nature of the genetic component controlling susceptibility to leprosy and its subtypes, 402 nuclear families were ascertained through a leprosy patient followed at the Dermatology Hospital in Ho Chi Minh City, Vietnam; 285 families were of Vietnamese origin and 117 were of Chinese origin with a higher proportion of lepromatous forms among Chinese patients. Segregation analyses were conducted using the model developed by Abel and Bonney [(1990) Genet Epidemiol 7:391-407], which accounted for variable age of onset and time-dependent covariates. Three phenotypes were considered: leprosy per se (all forms of leprosy together), nonlepromatous leprosy, and lepromatous leprosy. For each of this phenotype, analyses were performed on the whole sample and separately on the Vietnamese and the Chinese families. The results showed that a single Mendelian gene could not account for the familial distributions of leprosy per se and its two subtypes in the whole sample. However, these results were different according to the ethnic origin of the families. In the Vietnamese subsample, there was evidence for a codominant major gene with residual familial dependences for the leprosy per se phenotype, and borderline rejection of the Mendelian transmission hypothesis for the nonlepromatous phenotype. In Chinese families, strong rejection of Mendelian transmission was obtained in the analysis of leprosy per se, and no evidence for a familial component in the distribution of the nonlepromatous phenotype was observed. For the lepromatous phenotype, the discrimination between models was poor, and no definitive conclusion could be reached. Referring to immunological data, we suggest that these results could be explained by a heterogeneity in the definition of the lepromatous phenotype. It is likely that progress in the understanding of the genetic components involved in the expression of leprosy will come from a better definition of the phenotype under study, and immunological studies are ongoing in this population to investigate this hypothesis.
Assuntos
Frequência do Gene , Predisposição Genética para Doença , Hanseníase/genética , Modelos Genéticos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , China/etnologia , Heterogeneidade Genética , Variação Genética , Humanos , Lactente , Recém-Nascido , Hanseníase/epidemiologia , Hanseníase/imunologia , Pessoa de Meia-Idade , Fenótipo , Estudos de Amostragem , Vietnã/epidemiologia , Vietnã/etnologiaRESUMO
Several lines of evidence have suggested a role of genetic factors in susceptibility to leprosy. In the mouse, natural susceptibility to infection with mycobacteria is controlled by the chromosome 1 Bcg locus, a region which is syntenic with a fragment of the human chromosome 2q, region q31-q37. It has been postulated that a human homolog of the Bcg gene controls susceptibility to leprosy per se, and may be located on chromosome 2q. In order to test the influence of this putative gene on leprosy per se, we performed linkage analyses in a set of seven multicase French Polynesian pedigrees, using an affected sib pair method and the LOD score method employing different modes of inheritance. Family members were typed for eight polymorphic loci on chromosome 2q: CRYGP1, FN, TNP1, VIL, DES, INH, PAX3, and UGT1A1. Our data provide evidence against the presence of a gene controlling susceptibility to leprosy per se on human chromosome 2q in the French Polynesian population.
Assuntos
Cromossomos Humanos Par 2 , Hanseníase/genética , Feminino , Genes Recessivos , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Escore Lod , Masculino , Linhagem , PolinésiaRESUMO
The Mendelian segregation of resistance to infection in different strains of mice infected with mycobacteria, Salmonella and Leishmania spp, all of which live in macrophages, is currently under close scrutiny. Here, Erwin Schurr and colleagues review the nature and function of the Bcg gene in controlling innate resistance to mycobacterial infection in mice and speculate on the occurrence of a possible human equivalent.
Assuntos
Ativação de Macrófagos , Infecções por Mycobacterium/genética , Animais , Mapeamento Cromossômico , Regulação da Expressão Gênica , Genes Dominantes , Marcadores Genéticos , Humanos , Imunidade Inata/genética , Hanseníase/genética , Hanseníase/imunologia , Macrófagos/fisiologia , Camundongos/genética , Camundongos/imunologia , Camundongos/microbiologia , Infecções por Mycobacterium/imunologia , Fenótipo , Tuberculose/genética , Tuberculose/imunologiaRESUMO
In the mouse, innate resistance or susceptibility to infection with numerous mycobacteria is controlled by the Bcg host resistance locus located on the centromeric region of chromosome 1. The resistance/susceptibility phenotype is expressed by the mature tissue macrophage and Bcg has been identified as a locus that is involved in the regulation of macrophage activation and in the modulation of acquired immune responses to mycobacteria. Experiments aimed at the cloning of the Bcg gene via a "reverse genetics" approach have generated a detailed genetic map in the immediate vicinity of the locus, placing Bcg within the reach of long-range eukaryotic cloning techniques. The chromosomal segment around Bcg in the mouse is exactly conserved onto the long arm (q) of human chromosome 2. Linkage of genetic markers from human chromosome 2q with susceptibility to leprosy or tuberculosis would support both the existence of a susceptibility gene in humans and the contention that this susceptibility gene is a homologue of the mouse Bcg locus.