RESUMEN
Despite a natural reservoir of Mycobacterium leprae limited to humans and free availability of an effective antibiotic treatment, more than 200,000 people develop leprosy each year. This disease remains a major cause of disability and social stigma worldwide. The cause of this constant incidence is currently unknown and indicates that important aspects of the complex relationship between the pathogen and its human host remain to be discovered. An important contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability between individuals sustainably exposed to M. leprae. Given the inability to cultivate M. leprae in vitro and in the absence of relevant animal model, genetic epidemiology is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. Recent genome-wide studies have identified new pathophysiological pathways which importance is only beginning to be understood. In addition, the prism of human genetics placed leprosy at the crossroads of other common diseases such as Crohn's disease, asthma or myocardial infarction. Therefore, novel lights on the pathogenesis of many common diseases could eventually emerge from the detailed understanding of a disease of the shadows.
Asunto(s)
Enfermedades Transmisibles/genética , Predisposición Genética a la Enfermedad , Lepra/genética , Enfermedades Transmisibles/epidemiología , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/genética , Marcadores Genéticos/fisiología , Estudio de Asociación del Genoma Completo , Humanos , Inflamación/epidemiología , Inflamación/genética , Lepra/epidemiología , Mycobacterium lepraeRESUMEN
An overview of investigations indicating an important role of host genetics, both major histocompatibility complex (MHC) and non-MHC, in leprosy.
Asunto(s)
Predisposición Genética a la Enfermedad , Lepra/genética , Chaperonas Moleculares/genética , Infecciones por Mycobacterium/genética , Ubiquitina-Proteína Ligasas/genética , Humanos , Proteínas de Microfilamentos , Mycobacterium/genética , Infecciones por Mycobacterium/inmunologíaRESUMEN
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.
Asunto(s)
Ligamiento Genético/genética , Antígenos HLA/genética , Lepra/genética , Factor de Necrosis Tumoral alfa/genética , Cromosomas Humanos Par 6/genética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lepra/clasificación , Masculino , Linaje , FenotipoRESUMEN
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.
Asunto(s)
Masculino , Femenino , Humanos , Antígenos HLA/genética , /genética , Factor de Necrosis Tumoral alfa/genética , Genotipo , Lepra/clasificación , Lepra/genética , Ligamiento Genético/genética , Predisposición Genética a la Enfermedad , Fenotipo , LinajeRESUMEN
Humans are exposed worldwide to a variety of environmental mycobacteria (EM) and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. Although rarely pathogenic, poorly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. M. tuberculosis and M. leprae are more virulent, causing tuberculosis, and leprosy, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. There is now accumulating evidence that the large interindividual variability of clinical outcome results in part from variability in the human genes that control host defense. We review here in current knowledge about genetic predisposition to common (leprosy and tuberculosis) and rare (BCG and EM infections) mycobacterial infections.
Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Infecciones por Mycobacterium/etiología , Infecciones por Mycobacterium/genética , Mycobacterium/patogenicidad , Humanos , Lepra/etiología , Lepra/genética , Tuberculosis Pulmonar/etiología , Tuberculosis Pulmonar/genéticaRESUMEN
Humans are exposed worldwide to a variety of environmental mycobacteria (EM) and most children are inoculated with live Bacille Calmette-Guérin (BCG) vaccine. Although rarely pathogenic, poorly virulent mycobacteria, including BCG and most EM, may cause a variety of clinical diseases. M. tuberculosis and M. leprae are more virulent, causing tuberculosis, and leprosy, respectively. Remarkably, only a minority of individuals develop clinical disease, even if infected with virulent mycobacteria. There is now accumulating evidence that the large interindividual variability of clinical outcome results in part from variability in the human genes that control host defense. We review here in current knowledge about genetic predisposition to common (leprosy and tuberculosis) and rare (BCG and EM infections) mycobacterial infections.
Asunto(s)
Humanos , Lepra/etiología , Lepra/genética , Infecciones por Mycobacterium/etiología , Infecciones por Mycobacterium/genética , Mycobacterium/patogenicidad , Predisposición Genética a la Enfermedad , Tuberculosis Pulmonar/etiología , Tuberculosis Pulmonar/genética , Variación GenéticaRESUMEN
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.
Asunto(s)
Proteínas Portadoras/genética , Proteínas de Transporte de Catión , Predisposición Genética a la Enfermedad , Lepromina/inmunología , Lepra/inmunología , Proteínas de la Membrana/genética , Piel/inmunología , China/etnología , Femenino , Ligamiento Genético , Granuloma , Haplotipos , Humanos , Inmunidad Innata , Inyecciones Intradérmicas , Lepra Lepromatosa/inmunología , Lepra Tuberculoide/inmunología , Masculino , Núcleo Familiar , Linaje , Fenotipo , Linfocitos T Colaboradores-Inductores , VietnamRESUMEN
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.