RESUMEN
A genomewide association study in Chinese patients with leprosy detected association signals in 16 single-nucleotide polymorphisms (SNPs) belonging to 6 loci, of which 4 are related to the NOD2 signaling pathway and are Crohn's disease susceptibility loci. Here, we studied these 16 SNPs as potential leprosy susceptibility factors in 474 Vietnamese leprosy simplex families. We replicated SNPs at HLA-DR-DQ, RIPK2, CCDC122-LACC1, and NOD2 as leprosy susceptibility factors in Vietnam. These results validated the striking overlap in the genetic control of Crohn's disease and leprosy.
Asunto(s)
Pueblo Asiatico/genética , Enfermedad de Crohn/genética , Lepra/genética , Familia , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lepra/epidemiología , Proteína Adaptadora de Señalización NOD2/genética , Proteína Adaptadora de Señalización NOD2/metabolismo , Polimorfismo de Nucleótido Simple , Transducción de Señal , Vietnam/epidemiologíaRESUMEN
Leprosy is an infectious disease caused by Mycobacterium leprae. Tumor necrosis factor (TNF) plays a key role in the host response. Some association studies have implicated the single nucleotide polymorphism TNF -308G>A in leprosy susceptibility, but these results are still controversial. We first conducted 4 association studies (2639 individuals) that showed a protective effect of the -308A allele (odds ratio [OR] = 0.77; P = .005). Next, results of a meta-analysis reinforced this association after inclusion of our new data (OR = 0.74; P = .04). Furthermore, a subgroup analysis including only Brazilian studies suggested that the association is specific to this population (OR = 0.63; P = .005). Finally, functional analyses using whole blood cultures showed that patients carrying the -308A allele produced higher TNF levels after lipopolysaccharide (LPS) (6 hours) and M. leprae (3 hours) stimulation. These results reinforce the association between TNF and leprosy and suggest the -308A allele as a marker of disease resistance, especially among Brazilians.
Asunto(s)
Lepra/genética , Mycobacterium leprae/aislamiento & purificación , Factor de Necrosis Tumoral alfa/genética , Adulto , Brasil/epidemiología , Estudios de Casos y Controles , ADN/química , ADN/genética , Femenino , Variación Genética , Genotipo , Humanos , Lepra/epidemiología , Lepra/microbiología , Masculino , Reacción en Cadena de la Polimerasa , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
Fifty years ago, the first identification of a non Mendelian genetic contribution to the development of a common infectious disease, i.e. the association between malaria and sickle-cell trait, was shown using a supervised approach which tests a limited number of candidate genes selected by hypothesis. Since then, the few genes that were convincingly associated with susceptibility to human infectious diseases were identified following the same strategy. The study of leprosy has contributed to modifying this way of thinking. In the absence of a satisfying experimental model and because of the impossibility to grow the causative agent in vitro, the candidate gene approach has turned out to be of limited interest. Conversely, positional cloning led to the identification of two major genes involved in the control of the disease, establishing for the first time the oligogenic nature of a human genetic contribution to an infectious disease. It is likely that these major results obtained in leprosy and the recent burst of genomic tools will make the genome-wide screening (functional or positional) the main strategy of dissection of the genetic susceptibility to many common infectious diseases.
Asunto(s)
Predisposición Genética a la Enfermedad , Infecciones/genética , Lepra/genética , Mapeo Cromosómico , Cromosomas Humanos Par 10 , Antígenos HLA-DR/genética , Cadenas HLA-DRB1 , Humanos , Linfotoxina-alfa/genética , Fenotipo , Polimorfismo GenéticoRESUMEN
The Mitsuda reaction, a delayed granulomatous skin reaction elicited by the intradermal injection of heat-killed Mycobacterium leprae, is an in vivo test reflecting the ability to generate an immune granuloma after sensitization by diverse mycobacterial infections. Accumulating evidence for the genetic control of the Mitsuda reaction has been reported. We performed a genomewide linkage scan for the quantitative Mitsuda reaction in 19 large families from Vietnam with a history of leprosy (114 offspring). Suggestive linkage was found at chromosomal regions 2q35 (P = 9 x 10(-4) at the SLC11A1 locus) and 17q21-25 (P = 8 x 10(-4)). Interestingly, these 2 regions have been previously linked to mycobacterial infection and other granulomatous diseases.
Asunto(s)
Proteínas de Transporte de Catión/genética , Predisposición Genética a la Enfermedad/genética , Granuloma/genética , Lepra/genética , Mycobacterium leprae/inmunología , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 2/genética , Ligamiento Genético , Granuloma/inmunología , Granuloma/microbiología , Humanos , Lepra/inmunología , Mycobacterium leprae/patogenicidad , VietnamRESUMEN
Host genetics has an important role in leprosy, and variants in the shared promoter region of PARK2 and PACRG were the first major susceptibility factors identified by positional cloning. Here we report the linkage disequilibrium mapping of the second linkage peak of our previous genome-wide scan, located close to the HLA complex. In both a Vietnamese familial sample and an Indian case-control sample, the low-producing lymphotoxin-alpha (LTA)+80 A allele was significantly associated with an increase in leprosy risk (P = 0.007 and P = 0.01, respectively). Analysis of an additional case-control sample from Brazil and an additional familial sample from Vietnam showed that the LTA+80 effect was much stronger in young individuals. In the combined sample of 298 Vietnamese familial trios, the odds ratio of leprosy for LTA+80 AA/AC versus CC subjects was 2.11 (P = 0.000024), which increased to 5.63 (P = 0.0000004) in the subsample of 121 trios of affected individuals diagnosed before 16 years of age. In addition to identifying LTA as a major gene associated with early-onset leprosy, our study highlights the critical role of case- and population-specific factors in the dissection of susceptibility variants in complex diseases.
Asunto(s)
Predisposición Genética a la Enfermedad , Lepra/genética , Linfotoxina-alfa/genética , Proyectos de Investigación , Adolescente , Adulto , Edad de Inicio , Alelos , Brasil/epidemiología , Estudios de Casos y Controles , Niño , Humanos , India/epidemiología , Lepra/epidemiología , Desequilibrio de Ligamiento , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Vietnam/epidemiologíaRESUMEN
There is growing interest in the fundamental roles that B cells may play in regulating immune responses. Emerging animal studies point to an important contribution of B cell effector cytokines to immune modulation, yet little is known about the factors regulating such cytokine production. We report that the profile of human B cell cytokine production is context dependent, being critically influenced by the balance of signals through the B cell receptor and CD40. B cells appropriately stimulated by sequential B cell receptor and CD40 stimulation proliferate and secrete TNF-alpha, lymphotoxin, and IL-6, which can act not only as autocrine growth and differentiation factors, but also serve to amplify the ongoing immune response. In contrast, CD40 stimulation alone, a mimic of a B cell receiving bystander T cell help in the absence of specific Ag recognition, induces negligible proinflammatory cytokines, but significant production of IL-10 that serves to suppress inappropriate immune responses. We thus describe a novel paradigm of reciprocal regulation of B cell effector cytokines, and ascribe active roles for human B cells in either promoting or suppressing local immune responses through context-dependent cytokine production.