RESUMEN
The immunogenetic dictum "not all the infected develop the disease" can best be explained by a "Lotus and Cactus" model. Lotuses grow in ponds and cacti in deserts: analogously, we can say that tubercle patient's lung (genetic makeup) functions as an ideal 'broth' for Mycobacterium tuberculosis (M.tb) germs to grow, but not the lungs of an endemic control. HLA association studies from Europe to Asia since 1983 till date, have shown a persistent HLA DR2 (15) association. Further, HLA DR2 and non-DR2 endemic controls showed disparate patterns of immune responses and gene expressions. The host and pathogen MHC diversities, Th1-Th2 paradigm and cytokine circuits all may play a crucial role in TB susceptibility. It is possible to decipher the protective immunity by controlling the known confounders - epidemiological, demographic, socio-biological and also host and pathogen diversities. This has become significant with our understanding on the 'out of Africa' migration and neolithic co-dispersal of M.tb with modern human. Divergence and expansion of various MHCs (eg HLA-DRB1*15, HLA-B*57) and non-MHC alleles in various continents might be responsible for the skewed transmission and distribution of the infectious diseases around the globe. The 'Lotus and Cactus' model proposed here exemplifies this. A holistic genetic epidemiology approach employing modern tools is the need of the hour to better understand infectious disease susceptibility.
Asunto(s)
Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Modelos Biológicos , Alelos , Cactaceae/genética , Cactaceae/inmunología , Resistencia a la Enfermedad/genética , Resistencia a la Enfermedad/inmunología , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Antígenos de Histocompatibilidad/genética , Antígenos de Histocompatibilidad/inmunología , Humanos , Inmunidad Innata , Mycobacterium tuberculosis/inmunología , Nelumbo/genética , Nelumbo/inmunología , Polimorfismo Genético , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Tuberculosis/genética , Tuberculosis/inmunología , Tuberculosis/microbiología , Vacunas/inmunologíaRESUMEN
Leprosy is an infectious disease caused by the obligate intracellular pathogen Mycobacterium leprae and remains endemic in many parts of the world. Despite several major studies on susceptibility to leprosy, few genomic loci have been replicated independently. We have conducted an association analysis of more than 1,500 individuals from different case-control and family studies, and observed consistent associations between genetic variants in both TLR1 and the HLA-DRB1/DQA1 regions with susceptibility to leprosy (TLR1 I602S, case-control P = 5.7 x 10(-8), OR = 0.31, 95% CI = 0.20-0.48, and HLA-DQA1 rs1071630, case-control P = 4.9 x 10(-14), OR = 0.43, 95% CI = 0.35-0.54). The effect sizes of these associations suggest that TLR1 and HLA-DRB1/DQA1 are major susceptibility genes in susceptibility to leprosy. Further population differentiation analysis shows that the TLR1 locus is extremely differentiated. The protective dysfunctional 602S allele is rare in Africa but expands to become the dominant allele among individuals of European descent. This supports the hypothesis that this locus may be under selection from mycobacteria or other pathogens that are recognized by TLR1 and its co-receptors. These observations provide insight into the long standing host-pathogen relationship between human and mycobacteria and highlight the key role of the TLR pathway in infectious diseases.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Antígenos HLA-DR/genética , Lepra/genética , Receptor Toll-Like 1/genética , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ , Cadenas HLA-DRB1 , Humanos , Lepra/inmunología , Mycobacterium leprae/inmunología , Receptor Toll-Like 1/inmunologíaRESUMEN
Natural killer (NK) cells contribute to the essential functions of innate immunity and reproduction. Various genes encode NK cell receptors that recognize the major histocompatibility complex (MHC) Class I molecules expressed by other cells. For primate NK cells, the killer-cell immunoglobulin-like receptors (KIR) are a variable and rapidly evolving family of MHC Class I receptors. Studied here is KIR3DL1/S1, which encodes receptors for highly polymorphic human HLA-A and -B and comprises three ancient allelic lineages that have been preserved by balancing selection throughout human evolution. While the 3DS1 lineage of activating receptors has been conserved, the two 3DL1 lineages of inhibitory receptors were diversified through inter-lineage recombination with each other and with 3DS1. Prominent targets for recombination were D0-domain polymorphisms, which modulate enhancer function, and dimorphism at position 283 in the D2 domain, which influences inhibitory function. In African populations, unequal crossing over between the 3DL1 and 3DL2 genes produced a deleted KIR haplotype in which the telomeric "half" was reduced to a single fusion gene with functional properties distinct from its 3DL1 and 3DL2 parents. Conversely, in Eurasian populations, duplication of the KIR3DL1/S1 locus by unequal crossing over has enabled individuals to carry and express alleles of all three KIR3DL1/S1 lineages. These results demonstrate how meiotic recombination combines with an ancient, preserved diversity to create new KIR phenotypes upon which natural selection acts. A consequence of such recombination is to blur the distinction between alleles and loci in the rapidly evolving human KIR gene family.
Asunto(s)
Alelos , Variación Genética/genética , Haplotipos/genética , Meiosis/genética , Receptores de Células Asesinas Naturales/genética , Recombinación Genética/genética , Secuencia de Aminoácidos , Línea Celular , Evolución Molecular , Humanos , Modelos Genéticos , Datos de Secuencia Molecular , Fenotipo , Receptores KIR/genética , Receptores KIR3DL1/genéticaRESUMEN
By interacting with polymorphic HLA class I molecules, the killer cell immunoglobulin-like receptors (KIR) influence the innate and adaptive immune response to infection. The KIR family varies in gene content and sequence polymorphism, thereby, distinguishing individuals and populations. To investigate KIR diversity in the earliest settlers of India, we have characterized the KIR gene content in three Dravidian-speaking populations (Mollukurumba, Kanikar, and Paravar) from the state of Tamil Nadu, southern India. The activating KIR genes and putative group-B KIR haplotypes were frequent in Paravar and Kanikar, a scenario analogous to those seen previously in other populations of Indian origin, indicating that predominance of group-B KIR haplotypes is the characteristic feature of Indian populations. In contrast, the KIR gene profile of Mollukurumba was more related to Caucasian type. It is not clear whether a local-specific selection or a recent admixture from Iran is responsible for such discrete profile in Mollukurumba. Each southern Indian population had distinct KIR genotype profile. Comparative analyses with world populations revealed that group-B KIR haplotypes were frequent in the natives of India, Australia, and America, the populations associated with those involved in extensive prehistoric human migrations. Whether or not natural selection has acted to enrich group-B KIR haplotypes in these migratory descendants is an issue that requires objective testing.
Asunto(s)
Frecuencia de los Genes , Variación Genética , Genética de Población , Grupos Raciales/genética , Receptores KIR/genética , Haplotipos , Humanos , IndiaRESUMEN
Interactions of killer cell immunoglobulin-like receptors (KIRs) with major histocompatibility complex (MHC) class I ligands diversify natural killer cell responses to infection. By analyzing sequence variation in diverse human populations, we show that the KIR3DL1/S1 locus encodes two lineages of polymorphic inhibitory KIR3DL1 allotypes that recognize Bw4 epitopes of protein">HLA-A and HLA-B and one lineage of conserved activating KIR3DS1 allotypes, also implicated in Bw4 recognition. Balancing selection has maintained these three lineages for over 3 million years. Variation was selected at D1 and D2 domain residues that contact HLA class I and at two sites on D0, the domain that enhances the binding of KIR3D to HLA class I. HLA-B variants that gained Bw4 through interallelic microconversion are also products of selection. A worldwide comparison uncovers unusual KIR3DL1/S1 evolution in modern sub-Saharan Africans. Balancing selection is weak and confined to D0, KIR3DS1 is rare and KIR3DL1 allotypes with similar binding sites predominate. Natural killer cells express the dominant KIR3DL1 at a high frequency and with high surface density, providing strong responses to cells perturbed in Bw4 expression.
Asunto(s)
Población Negra/genética , Receptores KIR3DL1/genética , Receptores KIR3DS1/genética , Selección Genética , Alelos , Secuencia de Aminoácidos , Sitios de Unión/genética , Frecuencia de los Genes , Genética de Población , Antígenos HLA-B/química , Antígenos HLA-B/genética , Humanos , Desequilibrio de Ligamiento , Datos de Secuencia Molecular , Filogenia , Polimorfismo Genético , Estructura Terciaria de Proteína , Receptores KIR3DL1/química , Receptores KIR3DS1/química , Homología de Secuencia de AminoácidoRESUMEN
A major susceptibility locus for leprosy has recently been mapped on chromosome 10 (10p13) by genome-wide linkage analysis. Microsatellite markers from this genome screen that showed suggestive evidence of linkage to leprosy were evaluated in an additional 140 families with affected sib pairs. A second region of linkage has thus been identified on chromosome 20 (20p12). The peak of linkage lies at marker D20S115, which has a significant single-point maximum logarithm of odds score of 3.48 (P=.00003). Transmission disequilibrium testing of the microsatellite markers in 20p12 showed that the marker D20S835 is associated with protection against leprosy (P=.021), which suggests that a locus controlling susceptibility lies close to this marker.
Asunto(s)
Cromosomas Humanos Par 20/genética , Predisposición Genética a la Enfermedad/genética , Lepra/genética , Mapeo Cromosómico , Femenino , Marcadores Genéticos/genética , Genética de Población , Humanos , India , Masculino , Repeticiones de Microsatélite/genética , Mycobacterium lepraeRESUMEN
A major susceptibility locus for leprosy has recently been mapped on chromosome 10 (10p13) by genome-wide linkage analysis. Microsatellite markers from this genome screen that showed suggestive evidence of linkage to leprosy were evaluated in an additional 140 families with affected sib pairs. A second region of linkage has thus been identified on chromosome 20 (20p12). The peak of linkage lies at marker D20S115, which has a significant single-point maximum logarithm of odds score of 3.48 (P=.00003). Transmission disequilibrium testing of the microsatellite markers in 20p12 showed that the marker D20S835 is associated with protection against leprosy (P=.021), which suggests that a locus controlling susceptibility lies close to this marker.
