RESUMEN

In this commentary, Brian P. Lazzaro and David S. Schneider examine the topic of the Genetics of Immunity as explored in this month's issues of GENETICS and G3: Genes|Genomes|Genetics. These inaugural articles are part of a joint Genetics of Immunity collection (ongoing) in the GSA journals.

Asunto(s)

Inmunidad/genética , Animales , Humanos

Asunto(s)

Inmunidad/genética , Animales , Humanos

RESUMEN

The emergence of the disease chytridiomycosis caused by the chytrid fungus Batrachochytrium dendrobatidis (Bd) has been implicated in dramatic global amphibian declines. Although many species have undergone catastrophic declines and/or extinctions, others appear to be unaffected or persist at reduced frequencies after Bd outbreaks. The reasons behind this variance in disease outcomes are poorly understood: differences in host immune responses have been proposed, yet previous studies suggest a lack of robust immune responses to Bd in susceptible species. Here, we sequenced transcriptomes from clutch-mates of a highly susceptible amphibian, Atelopus zeteki, with different infection histories. We found significant changes in expression of numerous genes involved in innate and inflammatory responses in infected frogs despite high susceptibility to chytridiomycosis. We show evidence of acquired immune responses generated against Bd, including increased expression of immunoglobulins and major histocompatibility complex genes. In addition, fungal-killing genes had significantly greater expression in frogs previously exposed to Bd compared with Bd-naïve frogs, including chitinase and serine-type proteases. However, our results appear to confirm recent in vitro evidence of immune suppression by Bd, demonstrated by decreased expression of lymphocyte genes in the spleen of infected compared with control frogs. We propose susceptibility to chytridiomycosis is not due to lack of Bd-specific immune responses but instead is caused by failure of those responses to be effective. Ineffective immune pathway activation and timing of antibody production are discussed as potential mechanisms. However, in light of our findings, suppression of key immune responses by Bd is likely an important factor in the lethality of this fungus.

Asunto(s)

Bufonidae/genética , Quitridiomicetos/patogenicidad , Inmunidad Adaptativa , Animales , Bufonidae/inmunología , Quitinasas/genética , Quitinasas/metabolismo , Susceptibilidad a Enfermedades/inmunología , Inmunidad Innata , Micosis/inmunología , Micosis/microbiología , Análisis de Secuencia de ARN , Serina Proteasas/genética , Serina Proteasas/metabolismo , Transcriptoma

RESUMEN

An extraordinary diversity of amino acid sequences in the peptide-binding region (PBR) of human leukocyte antigen [HLA; human major histocompatibility complex (MHC)] molecules has been maintained by balancing selection. The process of accumulation of amino acid diversity in the PBR for six HLA genes (HLA-A, B, C, DRB1, DQB1, and DPB1) shows that the number of amino acid substitutions in the PBR among alleles does not linearly correlate with the divergence time of alleles at the six HLA loci. At these loci, some pairs of alleles show significantly less nonsynonymous substitutions at the PBR than expected from the divergence time. The same phenomenon was observed not only in the HLA but also in the rat MHC. To identify the cause for this, DRB1 sequences, a representative case of a typical nonlinear pattern of substitutions, were examined. When the amino acid substitutions in the PBR were placed with maximum parsimony on a maximum likelihood tree based on the non-PBR substitutions, heterogeneous rates of nonsynonymous substitutions in the PBR were observed on several branches. A computer simulation supported the hypothesis that allelic pairs with low PBR substitution rates were responsible for the stagnation of accumulation of PBR nonsynonymous substitutions. From these observations, we conclude that the nonsynonymous substitution rate at the PBR sites is not constant among the allelic lineages. The deceleration of the rate may be caused by the coexistence of certain pathogens for a substantially long time during HLA evolution.

Asunto(s)

Heterogeneidad Genética , Cadenas HLA-DRB1/genética , Péptidos/metabolismo , Alelos , Aminoácidos/genética , Aminoácidos/metabolismo , Evolución Biológica , Simulación por Computador , Ligamiento Genético , Sitios Genéticos , Cadenas HLA-DRB1/química , Cadenas HLA-DRB1/clasificación , Humanos , Cinética , Péptidos/química , Péptidos/genética , Filogenia , Unión Proteica

RESUMEN

To investigate the association of CLEC16A gene polymorphisms and autoimmune thyroid diseases (AITDs). Six hundred sixty seven Han Chinese patients with AITDs were selected as study subjects, including 417 patients with Graves' disease (GD), 250 patients with Hashimoto's thyroiditis (HT) and 301 healthy control patients. Polymerase chain reaction-restriction fragment length polymorphism (RFLP) and the mass spectrometry technique were used to genotype five CLEC16A single-nucleotide polymorphisms (SNPs) (rs12708716, rs12917716, rs12931878, rs2903692, and rs6498169). Higher frequency of G allele of rs6498169 CLEC16A gene in AITDs patients [P = 0.029, odds ratio (OR) 1.29 and 95% confidence interval 1.022-1.505] was observed. In addition an association between rs6498169 and HT was observed with statistical significance (P = 0.018, OR 1.335, 95% confidence interval 1.051-1.696). Furthermore, the GG haplotype containing the major allele of (rs12708716 and rs6498169) was associated with an increased risk of HT (P = 0.0148, OR 1.344). When patients with HT and controls were compared, results from the dominant and recessive models showed that the genotype frequency of rs6498169 were at borderline levels (P = 0.054 and P = 0.05), and the other four SNPs of CLEC16A gene showed no significant association with AITDs. Our results suggest that polymorphisms rs6498169 of CLEC16A gene confers susceptibility to AITDs. We therefore disclose for the first time the association of rs6498169 SNP with AITDs.

Asunto(s)

Enfermedades Autoinmunes/genética , Lectinas Tipo C/genética , Proteínas de Transporte de Monosacáridos/genética , Polimorfismo Genético , Enfermedades de la Tiroides/genética , Adolescente , Adulto , Anciano , Alelos , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Frecuencia de los Genes , Sitios Genéticos , Predisposición Genética a la Enfermedad , Genotipo , Enfermedad de Graves/diagnóstico , Enfermedad de Graves/genética , Enfermedad de Graves/inmunología , Haplotipos , Enfermedad de Hashimoto/diagnóstico , Enfermedad de Hashimoto/genética , Enfermedad de Hashimoto/inmunología , Humanos , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Enfermedades de la Tiroides/diagnóstico , Enfermedades de la Tiroides/inmunología , Adulto Joven

RESUMEN

In recent years, the synergistic relationship between NADPH oxidase (NOX)/dual oxidase (DUOX) enzymes and peroxidases has received increased attention. Peroxidases utilize NOX/DUOX-generated H2O2 for a myriad of functions including, but not limited to, thyroid hormone biosynthesis, cross-linking extracellular matrices (ECM), and immune defense. We postulated that one or more peroxidases produced by Caenorhabditis elegans would act in host defense, possibly in conjunction with BLI-3, the only NOX/DUOX enzyme encoded by the genome that is expressed. Animals exposed to RNA interference (RNAi) of the putative peroxidase genes were screened for susceptibility to the human pathogen Enterococcus faecalis. One of three genes identified, skpo-1 (ShkT-containing peroxidase), was studied in depth. Animals mutant for this gene were significantly more susceptible to E. faecalis, but not Pseudomonas aeruginosa. A slight decrease in longevity was also observed. The skpo-1 mutant animals had a dumpy phenotype of incomplete penetrance; half the animals displayed a dumpy phenotype ranging from slight to severe, and half were morphologically wild type. The SKPO-1 protein contains the critical catalytic residues necessary for peroxidase activity, and in a whole animal assay, more H2O2 was detected from the mutant compared to the wild type, consistent with the loss of an H2O2 sink. By using tissue-specific skpo-1 RNAi and immunohistochemical localization with an anti-SKPO-1 antibody, it was determined that the peroxidase is functionally and physically present in the hypodermis. In conclusion, these results characterize a peroxidase that functions protectively in the hypodermis during exposure to E. faecalis.

Asunto(s)

Proteínas de Caenorhabditis elegans/inmunología , Caenorhabditis elegans/enzimología , Resistencia a la Enfermedad/genética , Infecciones por Bacterias Grampositivas/inmunología , Peroxidasa/inmunología , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/microbiología , Proteínas de Caenorhabditis elegans/genética , Enterococcus faecalis/patogenicidad , Mutación , Penetrancia , Peroxidasa/genética , Fenotipo , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/patogenicidad , Interferencia de ARN

RESUMEN

Bovine mastitis is an inflammation-driven disease of the bovine mammary gland that costs the global dairy industry several billion dollars per year. Because disease susceptibility is a multifactorial complex phenotype, an integrative biology approach is required to dissect the molecular networks involved. Here, we report such an approach using next-generation sequencing combined with advanced network and pathway biology methods to simultaneously profile mRNA and miRNA expression at multiple time points (0, 12, 24, 36 and 48 hr) in milk and blood FACS-isolated CD14(+) monocytes from animals infected in vivo with Streptococcus uberis. More than 3700 differentially expressed (DE) genes were identified in milk-isolated monocytes (MIMs), a key immune cell recruited to the site of infection during mastitis. Upregulated genes were significantly enriched for inflammatory pathways, whereas downregulated genes were enriched for nonglycolytic metabolic pathways. Monocyte transcriptional changes in the blood, however, were more subtle but highlighted the impact of this infection systemically. Genes upregulated in blood-isolated monocytes (BIMs) showed a significant association with interferon and chemokine signaling. Furthermore, 26 miRNAs were DE in MIMs and three were DE in BIMs. Pathway analysis revealed that predicted targets of downregulated miRNAs were highly enriched for roles in innate immunity (FDR < 3.4E-8), particularly TLR signaling, whereas upregulated miRNAs preferentially targeted genes involved in metabolism. We conclude that during S. uberis infection miRNAs are key amplifiers of monocyte inflammatory response networks and repressors of several metabolic pathways.

Asunto(s)

Regulación de la Expresión Génica , Inflamación/genética , Inflamación/metabolismo , Redes y Vías Metabólicas , MicroARNs/genética , Monocitos/metabolismo , Animales , Bovinos , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Inmunidad Innata/genética , Inflamación/inmunología , Receptores de Lipopolisacáridos/metabolismo , Mastitis Bovina/genética , Mastitis Bovina/inmunología , Mastitis Bovina/metabolismo , Mastitis Bovina/microbiología , Monocitos/inmunología , Fenotipo , Interferencia de ARN , ARN Mensajero/genética , Transducción de Señal , Streptococcus

RESUMEN

A highly diverse set of protein kinases functions as early responders in the mitogen- and stress-activated protein kinase (MAPK/SAPK) signaling pathways. For instance, humans possess 14 MAPK kinase kinases (MAP3Ks) that activate Jun kinase (JNK) signaling downstream. A major challenge is to decipher the selective and redundant functions of these upstream MAP3Ks. Taking advantage of the relative simplicity of Drosophila melanogaster as a model system, we assessed MAP3K signaling specificity in several JNK-dependent processes during development and stress response. Our approach was to generate molecular chimeras between two MAP3K family members, the mixed lineage kinase, Slpr, and the TGF-ß activated kinase, Tak1, which share 32% amino acid identity across the kinase domain but otherwise differ in sequence and domain structure, and then test the contributions of various domains for protein localization, complementation of mutants, and activation of signaling. We found that overexpression of the wild-type kinases stimulated JNK signaling in alternate contexts, so cells were capable of responding to both MAP3Ks, but with distinct outcomes. Relative to wild-type, the catalytic domain swaps compensated weakly or not at all, despite having a shared substrate, the JNK kinase Hep. Tak1 C-terminal domain-containing constructs were inhibitory in Tak1 signaling contexts, including tumor necrosis factor-dependent cell death and innate immune signaling; however, depressing antimicrobial gene expression did not necessarily cause phenotypic susceptibility to infection. These same constructs were neutral in the context of Slpr-dependent developmental signaling, reflecting differential subcellular protein localization and by inference, point of activation. Altogether, our findings suggest that the selective deployment of a particular MAP3K can be attributed in part to its inherent sequence differences, cellular localization, and binding partner availability.

Asunto(s)

Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Quinasas Quinasa Quinasa PAM/metabolismo , Sistema de Señalización de MAP Quinasas , Animales , Animales Modificados Genéticamente , Quimera , Proteínas de Drosophila/genética , Drosophila melanogaster/inmunología , Femenino , Regulación del Desarrollo de la Expresión Génica , Genes Letales , Inmunidad Innata , Quinasas Quinasa Quinasa PAM/genética , Masculino , Mutagénesis Sitio-Dirigida , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/metabolismo , Dominios y Motivos de Interacción de Proteínas

RESUMEN

The extent of the innate immune response is regulated by many positively and negatively acting signaling proteins. This allows for proper activation of innate immunity to fight infection while ensuring that the response is limited to prevent unwanted complications. Thus mutations in innate immune regulators can lead to immune dysfunction or to inflammatory diseases such as arthritis or atherosclerosis. To identify novel innate immune regulators that could affect infectious or inflammatory disease, we have taken a comparative genomics RNAi screening approach in which we inhibit orthologous genes in the nematode Caenorhabditis elegans and murine macrophages, expecting that genes with evolutionarily conserved function also will regulate innate immunity in humans. Here we report the results of an RNAi screen of approximately half of the C. elegans genome, which led to the identification of many candidate genes that regulate innate immunity in C. elegans and mouse macrophages. One of these novel conserved regulators of innate immunity is the mRNA splicing regulator Eftud2, which we show controls the alternate splicing of the MyD88 innate immunity signaling adaptor to modulate the extent of the innate immune response.

Asunto(s)

Proteínas de Caenorhabditis elegans/inmunología , Inmunidad Innata/genética , Factores de Elongación de Péptidos/inmunología , Ribonucleoproteína Nuclear Pequeña U5/inmunología , Empalme Alternativo , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Línea Celular , Hibridación Genómica Comparativa , Macrófagos/citología , Ratones , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/inmunología , Factores de Elongación de Péptidos/genética , Interferencia de ARN , Ribonucleoproteína Nuclear Pequeña U5/genética

RESUMEN

A fundamental question in hematopoietic development is how multipotent progenitors achieve precise identities, while the progenitors themselves maintain quiescence. In Drosophila melanogaster larvae, multipotent hematopoietic progenitors support the production of three lineages, exhibit quiescence in response to cues from a niche, and from their differentiated progeny. Infection by parasitic wasps alters the course of hematopoiesis. Here we address the role of Notch (N) signaling in lamellocyte differentiation in response to wasp infection. We show that Notch activity is moderately high and ubiquitous in all cells of the lymph gland lobes, with crystal cells exhibiting the highest levels. Wasp infection reduces Notch activity, which results in fewer crystal cells and more lamellocytes. Robust lamellocyte differentiation is induced even in N mutants. Using RNA interference knockdown of N, Serrate, and neuralized (neur), and twin clone analysis of a N null allele, we show that all three genes inhibit lamellocyte differentiation. However, unlike its cell-autonomous function in crystal cell development, Notch's inhibitory influence on lamellocyte differentiation is not cell autonomous. High levels of reactive oxygen species in the lymph gland lobes, but not in the niche, accompany N(RNAi)-induced lamellocyte differentiation and lobe dispersal. Our results define a novel dual role for Notch signaling in maintaining competence for basal hematopoiesis: while crystal cell development is encouraged, lamellocytic fate remains repressed. Repression of Notch signaling in fly hematopoiesis is important for host defense against natural parasitic wasp infections. These findings can serve as a model to understand how reactive oxygen species and Notch signals are integrated and interpreted in vivo.

Asunto(s)

Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Células Madre Hematopoyéticas/citología , Especies Reactivas de Oxígeno/metabolismo , Receptores Notch/genética , Transducción de Señal , Animales , Proteínas de Unión al Calcio/genética , Diferenciación Celular , Drosophila melanogaster/parasitología , Femenino , Hematopoyesis , Péptidos y Proteínas de Señalización Intercelular/genética , Proteína Jagged-1 , Masculino , Proteínas de la Membrana/genética , Interferencia de ARN , Proteínas Serrate-Jagged , Ubiquitina-Proteína Ligasas/genética , Avispas

RESUMEN

The influence of individual vitamin on immunity has been described before. In this report, the comprehensive effect of vitamin A, E, riboflavin, pyridoxine and folic acid on the immune response was studied in the BALB/C mice. Animals were divided into five groups:control group, one-third requirement group, double requirement group, triple requirement group and restored group (feeding insufficient diet for six weeks, and then normal diet for another two weeks). The results showed that the percentages of the peripheral blood T cell, Tu cell were diminished significantly in the deficient group in comparison to controls, on the contrast, those in double and triple requirement groups increased obviously, and also did the restored group supplemented normally but no difference in the percentage of Ty in all groups. The study also showed a positive correlation between the relative, absolute thymic weight and the percentage of the peripheral blood T cell. The changes stated above of the peripheral blood T cell and its sub-populations are partially owing to the abnormality of the thymic tissue, but the distribution of lymphocyte shouldn't be neglected. The study found the plaque forming cells (PFC) of spleen, aud the ratio of 3H-thymidine incorporating into splenic lymphocyte after exposure to ConA, PHA and LPS in vitro were increased significantly in double and triple requirement groups; but with the vitamin complex under supply, the former was requced significantly, the latter was comparable to the controls. The PFC increased markedly and no difference with the double group after insufficient animals fed normal diet for two weeks. It is therefore not surprising that the vitamin complex plays a special role in the differentiation and maturation of PFC. According to the study, the vitamin complex may influence the growth of lymphoid tissue, the differentiation and maturation of immunocompetent cells and functional manifestation by mainly affecting the contents of cAMP, cGMP of lymphocyte, and the metabolism of nucleic acid and protein.