RESUMEN
Two novel CD1D alleles were identified in unrelated individuals from Morocco. They differ each from the common CD1D*01 allele by one nucleotide substitution in exon 2 resulting in one amino acid change in the G-ALPHA1-LIKE domain. According to the IMGT unique numbering for G domain, CD1D*03 has one nucleotide transition c136 > t in codon 46, with an arginine-to-cysteine amino acid change (R46 > C) in the D-STRAND, whereas CD1D*04 has one transition c98 > t in codon 33, with a threonine-to-methionine amino acid change (T33 > M) in the C-STRAND. This suggests that CD1D is more polymorphic than previously assumed.
Asunto(s)
Sustitución de Aminoácidos/genética , Antígenos CD1d/genética , Polimorfismo Genético , Alelos , Exones , Humanos , Datos de Secuencia Molecular , Marruecos , Conformación Proteica , Análisis de Secuencia de ADNRESUMEN
The killer cell immunoglobulin-like receptor (KIR)-human leukocyte antigen (HLA) interaction represents an example of genetic epistasis, where the concomitant presence of specific genes or alleles encoding receptor-ligand units is necessary for the activity of natural killer (NK) cells. Although KIR and HLA genes segregate independently, they co-evolved under environmental pressures to maintain particular KIR-HLA functional blocks for species survival. We investigated, in 270 Italian healthy individuals, the distribution of KIR and HLA polymorphisms in three climatic areas (from cold north to warm south), to verify their possible geographical stratification. We analyzed the presence of 13 KIR genes and genotyped KIR ligands belonging to HLA class I: HLA-C, HLA-B and HLA-A. We did not observe any genetic stratification for KIR genes and HLA-C ligands in Italy. By contrast, in a north-to-south direction, we found a decreasing trend for the HLA-A3 and HLA-A11 ligands (P = 0.012) and an increasing trend for the HLA-B ligands carrying the Bw4 epitope (P = 0.0003) and the Bw4 Ile80 epitope (P = 0.0005). The HLA-A and HLA-B KIR ligands were in negative linkage disequilibrium (correlation coefficient -0.1211), possibly as a consequence of their similar function in inhibiting NK cells. The distribution of the KIR-HLA functional blocks was different along Italy, as we observed a north-to-south ascending trend for KIR3DL1, when coupled with HLA-B Bw4 ligands (P = 0.0067) and with HLA-B Bw4 Ile80 (P = 0.0027), and a descending trend for KIR3DL2 when coupled with HLA-A3 and HLA-A11 ligands (P = 0.0044). Overall, people from South Italy preferentially use the KIR3DL1-HLA-B Bw4 functional unit, while those from the North Italy equally use both the KIR3DL2-HLA-A3/A11 and the KIR3DL1-HLA-B Bw4 functional units to fight infections. Thus, only KIR3DL receptors, which exert the unique role of microbial sensors through the specific D0 domain, and their cognate HLA-A and HLA-B ligands are selectively pressured in Italy according to geographical north-to-south distribution.
Asunto(s)
Genética de Población , Antígenos HLA/genética , Receptores KIR/genética , Adulto , Alelos , Femenino , Frecuencia de los Genes/genética , Geografía , Humanos , Italia , Ligandos , Desequilibrio de Ligamiento/genética , MasculinoRESUMEN
The aim of this study was to provide genetic and anthropological information on the Chaouya (CH), an Arabic-speaking population living in West Morocco, Atlantic coast (Settat). In 98 unrelated healthy CH volunteers, we first investigated the human leukocyte antigen (HLA) class I and II allele polymorphisms using a sequence-based typing method and examined haplotypes and relatedness of this group to other African and Mediterranean populations. The study showed the close relatedness with Tunisian population and other North Africans, together with a strong influence of various immigrations, mainly Spaniards, French, and Portuguese, as expected. Nevertheless, analysis of class II allele frequencies (afs) showed that Oromo and Amhara Ethiopian groups cluster together with the Berbers and other North Africans, confirming the relationship between these populations (Afro-Asiatic linguistic group, Hamites). South and sub-Saharan Africans cluster separately at a great distance from CH, except the sub-Saharan Bantu population from Congo Kinshasa, which shows a relatively close genetic relationship ascribable to the effect of a diversifying selection. On the other hand, considering HLA class I afs analyses, it was noteworthy that CH grouped together with sub-Saharans, showing a close genetic distance mainly with Ugandas and Kenians Luo.
Asunto(s)
Población Negra/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase I/genética , Polimorfismo Genético/genética , Adulto , Anciano , Alelos , Antropología Física , Femenino , Frecuencia de los Genes , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Marruecos/epidemiología , FilogeniaRESUMEN
During the 15th International Histocompatibility and Immunogenetics Workshop (IHIWS), 14 human leukocyte antigen (HLA) laboratories participated in the Analysis of HLA Population Data (AHPD) project where 18 new population samples were analyzed statistically and compared with data available from previous workshops. To that aim, an original methodology was developed and used (i) to estimate frequencies by taking into account ambiguous genotypic data, (ii) to test for Hardy-Weinberg equilibrium (HWE) by using a nested likelihood ratio test involving a parameter accounting for HWE deviations, (iii) to test for selective neutrality by using a resampling algorithm, and (iv) to provide explicit graphical representations including allele frequencies and basic statistics for each series of data. A total of 66 data series (1-7 loci per population) were analyzed with this standard approach. Frequency estimates were compliant with HWE in all but one population of mixed stem cell donors. Neutrality testing confirmed the observation of heterozygote excess at all HLA loci, although a significant deviation was established in only a few cases. Population comparisons showed that HLA genetic patterns were mostly shaped by geographic and/or linguistic differentiations in Africa and Europe, but not in America where both genetic drift in isolated populations and gene flow in admixed populations led to a more complex genetic structure. Overall, a fruitful collaboration between HLA typing laboratories and population geneticists allowed finding useful solutions to the problem of estimating gene frequencies and testing basic population diversity statistics on highly complex HLA data (high numbers of alleles and ambiguities), with promising applications in either anthropological, epidemiological, or transplantation studies.
Asunto(s)
Genética de Población/métodos , Antígenos HLA/genética , Inmunogenética , Grupos de Población/genética , Programas Informáticos , Frecuencia de los Genes , HumanosRESUMEN
The fat mass and obesity-associated (FTO) gene is one of the most important obesity susceptibility genes. Some FTO gene polymorphisms have been associated with obesity, diabetes, and hypertension, all conditions for which, after transplant, there is increased susceptibility, due to effects of immunosuppressive regimens. To evaluate whether FTO could be a candidate for targeted preventive intervention in the transplant setting, we investigated whether the common genetic variation, FTO rs9939609T>A, could affect weight gain and risk of cardiovascular complications in kidney transplantation. METHODS: In 198 kidney transplant recipients, FTO rs9939609 was investigated in association with body mass index (BMI)/obesity and with other clinical markers of posttransplant risk, then monitored up to 5 years after transplantation. Genotyping was performed using an allelic discrimination method on a real-time polymerase chain (PCR) system. Associations were analyzed using the chi-square test; differences between genotypes were examined with analysis of variance or Kruskal-Wallis test; tests for repeated measures and a general linear model analysis controlling for age and gender were also utilized. RESULTS: Allele and genotype frequencies of FTO rs9939609 in recipients (T/T, 29.8%; T/A, 49.0%; A/A, 21.2%; A, 45.7%; T, 54.3%) reflect those present in healthy Caucasian populations. In the face of pre-/posttransplant differences in total cholesterol, triglycerides, or fasting glucose, results did not show significant changes in these factors among genotypes either before or after transplantation. CONCLUSION: This study highlights a lack of association of FTO rs9939609T>A genotypes and posttransplant weight gain, plasma lipids, and fasting blood glucose in kidney transplantation.
Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Trasplante de Riñón , Obesidad/genética , Aumento de Peso/genética , Adulto , Glucemia/genética , Índice de Masa Corporal , Colesterol/sangre , Colesterol/genética , Femenino , Genotipo , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Obesidad/inducido químicamente , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Triglicéridos/sangre , Triglicéridos/genéticaRESUMEN
Alterations in the immune response play an important role in the pathogenesis of atopic dermatitis (AD). We evaluated the role of Th1/Th2 cytokine imbalance in paediatric AD and its progression towards other allergic manifestations. The levels of total interleukin (IL)-12 (p70+p40), IL-12 p70 and soluble CD30 (sCD30) were measured in paediatric patients affected by AD and in age-matched, non-atopic subjects (controls). The serum levels of total IL-12 and sCD30 were higher in patients than in controls (p=0.003 and p=0.053, respectively). Total IL-12 and sCD30 were also particularly increased in patients with severe disease. Serum levels of total IL-12 were negatively correlated with patient age (p=0.001): they were significantly higher in patients younger than 30 months, as compared to age-matched controls and to older patients and controls. Total IL-12 and sCD30 production were not significantly correlated with disease outcomes (atopic march) or with a family history of atopy. Our data show that total IL-12 levels are strongly associated with Th2 activation and severe disease in children with AD. The increased production of total IL-12 at an early age might indicate a different immune modulation and suggests the possibility of new therapeutic approaches for allergic diseases, in particular AD, early in childhood.
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Envejecimiento/fisiología , Dermatitis Atópica/metabolismo , Interleucina-12/metabolismo , Adolescente , Alérgenos/inmunología , Asma/metabolismo , Niño , Preescolar , Conjuntivitis/metabolismo , Dermatitis Atópica/patología , Femenino , Humanos , Inmunoglobulina E/sangre , Lactante , Antígeno Ki-1/metabolismo , Masculino , Monocitos/metabolismo , Pruebas Cutáneas , Células Th2/inmunologíaRESUMEN
BACKGROUND: Killer cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activatory receptors that are expressed by most natural killer (NK) cells. The KIR gene family is polymorphic: genomic diversity is achieved through differences in gene content and allelic polymorphism. The number of KIR loci has been reported to vary among individuals, resulting in different KIR haplotypes. In this study we report the genotypic structure of KIRs in 217 unrelated healthy Italian individuals from 22 immunogenetics laboratories, located in the northern, central and southern regions of Italy. METHODS: Two hundred and seventeen DNA samples were studied by a low resolution PCR-SSP kit designed to identify all KIR genes. RESULTS: All 17 KIR genes were observed in the population with different frequencies than other Caucasian and non-Caucasian populations; framework genes KIR3DL3, KIR3DP1, KIR2DL4 and KIR3DL2 were present in all individuals. Sixty-five different profiles were found in this Italian population study. Haplotype A remains the most prevalent and genotype 1, with a frequency of 28.5%, is the most commonly observed in the Italian population. CONCLUSION: The Italian Caucasian population shows polymorphism of the KIR gene family like other Caucasian and non-Caucasian populations. Although 64 genotypes have been observed, genotype 1 remains the most frequent as already observed in other populations. Such knowledge of the KIR gene distribution in populations is very useful in the study of associations with diseases and in selection of donors for haploidentical bone marrow transplantation.
RESUMEN
The aim of this study was to determine levels of Interleukin 6 (IL-6) in amniotic fluid at the beginning of the second trimester and to establish whether IL-6 can be used as a marker for premature birth as it would appear to be an important prenatal marker of chorionic inflammation. Thirty-three patients, between 16 and 19 weeks of gestation, who were undergoing amniocentesis to establish the presence or not of fetal genetic pathologies were enrolled into the study. Amniotic fluid (3 ml) was taken from each patient and used to perform enzyme-linked immunosorbent assays (ELISAs). The results were analyzed using the Mann-Whitney test and Pearson and Spearman coefficient. The patients were divided into three groups on the basis of the levels of IL-6 found: a) up to 450 pg/ml; b) between 450 and 900 pg/ml; c) over 900 pg/ml; These data were then evaluated alongside the date of parturition and the presence of any maternal or fetal pathologies. The results of our analyses, however, were inconclusive: levels of IL-6 were normal in patients presenting pathologies while obstetric pathologies were absent in patients with high levels of IL-6. In conclusion, this data would indicate that a different method or approach is required for the identification of a marker for premature birth.
Asunto(s)
Líquido Amniótico/química , Interleucina-6/análisis , Trabajo de Parto Prematuro/diagnóstico , Adulto , Biomarcadores/análisis , Femenino , Edad Gestacional , Humanos , Embarazo , Segundo Trimestre del Embarazo , Nacimiento Prematuro , Estudios RetrospectivosRESUMEN
BACKGROUND: Functional polymorphisms of molecules involved in immune-mediated mechanisms of allograft rejection could be predictive of increased risk for early and late post-transplant complications. In the past years, the challenge for long-term graft survival in kidney recipients is the implementation of personalized approaches. In this study, effects of interleukin (IL)-18-137G/C (rs187238), -607C/A (rs1946518), and other pro-inflammatory cytokine gene polymorphisms (tumor necrosis factor [TNF]-α-308G/A, rs1800629, IL-6-174G/C, rs1800795, and interferon [IFN]-γ+874A/T, rs2430561) on the main post-transplant risk parameters and diseases (metabolic, cardiovascular, infective, and chronic allograft rejection) were assessed in kidney-transplanted patients. METHODS: One hundred seventy-nine transplanted patients were retrospectively analyzed for clinical and biochemical parameters and onset of post-transplant complications. Taqman allelic discrimination and PCR-SSP (polymerase chain reaction-sequence specific primers) techniques were used for genotyping. RESULTS: No predictive effects of allele and genotypes of IL-18-607C/A, TNF-α-308G/A, IL-6-174G/C, and IFN-γ+874A/T gene polymorphisms and onset of risk factors and late complications were evidenced. However, Kaplan-Meier analysis evidenced a weak effect of IL-18-137G/C genotypes on graft survival. CONCLUSIONS: Analyzing associations between some pro-inflammatory cytokine gene polymorphisms and onset of the most relevant risk factors and late complications of kidney transplant, results suggested a possible impact of IL-18-137G/C genotypes on graft survival, which deserves further studies.
Asunto(s)
Supervivencia de Injerto/genética , Interleucina-18/genética , Trasplante de Riñón/efectos adversos , Polimorfismo Genético , Complicaciones Posoperatorias/genética , Adulto , Alelos , Citocinas/genética , Femenino , Genotipo , Rechazo de Injerto/genética , Humanos , Interleucina-6/genética , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
In order to study the role of interleukin-1beta (IL-1beta) in homeostasis, hypoxia and recovery of neuronal cells, we studied the expression and release of tumor necrosis factor-alpha (TNF-alpha) and nerve growth factor (NGF), in relation to the presence or absence of this cytokine in culture medium. Moreover, we evaluated cell mortality in the same conditions. For this aim, we used untreated and IL-1beta pre-immunoneutralized hippocampal neuronal cultures exposed to mild hypoxic stress and left to reoxygenate. Semiquantitative reverse-transciptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) determined gene expression and protein levels. Mild hypoxic stress provokes a decrease in both the expression and release of TNF-alpha and NGF. IL-1beta neutralization results in an inversion of this pattern since treated hypoxic cultures exhibited an increase of both expression and release of NGF. In pretreated hypoxic cells the increased expression of TNF-alpha was not followed by a rise in release. Reoxygenation reversed the observed effects in both cultures and the levels of cytokine expression and release were approaching control values. Our data show that in physiological conditions IL-1beta may have a neuroprotective action through positive modulation of NGF. Contrary to that, in presence of insult, IL-1beta may have an opposite role, since neutralization provoked an increase of expression and release of NGF. In addition, we demonstrated that neuronal cells are biochemically capable, not only of maintaining and recovering the homeostasis, but also of activating the appropriate response to insult. IL-1beta may have a pivotal role in this mechanism through the modulation of NGF and to a lesser degree of TNF-alpha.
Asunto(s)
Hipoxia/fisiopatología , Interleucina-1/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Animales , Muerte Celular , Células Cultivadas , Expresión Génica , Factor de Crecimiento Nervioso/genética , Factor de Crecimiento Nervioso/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: To determine the potential contribution of cytokines associated with lymphocyte activation to the pathogenesis of immune impairment in gastroenteric cancer, we examined the expression of cytokine mRNA in peripheral blood mononuclear cells (PBMCs) and tumor-draining lymph nodes (LNs). MATERIAL AND METHODS: Using a reverse transcriptase-polymerase chain reaction (RT-PCR) technique, mRNA transcripts for interleukin (IL)-4, IL-2, IL-5, IL-6, IL-1 beta, IFN gamma, IL-10 and IL-2-receptor(IL-2R)(p55) were detected in PBMCs from 16 patients with gastroenteric cancer, undergoing surgical resection, and from 13 healthy donors. RESULTS: Patients expressed a different pattern of cytokines. Significantly increased IL-2R(p55) and reduced IL-2 mRNA expression were found in patients (p = 0.034, p = 0.043). IL-10 expression was significantly correlated to IL-2R(p55) expression in both groups (p = 0.011, p = 0.009). In LNs, the results reflected those from PBMCs of the same patient. CONCLUSIONS: Gastroenteric cancer showed a suppressive pattern of cytokine expression, suggesting an impairment of T cell activation that can be evidenced from the specific pattern of PBMC cytokine expression.
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Neoplasias Gastrointestinales/inmunología , Interleucina-2/genética , Leucocitos Mononucleares/metabolismo , ARN Mensajero/análisis , Receptores de Interleucina-2/genética , Anciano , Femenino , Neoplasias Gastrointestinales/terapia , Humanos , Ganglios Linfáticos/química , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa InversaAsunto(s)
Trastorno por Déficit de Atención con Hiperactividad/diagnóstico , Trastorno por Déficit de Atención con Hiperactividad/etiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno por Déficit de Atención con Hiperactividad/psicología , Niño , Genes MHC Clase I , Genes MHC Clase II , Humanos , Masculino , Pruebas NeuropsicológicasRESUMEN
HLA-G, a nonclassical HLA molecule with limited polymorphism has immunomodulating/tolerogenic properties. The most common polymorphism of HLA-G is a deletion/insertion of 14 bp, located at the 3'UTR region of the gene (exon 8). This polymorphism is associated with modifications of mRNA stability that can lead to variations of membrane versus soluble HLA-G expression. HLA-G may be involved in the clinical outcomes of transplantation, as evidenced by studies in hematopoietic cell transplantation. We evaluated the possible prognostic importance of 14-bp polymorphisms of HLA-G among kidney transplantation patients. Using polymerase chain reaction amplification we genotyped 124 patients (mean organ survival: 878.95 +/- 595.12 days; range = 1-2565) and 98 control individuals representative of the Italian population. Products were visualized by electrophoresis on agarose gels. The results showed no differences between patients and controls. Twenty-nine patients with acute or chronic rejection or in whom clinical conditions required the use of steroid bolus treatments also showed no association with HLA-G 14-bp genotypes or alleles. The subset of patients with dyslipidemia during follow-up showed a significant decrease among the HLA-G-14/-14 genotype, compared with heterozygous (+14/-14) and nondeleted homozygous (+14/+14) genotype patients (P(c) = .03). These preliminary data showed that HLA-G 14-bp genotypes, although not predictive of rejection, may be useful to identify individuals at risk for the development of posttransplant complications.
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Dislipidemias/genética , Antígenos HLA-G/genética , Trasplante de Riñón , Eliminación de Gen , Frecuencia de los Genes , Genotipo , Rechazo de Injerto/inmunología , Humanos , Mutagénesis Insercional , Polimorfismo Genético , Complicaciones Posoperatorias/genética , PronósticoRESUMEN
A new human leukocyte antigen (HLA)-B allele, named B*3580, with an amino acid substitution at residue 156, has been identified during the sequence-based typing of a patient waiting for a hematopoietic cell transplantation.
Asunto(s)
Antígeno HLA-B35/genética , Trasplante de Células Madre Hematopoyéticas , Linfocitos T Citotóxicos/inmunología , Alelos , Sustitución de Aminoácidos/genética , Secuencia de Bases , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Humanos , Datos de Secuencia Molecular , Linfocitos T Citotóxicos/metabolismoRESUMEN
Sequence-based typing procedure (SBT) procedure permitted us to identify a new human leukocyte antigen-A allele in a patient attending hematopoietic stem cell transplantation.
Asunto(s)
Alelos , Antígenos HLA-A/genética , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia/genética , Leucemia/terapia , Persona de Mediana EdadRESUMEN
Dendritic cells (DC) play a pivotal role in shaping the immune response in both physiological and pathological conditions. In peripheral blood at least two subsets, the myeloid and plasmacytoid, have been described as having different T stimulatory functions and a variable degree of maturation. Certainly, antigen presentation plays a crucial role in the pathogenesis of coeliac disease and circulating immune cells are thought to reflect the state of immune response within the gut. Therefore, we aimed to investigate the quantitative and phenotypical modifications of peripheral blood DC, together with their functional properties, in this pathological condition. Blood samples from 11 untreated patients before and after a course of gluten-free diet, 27 treated patients and 14 controls underwent flow-cytometric analysis, while immunomagnetically sorted DC from the CD patients and eight human leucocyte antigen (HLA)-DQ2/8(+) bone marrow donors were used to evaluate maturation status through the CD83 expression, cytokine profile for interleukin (IL)-6, IL-10, IL-12 and interferon (IFN)-alpha by enzyme-linked immunosorbent assay (ELISA), and functional properties by mixed leucocyte reaction before and after pulsing with digested gliadin. We found that in both untreated and treated patients, a significant reduction of the entire DC population, mainly the plasmacytoid subset, in comparison to healthy controls was observed. In active disease, an impaired allogenic lymphocyte reaction and a significant reduction of IFN-alpha production, paralleled by the presence of a more immature status, were also demonstrated. All the latter modifications have been reverted by pulsing DC with digested gliadin.
Asunto(s)
Enfermedad Celíaca/inmunología , Células Dendríticas/inmunología , Adolescente , Adulto , Anciano , Enfermedad Celíaca/dietoterapia , Recuento de Células , Diferenciación Celular/inmunología , Citocinas/metabolismo , Femenino , Citometría de Flujo/métodos , Gliadina/administración & dosificación , Humanos , Inmunofenotipificación , Prueba de Cultivo Mixto de Linfocitos , Masculino , Persona de Mediana EdadRESUMEN
We describe an additional HLA-Cw*02 variant, HLA-Cw*0208, which has been identified in a renal transplant recipient of Caucasian origin (Italy). After performing preliminary serological typing, we analyzed exons 2 and 3 of the HLA-C locus polymorphism by cloning the amplified DNA and using a sequence-based typing method. The new allele differs from Cw*020202 by one nucleotide substitution at nucleotide 61 (G-->A) of exon 2, which translates to a difference of one amino acid at residue 21 (His-->Arg) of the HLA-C heavy chain. We propose that Cw*0208 was generated by a random point mutation in codon 21 from the Cw*020202 allele, or through gene conversion of Cw*020202 with another allele, probably the Cw*1205 and Cw*1602 alleles.
Asunto(s)
Antígenos HLA-C/genética , Alelos , Secuencia de Aminoácidos , Aminoácidos/química , Secuencia de Bases , Exones , Prueba de Histocompatibilidad , Humanos , Trasplante de Riñón , Datos de Secuencia Molecular , Mutación Puntual , Polimorfismo Genético , Estructura Secundaria de Proteína , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido NucleicoRESUMEN
A novel HLA-A*02 allele was detected in a Caucasian patient from central Italy, requiring a hematopoietic cell transplantation. Direct sequencing identified a variation in one nucleotide position, which was confirmed by cloning. The name A*027401 was officially assigned by the WHO Nomenclature Committee in November 2004. A*027401 differs from A*02010101 by a single G to A substitution at nucleotide position 595 in exon 3. The new variant would lead to a nonsynonymous nucleotide change (GGG to AGG) at codon 175, resulting in a basic Arg in the alpha-helix of the alpha2-domain, in place of a non-polar Gly. The presence of an uncommon variation at a highly conserved nucleotide position could have implications in unrelated hematopoietic cell transplantation.
Asunto(s)
Alelos , Antígenos HLA-A/genética , Secuencia de Aminoácidos , Secuencia de Bases , Prueba de Histocompatibilidad , Humanos , Italia/etnología , Datos de Secuencia Molecular , Polimorfismo Genético , Alineación de Secuencia , Análisis de Secuencia de ADN , Población Blanca/genéticaRESUMEN
The expression of cytokine mRNAs in tumor tissue, normal mucosa, and peripheral blood mononuclear cells (PBMCs) was studied in 12 patients with colorectal cancer undergoing surgical resection, to characterize local immune conditions. mRNA transcripts for interleukin (IL)-1 beta, IL-2, IL-2-R(p55), IL-4, IL-5, IL-6, and IL-10 were detected using the reverse transcriptase-polymerase chain reaction (RT-PCR) technique. IL-6 mRNA was expressed in tumor tissue in 83% of the cases but only in one case in normal mucosa (p < 0.001); serum levels of IL-6 did not show any correlation with IL-6 mRNA; IL-1 beta transcripts were present in all tumor tissue samples; no IL-4 expression was detected; IL-2 mRNA was only present in two tumors; IL-2R(p55) mRNA was found in 58% of tumors but not in normal mucosae (p = 0.005). The expression of IL-10 suggests that it does not play a central role in colorectal cancer immunosuppression, and cytokine expression in PBMCs indicates a different and independent activation. This study suggests a pattern of expression of inflammatory cytokines in the tumor microenvironment, probably produced by infiltrating immune cells. The absence of the specific immune-activating cytokines, IL-2 and IL-4, could indicate an impairment of the anticancer immune response; IL-2R results confirm the dysregulation of the IL-2/IL-2R activation pathway. These findings may lead to a better understanding of the role of cytokines and especially IL-6 at the tumor site and hence their importance in developing an effective immunotherapy.
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Neoplasias Colorrectales/metabolismo , Expresión Génica , Interleucina-6/genética , Interleucinas/genética , Anciano , Colon/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Femenino , Humanos , Técnicas para Inmunoenzimas , Interleucina-6/sangre , Mucosa Intestinal/metabolismo , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Soluble interleukin-2 receptor (sIL-2R) levels have been found to be elevated in several clinical conditions, including disseminated solid neoplasms, whereas they are generally within the normal range in patients with locally limited neoplastic disease. The aim of the present study was to examine this in our colon cancer patients, and to assess if this situation can affect the in vitro activation of peripheral blood mononuclear cells (PBMC), examining the proliferative response to IL-2 and anti-CD3 monoclonal antibody, the IL-2 serum levels and the PBMC phenotype. The results show that sIL-2R levels were significantly correlated with the stage of the disease, showing an increase from stage I to stage IV; moreover, it is worth noting that the proliferative response to IL-2 plus anti-CD3 is significantly higher than to IL-2 alone in stage IV, without significant alteration in the numerical presence of T and natural killer cells. So it seems that in the peripheral blood of patients, connected with the disease progression, are present cellular populations showing a different response to activation, and that T cells acquire a better response condition than NK. Thus, since the T cellular population includes the tumour-specific cytotoxic precursor cells, this should be helpful for its tumour regressive activity, but it is conceivable that this population cannot perform its functions, owing to a deficiency in responsiveness of the specific ThCD4+ subpopulation.