RESUMEN
Pregnancy is a unique immunological situation in which a fetus-bearing paternal histocompatibility antigens can survive in a maternal environment without apparent rejection. To face this challenge, cells of the uterine immune system show characteristic changes in absolute number and composition during pregnancy. Particularly relevant to this process are uterine natural killer (uNK) cells and their cell surface receptors, killer immunoglobulin-like receptors (KIRs). The main purpose of this review is to outline the current body of knowledge on the involvement of KIRs in the complications of pregnancy. Implantation depends on the invasion of embryonic trophoblast cells into maternal uterine tissue and remodeling of the uterine spiral arterioles, which is essential for placental perfusion and successful pregnancy. The proper interaction between maternal KIRs and their ligands human leukocyte antigen (HLA) class I molecules, expressed by the extravillous trophoblast cells, is crucial in this process. KIRs are a complex family that includes both activator and inhibitory receptors. The activation profile is genetically determined in each individual and leads to diverse levels of functionality for NK and T cells on engagement with specific HLA class I molecules. An association between different KIR alleles and HLA molecules has been reported in pregnancy complications, supporting the idea of a relevant role of these receptors in successful pregnancy.
Asunto(s)
Implantación del Embrión/inmunología , Antígenos HLA/inmunología , Células Asesinas Naturales/inmunología , Placentación/inmunología , Complicaciones del Embarazo/inmunología , Complicaciones del Embarazo/patología , Receptores KIR/inmunología , Femenino , Antígenos HLA/metabolismo , Humanos , Células Asesinas Naturales/metabolismo , Embarazo , Receptores KIR/metabolismoRESUMEN
The aim of this study was to analyse the association of specific killer cell immunoglobulin-like receptors (KIR) genes and haplotypes with susceptibility to ankylosing spondylitis (AS) and its different clinical manifestations in a Spanish population. The presence or absence of all KIR genes was studied for their association with AS. A total of 176 patients with AS and 435 healthy control subjects were selected for this study based on clinical criteria. The commercial KIR-sequence-specific oligonucleotides (SSO) typing kit was used to investigate KIR typing. Frequencies of KIR2DS1 and KIR3DS1 genes were increased significantly in patients compared with healthy controls [52·8 versus 38·2%, PBonf < 0·01, odds ratio (OR) = 1·81 (1·28-2·59); 51·7 versus 37·5%, PBonf < 0·01, OR = 1·79 (1·25-2·54)]. Moreover, the frequency of activating genotypes in the AS patient group was significantly higher than in the healthy control group (P < 0·05). KIR2DS1 and KIR3DS1, in addition to human leucocyte antigen (HLA)-B27, may play an important role in the pathogenesis of AS. However, we show that the contribution of the KIR genes to AS susceptibility extends beyond the association with individual KIRs, with an imbalance between activating and inhibitory KIR genes seeming to influence the susceptibility to AS.
Asunto(s)
Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Receptores KIR3DS1/genética , Receptores KIR/genética , Espondilitis Anquilosante/genética , Femenino , Técnicas de Genotipaje , Antígeno HLA-B27/genética , Antígeno HLA-B27/inmunología , Humanos , Masculino , Receptores KIR/inmunología , Receptores KIR3DS1/inmunología , Espondilitis Anquilosante/inmunología , Espondilitis Anquilosante/patologíaRESUMEN
Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that primarily involves the axial skeleton and the sacroiliac joint, but may also affect peripheral joints and entheses. AS susceptibility is clearly attributable to genetic factors and the link between human leukocyte antigen (HLA)-B27 and AS is the strongest association between an HLA class I molecule and a disease. However, there is evidence for the involvement of other, non-B27 factors within the major histocompatibility complex (MHC) in AS susceptibility. MHC class I is clearly the most significant genetic region for the disease, although most of the genetic association of this region is driven by HLA-B27. Moreover, several studies have investigated the MHC class II region and its association with AS. This review summarizes the current findings concerning the MHC genetics of the disease, focusing in particular on the associations of HLA with AS found in different ethnic populations throughout the world, and the possible mechanisms underlying them.
Asunto(s)
Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase I/genética , Espondilitis Anquilosante/genética , Espondilitis Anquilosante/inmunología , Frecuencia de los Genes/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , HumanosRESUMEN
Killer immunoglobulin-like receptors (KIRs) are related to the activation and inhibition of NK cells and may play an important role in the innate response against infection with viruses such as hepatitis C virus (HCV). We examined whether the different combinations of KIRs with their HLA class I ligands influenced the response to combined treatment (pegylated alpha interferon and ribavirin) of patients infected by HCV. A total of 186 consecutive patients diagnosed with chronic HCV infection were analyzed. Seventy-seven patients exhibited HCV RNA levels at 6 months posttreatment and were called nonresponders (NR), while 109 cleared viral RNA and were named sustained viral responders (SVR). Patients were typed for HLA-B, HLA-Cw, KIR genes, and HCV genotype. In our study, the frequency of the KIR2DL2 allele was significantly increased in NR (P < 0.001; odds ratio [OR] = 1.95), as was the frequency of the KIR2DL2/KIR2DL2 genotype (P < 0.005; OR = 2.52). In contrast, the frequencies of the KIR2DL3 genotype (P < 0.001) and KIR2DL3/KIR2DL3 genotype (P < 0.05; OR = 0.54) were significantly increased in the SVR. Different combinations of KIR2DL2 and KIR2DL3 alleles with their ligands were analyzed. The frequency of the KIR2DL2/KIR2DL2-HLA-C1C2 genotype was significantly increased in the NR (P < 0.01; OR = 3.15). Additionally, we found a higher frequency of the KIR2DL3/KIR2DL3-HLA-C1C1 genotype in the SVR group (P < 0.05; OR = 0.33). These results were not affected by the HCV genotype. In conclusion, patients who carried the KIR2DL2/KIR2DL2-HLA-C1C2 genotype were less prone to respond to treatment. However, the KIR2DL3/KIR2DL3-HLA-C1C1 genotype clearly correlated with a satisfactory response to treatment, defined by the clearance of HCV RNA.
Asunto(s)
Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/inmunología , Receptores KIR/genética , Adulto , Antivirales/uso terapéutico , Quimioterapia Combinada , Femenino , Genotipo , Antígenos HLA/genética , Hepacivirus/genética , Humanos , Interferón-alfa/uso terapéutico , Masculino , Persona de Mediana Edad , Farmacogenética/métodos , ARN Viral/sangre , Receptores KIR2DL2 , Receptores KIR2DL3 , Ribavirina/uso terapéutico , Resultado del Tratamiento , Carga Viral/efectos de los fármacosRESUMEN
Large genome-wide association studies (GWAS) have increased our knowledge of the genetic risk factors of rheumatoid arthritis (RA). However, little is known about genetic susceptibility in populations with a large admixture of Amerindian ancestry. The aim of the present study was to test the generalizability of previously reported RA loci in a Latin American (LA) population with admixed ancestry. We selected 128 single nucleotide polymorphisms (SNPs) in linkage equilibrium, with high association to RA in multiple populations of non-Amerindian origin. Genotyping of 118 SNPs was performed in 313 RA patients/487 healthy control subjects by mid-density arrays of polymerase chain reaction (PCR). Some of the identified associations were validated in an additional cohort (250 cases/290 controls). One marker, the SNP rs2451258, located upstream of T Cell Activation RhoGTPase Activating Protein (TAGAP) gene, showed significant association with RA (p = 5 × 10-3), whereas 18 markers exhibited suggestive associations (p < 0.05). Haplotype testing showed association of some groups of adjacent SNPs around the signal transducer and activator of transcription 4 (STAT4) gene (p = 9.82 × 10-3 to 2.04 × 10-3) with RA. Our major finding was little replication of previously reported genetic associations with RA. These results suggest that performing GWAS and admixture mapping in LA populations has the potential to reveal novel loci associated with RA. This in turn might help to gain insight into the 'pathogenomics' of this disease and to explore trans-population differences for RA in general.
Asunto(s)
Artritis Reumatoide/genética , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Polimorfismo de Nucleótido Simple , Adolescente , Adulto , Anciano , Artritis Reumatoide/etnología , Pueblo Asiatico/genética , Estudios de Cohortes , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética/estadística & datos numéricos , Predisposición Genética a la Enfermedad/etnología , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Genotipo , Humanos , América Latina , Masculino , Persona de Mediana Edad , Población Blanca/genética , Adulto JovenAsunto(s)
Antígeno HLA-B14/genética , Antígeno HLA-B27/genética , Grupos de Población , Espondilitis Anquilosante/genética , África del Sur del Sahara , Burkina Faso , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Prueba de Histocompatibilidad , Humanos , Polimorfismo Genético , Espondilitis Anquilosante/epidemiología , Espondilitis Anquilosante/inmunología , Togo , ZambiaRESUMEN
A randomized clinical trial was performed in children with cancer, fever and neutropenia, to evaluate the efficacy of amikacin once daily versus thrice daily dosing plus carbenicillin in both groups. Fifty patients were included, 25 patients in group A who received amikacin once daily and 25 in group B who received amikacin thrice daily. No intergroup differences were observed, i.e., fever diminished in a median of 6 days (2-8 days) vs. 7 days (3-12 days) in groups A and B respectively (p = 0.37);clinical improvement was observed in a median of 6 days (3-10 days) vs 7 days (2-14 days) (p = 0.68). One patient in group A and two in B died. The peak levels of amikacin on the 7th day of treatment were 10-60 and 7-25 micrograms/mL in groups A and B respectively, and the serum creatinine levels were 0.3 - 0.7 for group A and 0.2 - 0.8 mg/dL for group B; none of the patients presented a creatinine above 40% of the basal value. Three patients of group A had amikacin levels higher than 40 micrograms/mL without increasing the creatinine levels; our observations do not suggest that toxicity is higher. We conclude that the administration of aminoglycoside once daily seems to be as effective as the traditional dosing.
Asunto(s)
Amicacina/uso terapéutico , Antibacterianos/uso terapéutico , Infecciones Bacterianas/tratamiento farmacológico , Fiebre/tratamiento farmacológico , Neutropenia/complicaciones , Infecciones Bacterianas/etiología , Niño , Preescolar , Esquema de Medicación , Femenino , Fiebre/etiología , Humanos , Huésped Inmunocomprometido , Masculino , Resultado del TratamientoRESUMEN
HLA-B27 confers susceptibility to ankylosing spondylitis but AS disease mechanisms remain unknown. We determined here the effect of polymorphism and tapasin dependence on the expression, intracellular maturation and homodimer formation among HLA-B27 subtypes. We found that B*2709 with a histidine at position 116 was strongly associated with the transporter associated with antigen processing complex, correlated with lower, non-conformational expression on the cell surface, delayed maturation rate and minimal conformational and non-conformational homodimer formation. In contrast, B*2705 showed a low dependence for transporter associated with antigen processing, faster intracellular maturation and increased levels of homodimeric forms. The absence of tapasin significantly influenced the rate of intracellular maturation of B*2709, showing faster transport out of the endoplasmic reticulum, but similar to that of B*2705. All B27 subtypes examined were unable to express conformational homodimeric forms in the absence of tapasin. This study suggests that HLA-B27 polymorphism drives the tapasin dependency, rates of intracellular maturation and expressions of homodimers.
Asunto(s)
Dimerización , Antígeno HLA-B27/genética , Antígeno HLA-B27/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Células Cultivadas , Antígeno HLA-B27/química , Humanos , Polimorfismo Genético , Unión Proteica/genética , Conformación Proteica , Pliegue de Proteína , Multimerización de Proteína/genética , Transporte de Proteínas/genética , Espondiloartropatías/genética , Espondiloartropatías/metabolismoRESUMEN
Invasive fungal infection in critically ill children is associated with significant morbimortality. However, there is limited information on the behavior of infections by Candida spp. in this population, since on the one hand, very few clinical trials on antifungal efficacy have been published to date, and on the other hand most of these trials were performed on children with fever and neutropenia, and in neonates with invasive candidiasis. As a result, there are very few reviews on critically ill patients outside the neonatal stage. We therefore recommend reviewing international literature, national experience and work groups in a number of countrywide third-level pediatric hospitals.