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CONCLUSIONS: This update of the Knops (KN) blood group system (Moulds JM. The Knops blood group system. Immunohematology 2010;26:2-7) adds no new antigens to this system (International Society of Blood Transfusion system 22), which currently has nine antigens. However, the molecular basis of York, KN5, or Yka has been identified as c.4223C>T and designated KN*01.-05. Although not considered clinically significant in the field of transfusion medicine, there has been great interest in the Knops polymorphism by investigators working on malaria documented by numerous studies over the past 8 years.
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Antígenos de Grupos Sanguíneos/análisis , Humanos , Polimorfismo Genético , Receptores de Complemento 3bRESUMEN
BACKGROUND: Hyperhemolysis syndrome (HHS) is an uncommon, but life-threatening, transfusion-related complication of red blood cell transfusion. HHS has predominantly been described in patients with sickle cell disease (SCD) and is difficult to diagnose and treat. The pathogenesis of HHS, including its occurrence in only a subset of apparently susceptible individuals, is poorly understood. We undertook whole-exome sequencing (WES) of 12 SCD-HHS patients to identify shared genetic variants that might be relevant to the development of HHS. STUDY DESIGN AND METHODS: DNA from adults with SCD having at least one previous episode of HHS were subject to WES. High-quality variants were passed through a series of bioinformatics filters to identify variants that were uncommon among African populations represented in public databases. Recurrent, putative loss-of-function variants occurring in biologically plausible genes were prioritized and then genotyped in a larger, ancestry-matched cohort of non-HHS controls. RESULTS: A rare, heterozygous stop-gain variant (p.Glu210Ter) in MBL2 was significantly enriched among HHS cases (p = 0.002). This variant is predicted to result in a premature termination codon that escapes nonsense-mediated mRNA decay, potentially leading to a novel phenotype. We also observed a complex insertion-deletion variant in the final exon of KLRC3 that was enriched among cases (p = 0.0019), although neither variant was found among seven pediatric SCD-HHS patients. CONCLUSION: Our results suggest a potential role for rare genetic defects in the development of HHS among adult SCD patients. Such enriched variants may ultimately be useful for identifying high-risk individuals and informing therapeutic approaches in HHS.
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Anemia de Células Falciformes , Exoma , Predisposición Genética a la Enfermedad , Variación Genética , Hemólisis/genética , Adolescente , Adulto , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Niño , Preescolar , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , SíndromeRESUMEN
BACKGROUND: The r'(s) haplotype is found in 5% to 15% of individuals of African descent. Persons with this haplotype have a partial C antigen and weakened e and can produce anti-C or other "e-like" alloantibodies. Thus, for these chronically transfused patients, accurate detection of the r'(s) haplotype is important for selection of matched units. STUDY DESIGN AND METHODS: African-American donors were genotyped using the human erythrocyte antigen (HEA) microarray. Samples (n = 125) identified as "possible r'(s) " were then tested by IDCORE XT and RHD and RHCE microarrays. DNA sequencing was used to resolve discordant samples. The genotyping results were compared to serologic testing using a monoclonal anti-C reagent (Clone MS24). RESULTS: Of the 125 possible r'(s) samples identified by HEA, only 94 (75%) were confirmed by both RHD and RHCE microarrays. The IDCORE XT accurately detected 93 of 94 (99%) of the confirmed r'(s) and had no false positives. DNA sequencing of the one discordant sample revealed the presence of a compound heterozygote with RHD* DIII.4/RHCE*ceVS.02 as one haplotype and r'(s) Type 2 as the other. The 31 unconfirmed r'(s) samples carried RHCE*ceVS.03 not linked to the hybrid RHD-CE-D. This occurred most often with RHD*DIIIa (55%) or RHD*01 (19%) and rarely with DIII.4, DIII.6, DAU3, and weak D Type 14. Serologic testing with anti-C gave 100% concordance with the r'(s) samples. CONCLUSIONS: The predominant type of r'(s) in African-Americans is Type 1, which can be detected either by a reagent anti-C containing Clone MS24 or by IDCORE XT. However, serology cannot differentiate between a normal C allele and the hybrid.
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Técnicas de Genotipaje/métodos , Prueba de Histocompatibilidad/métodos , Sistema del Grupo Sanguíneo Rh-Hr/genética , Negro o Afroamericano/genética , Alelos , Antígenos de Grupos Sanguíneos/genética , Antígenos de Grupos Sanguíneos/inmunología , Eritrocitos/inmunología , Eritrocitos/metabolismo , Haplotipos , Humanos , Isoanticuerpos/genética , Isoanticuerpos/inmunología , Datos de Secuencia Molecular , Polimorfismo de Nucleótido SimpleRESUMEN
BACKGROUND: Moving to automation is a major focus of transfusion centers. Erytra (Grifols) is a walk-away analyzer with high-performance and -throughput capacity for pretransfusion testing. Efficiency and performance of Erytra with its cards and reagents were evaluated in comparison to Food and Drug Administration (FDA)-approved reference methods. STUDY DESIGN AND METHODS: A total of 5279 blood samples (46% patients; 54% donors) were obtained from US blood establishment facilities. Samples were analyzed with Erytra and results were compared with the routine FDA-licensed automated platforms used by the clinical study sites. A total of 25,217 tests were performed (15,322 ABO/D/reverse typing; 4916 Rh phenotypes, 669 K typing, 838 antibody screens, 759 antibody identifications, 250 cross-matches, 244 ABO compatibilities by immediate-spin cross-match, and 219 direct antiglobulin tests [DATs]). RESULTS: Global agreement between Erytra and the comparison platforms was 99.66%, with 99.82% positive percent agreement (95% lower confidence bound [LCB], 99.75%) and 99.50% negative percent agreement (95% LCB, 99.37%). There were 85 discrepancies (0.34%), including cross-matches (n = 13), antibody screens (n = 10), antibody identifications (n = 21), and DATs (n = 5), whereas an excellent concordance was obtained in blood grouping determinations (ABO/D/C/E/c/e/K, 0.04%-0.22% discrepancies). Analysis of the discrepancies showed that Erytra provided the correct result in 51 of them (60%), with only five false negatives (one O patient transplanted with A, one mixed-field reaction in a very weak D, one anti-Vel, two A2rr). Erytra results were 100% reproducible in a series of 3760 repetition tests. CONCLUSION: Grifols' Erytra analyzer showed reliable efficacy compared with equivalent FDA-licensed reagents and FDA-cleared instruments.
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Automatización de Laboratorios , Tipificación y Pruebas Cruzadas Sanguíneas , Transfusión Sanguínea , Ensayos Analíticos de Alto Rendimiento/instrumentación , Sistema del Grupo Sanguíneo ABO/sangre , Automatización de Laboratorios/instrumentación , Automatización de Laboratorios/normas , Donantes de Sangre , Tipificación y Pruebas Cruzadas Sanguíneas/instrumentación , Tipificación y Pruebas Cruzadas Sanguíneas/métodos , Tipificación y Pruebas Cruzadas Sanguíneas/normas , Transfusión Sanguínea/normas , Transfusión Sanguínea/estadística & datos numéricos , Prueba de Coombs/instrumentación , Prueba de Coombs/normas , Ensayos Analíticos de Alto Rendimiento/métodos , Ensayos Analíticos de Alto Rendimiento/normas , Humanos , Indicadores y Reactivos , Ensayos de Aptitud de Laboratorios , Reproducibilidad de los Resultados , Sistema del Grupo Sanguíneo Rh-Hr/sangre , Estados UnidosRESUMEN
The Rh D antigen posed both a significant clinical risk and inventory supply issue in transfusion medicine. The successful development of the immunocamouflaged RBC has the potential to address both the risk of acute anti-D transfusion reactions and to improve D- blood inventory in geographic locations where D- blood is rare (e.g., China). The immunocamouflage of RBC was mediated by the covalent grafting of methoxy(polyethylene glycol) to the cell membrane thereby obscuring the D protein from the immune system. To determine the potential efficacy of mPEG-D+ RBC in D- recipients, anti-D alloantibodies from previously alloimmunized individuals were utilized. The effects of polymer chain size (2-30 kDa) and grafting concentration (0-4 mM) on antibody binding and erythrophagocytosis were determined using the clinically validated monocyte monolayer assay (MMA) and flow cytometry. The immunocamouflage of D was polymer size and grafting concentration dependent as determined using human anti-D alloantibodies (both pooled [RhoGAM] and single donors). Importantly, the 20 kDa polymer provided excellent immunocamouflage of D and reached a clinically significant level of protection, as measured by the MMA, at grafting concentrations of ≥1.5 mM. These findings further support the potential use of immunocamouflaged RBC to reduce the risk of acute transfusion reactions following administration of D+ blood to D- recipients in situations where D- units are unavailable or supply is geographically constrained.
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Transfusión de Eritrocitos/métodos , Isoanticuerpos/inmunología , Proteínas Opsoninas/metabolismo , Globulina Inmune rho(D)/inmunología , Humanos , Fagocitos , PolímerosRESUMEN
Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia (AIHA) characterized by the presence of a Donath-Landsteiner (D-L) antibody. PCH occurs most commonly in young children and is associated with acute, often self-limited hemolytic anemia. The D-L antibody is classically a biphasic IgG anti-P autoantibody identified by the D-L test. Rare case reports confirm the existence of IgM D-L antibodies. We report the case of a 2-year-old male diagnosed with acute AIHA and found to have PCH caused by an IgA D-L antibody. The clinical course and treatment of this condition, which has not been reported previously, are described.
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Autoanticuerpos/sangre , Hemoglobinuria Paroxística/sangre , Hemoglobinuria Paroxística/diagnóstico , Inmunoglobulina A/sangre , Preescolar , Hemoglobinuria Paroxística/terapia , Humanos , MasculinoRESUMEN
BACKGROUND: A selective susceptibility of certain individuals to form multiple alloantibodies in response to red cell transfusion is well-recognized in clinical practice, and is a particular problem in persons with sickle cell disease (SCD). The reason for this differential susceptibility is unclear, but inter-individual genetic differences are likely to contribute. METHODS: We conducted a pilot case-control genome-wide association study using 1,000,000 SNPs in 94 alloimmune responders (cases) and non-responders (controls) with SCD in order to identify loci of large effect size associated with alloimmunization. RESULTS: No loci showed evidence of association at a genome-wide significance cut-off (p < 0.5 × 10(-8)). SNPs in the ARAP1/STARD10 region showed suggestive association (p < 1 × 10(-6)), but no association was observed at previously implicated loci TRIM21 or HLA. In analyses of the number of accumulated antibodies, a modest association was found with SNPs in the Toll-like receptor gene TLR10 (p < 1 × 10(-4)). CONCLUSIONS: Alloimmunization in persons with SCD is unlikely to be mediated by loci of very large effect size; however, larger and more comprehensive studies are required to fully evaluate loci with more moderate effects. This study provides a working approach to such future studies in SCD.
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BACKGROUND: The D typing strategies in several European countries protect carriers of D category VI (DVI) from anti-D immunization but not carriers of other partial D. Besides DVI, one of the clinically most important partial D is D category IV (DIV). A detailed description and direct comparison of the different DIV types was missing. STUDY DESIGN AND METHODS: RHD nucleotide sequences were determined from genomic DNA. D epitope patterns were established with commercial monoclonal anti-D panels. RESULTS: DIV comprises several variants of the D antigen with distinct serology, molecular structures, evolutionary origins, and ethnic prevalences. The DIV phenotype is determined by 350H shared by all, but not limited to, DIV variants which are further divided into DIVa and DIVb. The DIVa phenotype is expressed by DIV Type 1.0 harboring 350H and the dispersed amino acids 62F, 137V, and 152T. The DIVb phenotype is expressed by DIV Type 3 to Type 5 representing RHD-CE-D hybrids. Four of the six postulated DIV variants were encountered among 23 DIV samples analyzed. Of 12 DIV carriers with anti-D, 10 were female and seven likely immunized by pregnancy. Two DIV-related alleles are newly described: DWN, which differs from DIV Type 4 by 350D and epitope pattern. DNT carries 152T, known to cause a large D antigen density. CONCLUSION: DIV alleles arose from at least two independent evolutionary events. DIV Type 1.0 with DIVa phenotype belongs to the oldest extant human RHD alleles. DIV Type 2 to Type 5 with DIVb phenotype arose from more recent gene conversions. Anti-D immunization, especially dreaded in pregnancies, will be avoided not only in carriers of DVI but also in carriers of other D variants like DIV, if our proposed D typing strategy is adopted.
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Isoinmunización Rh/genética , Sistema del Grupo Sanguíneo Rh-Hr/clasificación , Sistema del Grupo Sanguíneo Rh-Hr/genética , Adulto , Sustitución de Aminoácidos , Etnicidad/genética , Evolución Molecular , Femenino , Tamización de Portadores Genéticos , Humanos , Masculino , Datos de Secuencia Molecular , Fenotipo , Filogenia , Polimorfismo de Nucleótido Simple , Embarazo , Isoinmunización Rh/etnología , Isoinmunización Rh/inmunología , Sistema del Grupo Sanguíneo Rh-Hr/inmunologíaRESUMEN
BACKGROUND: Variant alleles that do not produce RhCE antigens are rare. Consequently, they pose a challenge to transfusion when found in alloimmunized patients and make blood units valuable when found in donors. STUDY DESIGN AND METHODS: Five index cases and their relatives were studied by both serologic and molecular techniques. Genomic DNA was subjected to microarray genotyping, sequencing, exon scanning, and/or copy number determination assays to identify the RHCE allele(s) responsible for their D+ C- c- E- e- (D- -) phenotype. RESULTS: The five apparent D- - phenotypes were confirmed by molecular methods. Three of them contained unreported RHCE-null alleles, namely, RHCE*Ce-D(3-9)-Ce, RHCE*Ce87_93insT, and RHCE*cE221A. CONCLUSION: Molecular analysis of D- - phenotypes allows the identification of new RHCE-null variants. Conversely, detection of described RHCE-null variants facilitates confirmation of D- - phenotypes in patients and donors, helping improve transfusion safety.
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Variación Genética , Sistema del Grupo Sanguíneo Rh-Hr/genética , Alelos , Femenino , Humanos , Recién Nacido , Masculino , Linaje , Fenotipo , EmbarazoRESUMEN
BACKGROUND: Antibodies to Kell antigens can be clinically important but only limited data are published regarding anti-Ku. Missense nucleotide changes in KEL account for the numerous Kell antigens, the K(mod) phenotype, and even the K(null) phenotype. STUDY DESIGN AND METHODS: DNA and RNA were extracted from white blood cells and polymerase chain reaction-based assays, cloning, and sequencing were done using standard protocols. RESULTS: The anti-Ku in Proband 1, which caused hemolytic disease and anemia of the fetus and newborn, was a mixture of immunoglobulin (Ig)G1 and IgG2 and gave macrophage indexes ranging from 47.8 to 59.3 (>20 is clinically significant) in a monocyte monolayer assay. The proband, her daughter, and compatible sister had a heterozygous deletion of a G in Exon 18 (Nucleotide c.1972_1975delG) in a KEL*02 allele causing a frameshift. The mechanism for silencing of the other KE*02 allele was undetermined. Proband 2 was heterozygous for a nonsense change (KEL*382C/T; Arg128Stop), a missense change (KEL*244T/C; Cys82Arg), and KEL*578T/C (KEL*01/KEL*02). Direct sequencing of cDNA and cloning showed that the KEL*01 allele had 244C, 382C, 578T and the KEL*02 allele carried 244T, 382T, 578C. CONCLUSIONS: We report a novel single-nucleotide deletion, a novel nonsense allele, and a novel missense allele all resulting in the K(null) phenotype. The anti-Ku from Proband 1 was clinically important.
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Alelos , Eritroblastosis Fetal/genética , Sistema del Grupo Sanguíneo de Kell/genética , Mutación Missense , Adulto , Eritroblastosis Fetal/inmunología , Femenino , Silenciador del Gen , Humanos , Indígenas Norteamericanos/genética , Recién Nacido , Sistema del Grupo Sanguíneo de Kell/inmunología , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Fenotipo , EmbarazoRESUMEN
The Jknun (Jk-3) phenotype, attributable to null or silenced alleles, has predominantly been found in persons of Polynesian descent. With the increased use of molecular genotyping, many new silencing mutations have been identified in persons of other ethnic backgrounds. To date, only two JK null alleles have been reported in African Americans, JK*01N.04 and JK*OlN.OS.A comparative study was undertaken to determine whether JK mutations were present in the regional African American population. Results of donor genotyping were compared with previously recorded results of serologic tests, and discrepant results were investigated. Although the two previously identified polymorphisms were not detected in the discrepant samples, a novel allele (191G>A) was identified and was assigned the ISBT number JK*02N.09. This study illustrates a limitation of using single-nucleotide polymorphisms for prediction of blood group antigens.
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Alelos , Negro o Afroamericano/genética , Sistema del Grupo Sanguíneo de Kidd/genética , Técnicas de Genotipaje , Humanos , Sistema del Grupo Sanguíneo de Kidd/metabolismo , Polimorfismo de Nucleótido Simple , Estudios RetrospectivosRESUMEN
BACKGROUND: The Jk(a-b-) null phenotype is not common but is more prevalent in Polynesian and Asian persons and appears to be rare in blacks. We determined the molecular basis for Jk(a-b-) in an African American family. DNA testing of samples from random African American, Caucasian, and Brazilian blacks was done to estimate the allele frequency. STUDY DESIGN AND METHODS: Standard methods were used for red blood cell (RBC) typing. DNA was isolated from white blood cells, and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and amplification and sequencing of the coding regions of JK were performed by routine molecular methods. A MaeIII PCR-RFLP assay was designed to target the nucleotide (nt) change. RESULTS: RBCs from the proband typed as Jk(a-b-) and DNA testing indicated JK*A/JK*A. JK sequencing found that the sample was homozygous for nt561C>A change, predicted to encode a premature stop in the protein (187Stop). The altered allele was present in the heterozygous state in three of six siblings. Testing of 500 African American and 100 Caucasian donors from the same region and 500 African American donors from the southern United States found no additional examples. Screening of 1174 Brazilian blacks revealed seven examples: one homozygote and six heterozygotes. CONCLUSIONS: JK*A (561C>A) is associated with a Kidd-null phenotype in this African American family. The allele was present in approximately one in 168 Brazilian blacks, suggesting that detection of this allele is important to avoid false-positive prediction of Jk(a) status in this population.
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Alelos , Silenciador del Gen , Sistema del Grupo Sanguíneo de Kidd/genética , Negro o Afroamericano , Secuencia de Bases , Femenino , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
BACKGROUND: Complement receptor 1 (CR1) protein carries the Knops blood group antigens and is the receptor for the major ligand involved in Mycobacterium tuberculosis (Mtb) adhesion to macrophages. Erythrocyte CR1 binds immune complexes (ICs) formed during Mtb invasion, facilitating their clearance by the host immune system. The occurrence of specific Knops blood group genotypes among African populations was investigated to evaluate their impact on resistance or susceptibility to Mtb infection. STUDY DESIGN AND METHODS: The distribution of the Knops blood group genotypes (McC and Sl) was compared between tuberculosis (TB) patients with confirmed diagnosis of Mtb in isolates and negative controls. Conditional logistic regression was used to access the association between genotypes distribution and susceptibility to Mtb infection. RESULTS: At the McC locus, individuals heterozygous (McC(a) /McC(b) ) were more resistant to Mtb infection (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.22-0.81; p = 0.007). Although less significant, a similar effect was conferred by Sl1/Sl2 genotype (OR, 0.05; 95% CI, 0.28-0.9; p = 0.02). This protective effect was maintained among individuals presenting the McC(b) /Sl2 haplotype (OR, 0.25; 95% CI, 0.08-0.74; p = 0.008). CONCLUSION: Acquisition of McC(b) and Sl2 alleles among African population is correlated with resistance to Mtb infection, adding this bacterium to the list of mechanisms underlying the selection of the Knops blood group polymorphism among these populations.
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Antígenos de Grupos Sanguíneos/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Receptores de Complemento 3b/genética , Tuberculosis/genética , Frecuencia de los Genes , Genotipo , Humanos , Modelos LogísticosRESUMEN
BACKGROUND: MER2 (RAPH1), the only antigen of the RAPH blood group system, is located on the tetraspanin CD151. Only four examples of alloanti-MER2 are known. We report here two new examples of alloanti-MER2, in women of Pakistani and Turkish origin, one of whom showed signs of a hemolytic transfusion reaction (HTR) after transfusion of 3 units of red cells (RBCs). STUDY DESIGN AND METHODS: Standard serologic methods were used. A monocyte monolayer assay (MMA) was used to assess the potential clinical significance of one of the antibodies. All exons and flanking intronic sequences of CD151 were amplified and sequenced. A homology model for CD151 second extracellular loop (EC2) was constructed based on the crystal structure of CD81. RESULTS: RBCs of both patients did not react with alloanti-MER2, and neither of their antibodies reacted with MER2-negative RBCs. The MMA results suggested that the antibody that appeared to have caused an HTR had the potential to be clinically significant. Both patients were homozygous for a 511C>T mutation in CD151 encoding an Arg171Cys change. This change did not result in any significant structural rearrangement in the protein model. CONCLUSIONS: Two MER2-negative patients with anti-MER2 are homozygous for the same novel mutation encoding an amino acid substitution in the EC2 of CD151. One of the antibodies may have been responsible for an HTR, and crossmatch-compatible RBCs should be recommended for transfusion to patients with anti-MER2.
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Antígenos CD/genética , Antígenos de Grupos Sanguíneos/genética , Mutación , Anciano de 80 o más Años , Antígenos CD/química , Antígenos CD/metabolismo , Antígenos de Grupos Sanguíneos/inmunología , Femenino , Humanos , Isoanticuerpos/inmunología , Modelos Moleculares , Polimorfismo Genético , Estructura Secundaria de Proteína , Tetraspanina 24 , Reacción a la TransfusiónRESUMEN
Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between Sl2 and McCb and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.
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Malaria Cerebral/genética , Malaria Cerebral/patología , Polimorfismo Genético , Receptores de Complemento 3b/genética , Talasemia alfa/genética , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Humanos , Lactante , Recién Nacido , Kenia , Masculino , Malí , Modelos EstadísticosRESUMEN
Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1), a major adhesin molecule expressed on Plasmodium-falciparum-infected erythrocytes, interacts with several receptors on endothelial cells and uninfected erythrocytes. This 'stickiness', known as rosetting, is a strategy used by the parasite to remain sequestered in the microvasculature to avoid destruction in the spleen and liver. Erythrocyte rosetting causes obstruction of the blood flow in microcapillaries. Recent data suggest a direct interaction between PfEMP1 and a functional site of complement receptor type 1 (CR1; CD35) on uninfected erythrocytes. Consistent with the hypothesis that CR1 is important in malaria pathogenesis is a 40-70-fold increase in the frequency of two CR1 blood-group antigens (at least one of which might rosette less efficiently) in malaria-exposed African populations. Furthermore, structural differences in erythrocyte CR1 between human and non-human primates are probably explained by the selective pressure of malaria.
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Malaria Falciparum/metabolismo , Proteínas Protozoarias/metabolismo , Receptores de Complemento/metabolismo , Animales , Sitios de Unión/genética , Sitios de Unión/inmunología , Adhesión Celular , Humanos , Modelos Moleculares , Plasmodium falciparum/citología , Plasmodium falciparum/inmunología , Polimorfismo Genético , Receptores de Complemento/genética , Receptores Inmunológicos/metabolismoRESUMEN
BACKGROUND: It has been hypothesized that the African alleles Sl2 and McCb of the Swain-Langley (Sl) and McCoy (McC) blood group antigens of the complement receptor 1 (CR1) may confer a survival advantage in the setting of Plasmodium falciparum malaria, but this has not been demonstrated. METHODS: To test this hypothesis, children in western Kenya with severe malaria-associated anaemia or cerebral malaria were matched to symptomatic uncomplicated malaria controls by age and gender. Swain-Langley and McCoy blood group alleles were determined by restriction fragment length polymorphism and conditional logistic regression was carried out. RESULTS: No significant association was found between the African alleles and severe malaria-associated anaemia. However, children with Sl2/2 genotype were less likely to have cerebral malaria (OR = 0.17, 95% CI 0.04 to 0.72, P = 0.02) than children with Sl1/1. In particular, individuals with Sl2/2 McC(a/b) genotype were less likely to have cerebral malaria (OR = 0.18, 95% CI 0.04 to 0.77, P = 0.02) than individuals with Sl1/1 McC(a/a). CONCLUSION: These results support the hypothesis that the Sl2 allele and, possibly, the McCb allele evolved in the context of malaria transmission and that in certain combinations probably confer a survival advantage on these populations.
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Predisposición Genética a la Enfermedad , Malaria Falciparum/genética , Polimorfismo Genético , Receptores de Complemento/genética , Preescolar , Femenino , Genotipo , Humanos , Lactante , Kenia , Modelos Logísticos , Malaria Cerebral/genética , Masculino , Oportunidad Relativa , Factores de RiesgoRESUMEN
BACKGROUND: Aberrant and non-functional RHD alleles are much more frequent in Africans than in Europeans. The DAU cluster of RHD alleles exemplifies that the alleles frequent in Africans have evaded recognition until recently. A comprehensive survey of RHD alleles in any African population was lacking. RESULTS: We surveyed the molecular structure and frequency of RHD alleles in Mali (West Africa) by evaluating 116 haplotypes. Only 69% could be attributed to standard RHD (55%) or the RHD deletion (14%). The aberrant RHD allele DAU-0 was predicted for 19%, RHDPsi for 7% and Ccdes for 4% of all haplotypes. DAU-3 and the new RHD allele RHD(L207F), dubbed DMA, were found in one haplotype each. A PCR-RFLP for the detection of the hybrid Rhesus box diagnostic for the RHD deletion in Europeans was false positive in 9 individuals, including all carriers of RHDPsi. Including two silent mutations and the RHD deletion, a total of 9 alleles could be differentiated. CONCLUSION: Besides standard RHD and the RHD deletion, DAU-0, RHDPsi and Ccdes are major alleles in Mali. Our survey proved that the most frequent alleles of West Africans have been recognized allowing to devise reliable genotyping and phenotyping strategies.
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Población Negra/genética , Frecuencia de los Genes , Sistema del Grupo Sanguíneo Rh-Hr/genética , Alelos , Secuencia de Bases , Haplotipos , Humanos , Malí/etnología , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción , Eliminación de SecuenciaAsunto(s)
Transfusión Sanguínea , Proteínas del Sistema Complemento/inmunología , Inmunoglobulinas/inmunología , Especificidad de Anticuerpos , Complejo Antígeno-Anticuerpo , Activación de Complemento , Humanos , Inmunoglobulina G/inmunología , Inmunoglobulina M/inmunología , Inmunoglobulinas/química , Inmunoglobulinas/clasificaciónRESUMEN
Complement receptor one (CR1) is essential for removing circulating immune complexes (CIC), with malaria infection contributing to the formation of large amounts of CIC. We investigated CIC levels in children with malaria, of varying severity and seasonality. Two hundred age and sex-matched severe and mild malaria cases were studied during and after active disease. Pediatric controls had increased CIC levels (mean = 32 µg mEq/mL) compared to adult controls (mean = 26.9 µg mEq/mL). The highest levels of CIC were reported in severe malaria (mean = 39 µg mEq/mL). Higher levels of CIC were recorded in younger children and those with low E-CR1 copy numbers. Our data suggest that low levels of E-CR1 copy numbers, found in children with severe malaria, may adversely affect the ability to remove IC. Furthermore, the high background for circulating immune complex imply that Malian children are under constant assault by other pathogens that evoke a strong immune response.