RESUMEN
The dimeric architecture of tandem-repeat type galectins, such as galectin-4 (Gal-4), modulates their biological activities, although the underlying molecular mechanisms have remained elusive. Emerging evidence show that tandem-repeat galectins play an important role in innate immunity by recognizing carbohydrate antigens present on the surface of certain pathogens, which very often mimic the structures of the human self-glycan antigens. Herein, we have analyzed the binding preferences of the C-domain of Gal-4 (Gal-4C) toward the ABH-carbohydrate histo-blood antigens with different core presentations and their recognition features have been rationalized by using a combined experimental approach including NMR, solid-phase and hemagglutination assays, and molecular modeling. The data show that Gal-4C prefers A over B antigens (two-fold in affinity), contrary to the N-domain (Gal-4N), although both domains share the same preference for the type-6 presentations. The behavior of the full-length Gal-4 (Gal-4FL) tandem-repeat form has been additionally scrutinized. Isothermal titration calorimetry and NMR data demonstrate that both domains within full-length Gal-4 bind to the histo-blood antigens independently of each other, with no communication between them. In this context, the heterodimeric architecture does not play any major role, apart from the complementary A and B antigen binding preferences. However, upon binding to a bacterial lipopolysaccharide containing a multivalent version of an H-antigen mimetic as O-antigen, the significance of the galectin architecture was revealed. Indeed, our data point to the linker peptide domain and the F-face of the C-domain as key elements that provide Gal-4 with the ability to cross-link multivalent ligands, beyond the glycan binding capacity of the dimer.
Asunto(s)
Galectina 4 , Lipopolisacáridos , Oligosacáridos , Humanos , Lipopolisacáridos/química , Galectina 4/metabolismo , Galectina 4/química , Oligosacáridos/química , Oligosacáridos/metabolismo , Multimerización de Proteína , Unión Proteica , Sistema del Grupo Sanguíneo ABO/química , Sistema del Grupo Sanguíneo ABO/metabolismo , Dominios ProteicosRESUMEN
Although immune tolerance evolved to reduce reactivity with self, it creates a gap in the adaptive immune response against microbes that decorate themselves in self-like antigens. This is particularly apparent with carbohydrate-based blood group antigens, wherein microbes can envelope themselves in blood group structures similar to human cells. In this study, we demonstrate that the innate immune lectin, galectin-4 (Gal-4), exhibits strain-specific binding and killing behavior towards microbes that display blood group-like antigens. Examination of binding preferences using a combination of microarrays populated with ABO(H) glycans and a variety of microbial strains, including those that express blood group-like antigens, demonstrated that Gal-4 binds mammalian and microbial antigens that have features of blood group and mammalian-like structures. Although Gal-4 was thought to exist as a monomer that achieves functional bivalency through its two linked carbohydrate recognition domains, our data demonstrate that Gal-4 forms dimers and that differences in the intrinsic ability of each domain to dimerize likely influences binding affinity. While each Gal-4 domain exhibited blood group-binding activity, the C-terminal domain (Gal-4C) exhibited dimeric properties, while the N-terminal domain (Gal-4N) failed to similarly display dimeric activity. Gal-4C not only exhibited the ability to dimerize but also possessed higher affinity toward ABO(H) blood group antigens and microbes expressing glycans with blood group-like features. Furthermore, when compared to Gal-4N, Gal-4C exhibited more potent antimicrobial activity. Even in the context of the full-length protein, where Gal-4N is functionally bivalent by virtue of Gal-4C dimerization, Gal-4C continued to display higher antimicrobial activity. These results demonstrate that Gal-4 exists as a dimer and exhibits its antimicrobial activity primarily through its C-terminal domain. In doing so, these data provide important insight into key features of Gal-4 responsible for its innate immune activity against molecular mimicry.
Asunto(s)
Galectina 4 , Humanos , Galectina 4/metabolismo , Dominios Proteicos , Unión Proteica , Multimerización de Proteína , Antígenos de Grupos Sanguíneos/metabolismo , Escherichia coli/metabolismo , Antiinfecciosos/farmacología , Sistema del Grupo Sanguíneo ABO/metabolismo , Sistema del Grupo Sanguíneo ABO/inmunologíaRESUMEN
Glycoside hydrolases (GHs) have been employed for industrial and biotechnological purposes and often play an important role in new applications. The red blood cell (RBC) antigen system depends on the composition of oligosaccharides on the surface of erythrocytes, thus defining the ABO blood type classification. Incorrect blood transfusions may lead to fatal consequences, making the availability of the correct blood group critical. In this regard, it has been demonstrated that some GHs may be helpful in the conversion of groups A and B blood types to produce group O universal donor blood. GHs belonging to the GH109 family are of particular interest for this application due to their ability to convert blood from group A to group O. This work describes the biochemical characterisation of three novel GH109 enzymes (NAg68, NAg69 and NAg71) and the exploration of their ability to produce enzymatically converted RBCs (ECO-RBC). The three enzymes showed superior specificity on pNP-α-N-acetylgalactosamine compared to previously reported GH109 enzymes. These novel enzymes were able to act on purified antigen-A trisaccharides and produce ECO-RBC from human donor blood. NAg71 converted type A RBC to group O with increased efficiency in the presence of dextran compared to a commercially available GH109, previously used for this application.
Asunto(s)
Eritrocitos , Donantes de Tejidos , Humanos , Eritrocitos/metabolismo , Glicósido Hidrolasas/metabolismo , Oligosacáridos , Biotecnología , Sistema del Grupo Sanguíneo ABO/análisis , Sistema del Grupo Sanguíneo ABO/química , Sistema del Grupo Sanguíneo ABO/metabolismoRESUMEN
A- and B-antigens are present on red blood cells (RBCs) as well as other cells and secretions in Hominoidea including humans and apes such as chimpanzees and gibbons, whereas expression of these antigens on RBCs is subtle in monkeys such as Japanese macaques. Previous studies have indicated that H-antigen expression has not completely developed on RBCs in monkeys. Such antigen expression requires the presence of H-antigen and A- or B-transferase expression in cells of erythroid lineage, although whether or not ABO gene regulation is associated with the difference of A- or B-antigen expression between Hominoidea and monkeys has not been examined. Since it has been suggested that ABO expression on human erythrocytes is dependent upon an erythroid cell-specific regulatory region or the + 5.8-kb site in intron 1, we compared the sequences of ABO intron 1 among non-human primates, and demonstrated the presence of sites orthologous to the + 5.8-kb site in chimpanzees and gibbons, and their absence in Japanese macaques. In addition, luciferase assays revealed that the former orthologues enhanced promoter activity, whereas the corresponding site in the latter did not. These results suggested that the A- or B-antigens on RBCs might be ascribed to emergence of the + 5.8-kb site or the corresponding regions in ABO through genetic evolution.
Asunto(s)
Hylobates , Pan troglodytes , Animales , Intrones/genética , Pan troglodytes/genética , Hylobates/genética , Macaca fuscata , Sistema del Grupo Sanguíneo ABO/genética , Sistema del Grupo Sanguíneo ABO/metabolismo , Células Eritroides/metabolismo , Secuencias Reguladoras de Ácidos Nucleicos , Eritrocitos/metabolismo , Primates/genética , Antígenos/metabolismoRESUMEN
We conducted a case-control study in order to evaluate whether ABO gene polymorphisms were associated with a high risk of developing COVID-19 in a cohort of patients. Six ABO gene polymorphisms (rs651007 T/C, rs579459 T/C, rs495828 T/G, rs8176746 A/C, rs8176740 T/A, and rs512770 T/C) were determined using TaqMan genotyping assays in a group of 415 COVID-19 patients and 288 healthy controls. The distribution of rs651007 T/C, rs579459 T/C, rs495828 T/G, and rs8176746 A/C polymorphisms was similar in patients and healthy controls. Nonetheless, under co-dominant (OR = 1.89, pCCo-dominant = 6 × 10-6), recessive (OR = 1.98, pCRecessive = 1 × 10-4), and additive (OR = 1.36, pCAdditive = 3 × 10-3) models, the TT genotype of the rs8176740 T/A polymorphism increased the risk of developing COVID-19. In the same way, under co-dominant, recessive, and additive models, the TT genotype of the rs512770 T/C polymorphism was associated with a high risk of developing COVID-19 (OR = 1.87, pCCo-dominant = 2 × 10-3; OR = 1.87, pCRecessive = 5 × 10-4; and OR = 1.35, pCAdditive = 4 × 10-3, respectively). On the other hand, the GTC and GAT haplotypes were associated with a high risk of COVID-19 (OR = 5.45, pC = 1 × 10-6 and OR = 6.33, pC = 1 × 10-6, respectively). In addition, the rs8176740 TT genotype was associated with high-platelet plasma concentrations in patients with COVID-19. Our data suggested that the ABO rs512770 T/C and rs8176740 T/A polymorphisms increased the risk of developing COVID-19 and the plasma concentration of platelets.
Asunto(s)
Sistema del Grupo Sanguíneo ABO , COVID-19 , Galactosiltransferasas , Predisposición Genética a la Enfermedad , Sistema del Grupo Sanguíneo ABO/genética , Sistema del Grupo Sanguíneo ABO/metabolismo , Plaquetas , COVID-19/genética , Estudios de Casos y Controles , Galactosiltransferasas/genética , Galactosiltransferasas/metabolismo , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
Beside the role of ABO group in immunohaematology, there is accumulating evidence that the ABO blood group also plays a key role in various human disorders. The interest in blood groups and their association with disease stems from the awareness that blood group antigens are incredibly important components in the process of cell maturation and control. Studies have indicated a link between cancer and the ABO blood group. The appearance or disappearance of blood type antigens is now considered a hallmark of malignancy in many common cancers. Several tumour markers are in fact known blood group antigens. The aim of this review is to describe the history and possible functions of the ABO group and then summarize the association between blood groups and skin cancers.
Asunto(s)
Sistema del Grupo Sanguíneo ABO , Neoplasias Cutáneas , Sistema del Grupo Sanguíneo ABO/metabolismo , Biomarcadores de Tumor , HumanosRESUMEN
The main categories of glycan changes in cancer are: (1)â decreased expression of histo-blood group A and/or B antigens and increased Lewis-related antigens, (2)â appearance of cryptic antigens, such as Tn and T, (3)â emergence of genetically incompatible glycans, such as A antigen expressed in tumors of individuals of group B or O and heterophilic expression of Forssman antigen (FORS1), and (4)â appearance of neoglycans. This review focuses on the expression of genetically incompatible A/B/FORS1 antigens in cancer. Several possible molecular mechanisms are exemplified, including missense mutations that alter the sugar specificity of A and B glycosyltransferases (AT and BT, respectively), restoration of the correct codon reading frame of O alleles, and modification of acceptor specificity of AT to synthesize the FORS1 antigen by missense mutations and/or altered splicing. Taking advantage of pre-existing natural immunity, the potential uses of these glycans for immunotherapeutic targeting will also be discussed.
Asunto(s)
Glicosiltransferasas , Neoplasias , Sistema del Grupo Sanguíneo ABO/metabolismo , Glicosiltransferasas/genética , Glicosiltransferasas/metabolismo , Humanos , Neoplasias/terapia , Polisacáridos , AzúcaresRESUMEN
Personal identification of two individuals in mixed semen samples in forensic DNA testing in general usually involves analysis using autosomal and Y chromosome short tandem repeats (STRs). Results may exclude unrelated donors but cannot identify individuals. In this study, sperm cell capture based on ABH antigen differences was used to obtain the cells with the single ABO blood type. Immunohistochemical staining using labeled anti-A, anti-B, and anti-H antibodies and the laser microdissection system can be used to enrich sperm with different ABO types in mixed seminal stains from two individuals. Then, PCR amplification and capillary electrophoresis were performed to genotype the STR loci. To some extent, after sperm cell capture based on ABH antigen differences, autosomal STR typing using enriched single blood group cells can be utilized to partially identify different individuals in a mixed seminal stain sample from two individuals.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/metabolismo , Antígenos/metabolismo , Colorantes/metabolismo , Semen/metabolismo , Espermatozoides/metabolismo , Sistema del Grupo Sanguíneo ABO/genética , Antígenos/genética , ADN/genética , ADN/metabolismo , Dermatoglifia del ADN/métodos , Genotipo , Humanos , Captura por Microdisección con Láser/métodos , Masculino , Repeticiones de Microsatélite/genética , Coloración y Etiquetado/métodosRESUMEN
The establishment of a hyperacute rejection (HAR) model of ABO-incompatible kidney transplantation (ABOi-KTx) in nonhuman primates is of great significance for the study of the relevant clinical pathophysiological processes and related interventions in ABOi-KTx. In this study, blood group B cynomolgus monkeys were presensitized with synthetic blood group A-antigen conjugated to keyhole limpet hemocyanin (A-KLH) to boost circulating anti-A antibody levels. The serum anti-A antibody levels were measured by flow cytometry using type A human reagent red blood cells (RBCs) or monkey primary renal tubular epithelial cells (RTECs) as target cells. ABOi-KTx was performed in type B monkeys using type A monkeys as donors. After 14 days of A-KLH sensitization, 12 of 16 (75%) type B monkeys had significantly elevated anti-A antibody levels. We found that in order to avoid irregular results in the detection of blood group antibodies by flow cytometry, it was more effective to use RTECs rather than RBCs as target cells. In the absence of presensitization, ABOi-KTx in three monkeys with relatively high levels of natural anti-A antibodies did not produce HAR. However, when four Type B monkeys with significantly increased anti-A antibodies after presensitization were randomly selected as recipients for ABOi-KTx, the allografts in all four monkeys developed HAR with typical pathologic characteristics. Thus, we have successfully established a monkey model of HAR in ABOi-KTx via blood group antigen presensitization, which will be helpful for the further study of rejection, accommodation, and clinical intervention in ABOi-KTx.
Asunto(s)
Incompatibilidad de Grupos Sanguíneos/inmunología , Modelos Animales de Enfermedad , Rechazo de Injerto/etiología , Trasplante de Riñón , Primates , Sistema del Grupo Sanguíneo ABO/inmunología , Sistema del Grupo Sanguíneo ABO/metabolismo , Enfermedad Aguda , Animales , Biomarcadores , Biopsia , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/prevención & control , Humanos , Inmunohistoquímica , Inmunofenotipificación , Inmunosupresores/uso terapéutico , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Trasplante HomólogoRESUMEN
BACKGROUND: Currently, research on the quantitative distribution of ABO antigens in different organs and tissues remains limited. We aimed to examine the individual characteristics of blood group glycoprotein A and B antigen expression in human kidneys and livers. METHODS: We obtained human samples, including the renal artery, renal vein, renal tissue, hepatic artery, hepatic vein, portal vein, and hepatic tissue, from 24 deceased organ transplant donors. The expression of the blood group antigens glycoprotein A and B was analysed and compared by Western blotting. RESULTS: There was no significant difference in the expression between blood group glycoprotein A and B antigens at any of the seven sites (p > 0.05). The expression of both A and B antigens was highest in renal tissue and the portal vein and was lowest in the renal artery. A large difference in glycoprotein antigen expression was observed among various donors or different regions of the same individual. Univariate analysis revealed that glycoprotein A/B antigens were affected by the age and sex of donors and were significantly higher in males and in young people. CONCLUSIONS: Our study found that blood group glycoprotein antigen expression showed certain trends and distinct distribution in the kidney, liver, and vessels among individuals and in different regions of the same individual, which may explain the different clinical outcomes of patients who received ABO-incompatible transplantation.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/metabolismo , Factores de Edad , Riñón/metabolismo , Hígado/metabolismo , Trasplante de Órganos , Arteria Renal/metabolismo , Factores Sexuales , Histocompatibilidad , Humanos , Riñón/patología , Masculino , Especificidad de Órganos , Especificidad de la Especie , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: There are few published researches on blood groups, hematological parameters [hemoglobin, red cell distribution width (RDW), white blood cells (WBCs), mean platelets volume (MPV)] and gestational diabetes mellitus (GDM). The aim of this study was to investigate the association of haematological indices with GDM in early pregnancy. METHODS: The study was carried out at Saad Abuelela Hospital (Khartoum, Sudan) during March-November of 2018. Pregnant Sudanese women in early pregnancy (gestational age <14 weeks) were enrolled in the study. The details of the medical and obstetrics history were recorded. The women were then followed up until 24-28 weeks of gestation when a 75-gram oral glucose tolerance test was performed. RESULTS: Two hundred and fifty-three women at 10.2 week of gestational age completed the follow-up. The mean (SD) of the age and gravidity at the initial antenatal visit were 28.03 (5.6) years, 2.32 (2.41). The mean (SD) of body mass index (BMI) was 27.28 (24.41-30.80) kg/m2. Fifty women (19.8%) had GDM. Age, parity, BMI, place of residence, employment and education were not significantly different between the two groups. Moreover, there was no significant difference in the blood groups and hematological parameters between women with and without GDM. CONCLUSION: In this study, the blood groups and other hematological parameters were not different between women with and without GDM.
Asunto(s)
Antígenos de Grupos Sanguíneos/análisis , Diabetes Gestacional/sangre , Diabetes Gestacional/metabolismo , Sistema del Grupo Sanguíneo ABO/genética , Sistema del Grupo Sanguíneo ABO/metabolismo , Adulto , Glucemia , Antígenos de Grupos Sanguíneos/genética , Antígenos de Grupos Sanguíneos/metabolismo , Índice de Masa Corporal , Ayuno/sangre , Femenino , Edad Gestacional , Prueba de Tolerancia a la Glucosa , Pruebas Hematológicas/métodos , Humanos , Embarazo , Primer Trimestre del Embarazo/sangre , Factores de Riesgo , SudánRESUMEN
COVID-19 is the currently evolving viral disease worldwide. It mainly targets the respiratory organs, tissues and causes illness. A plethora of studies has been performing to bring proper treatment and prevent people from the infection. Likewise, susceptibility to some infectious diseases has been associated with blood group phenotypes. The co-relationship of blood group with the occurrence of SARS-CoV-2 infection and death has been examined in numerous studies. This review explained the described studies regarding the correlation of blood group and the other essential factors with COVID-19.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/genética , COVID-19/epidemiología , COVID-19/etiología , Susceptibilidad a Enfermedades , Fenotipo , SARS-CoV-2 , Sistema del Grupo Sanguíneo ABO/química , Sistema del Grupo Sanguíneo ABO/inmunología , Sistema del Grupo Sanguíneo ABO/metabolismo , Coronavirus/clasificación , Coronavirus/inmunología , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Unión Proteica , Receptores Virales/química , Receptores Virales/metabolismo , SARS-CoV-2/inmunología , SARS-CoV-2/fisiología , Relación Estructura-Actividad , Tromboplastina/metabolismo , Factor de von Willebrand/metabolismoRESUMEN
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide as a pandemic throughout 2020. Since the virus uses angiotensin-converting enzyme 2 (ACE2) as a receptor for cellular entry, increment of ACE2 would lead to an increased risk of SARS-CoV-2 infection. At the same time, an association of the ABO blood group system with COVID-19 has also been highlighted: there is increasing evidence to suggest that non-O individuals are at higher risk of severe COVID-19 than O individuals. These findings imply that simultaneous suppression of ACE2 and ABO would be a promising approach for prevention or treatment of COVID-19. Notably, we have previously clarified that histone deacetylase inhibitors (HDACIs) are able to suppress ABO expression in vitro. Against this background, we further evaluated the effect of HDACIs on cultured epithelial cell lines, and found that HDACIs suppress both ACE2 and ABO expression simultaneously. Furthermore, the amount of ACE2 protein was shown to be decreased by one of the clinically-used HDACIs, panobinostat, which has been reported to reduce B-antigens on cell surfaces. On the basis of these findings, we conclude that panobinostat could have the potential to serve as a preventive drug against COVID-19.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/metabolismo , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Panobinostat/farmacología , Ácido Butírico/farmacología , COVID-19/prevención & control , Línea Celular , Células Epiteliales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Serina Endopeptidasas , Tratamiento Farmacológico de COVID-19RESUMEN
SARS-CoV-2 is responsible for the coronavirus disease 2019 (COVID-19) and the current health crisis. Despite intensive research efforts, the genes and pathways that contribute to COVID-19 remain poorly understood. We, therefore, used an integrative genomics (IG) approach to identify candidate genes responsible for COVID-19 and its severity. We used Bayesian colocalization (COLOC) and summary-based Mendelian randomization to combine gene expression quantitative trait loci (eQTLs) from the Lung eQTL (n = 1,038) and eQTLGen (n = 31,784) studies with published COVID-19 genome-wide association study (GWAS) data from the COVID-19 Host Genetics Initiative. Additionally, we used COLOC to integrate plasma protein quantitative trait loci (pQTL) from the INTERVAL study (n = 3,301) with COVID-19 loci. Finally, we determined any causal associations between plasma proteins and COVID-19 using multi-variable two-sample Mendelian randomization (MR). The expression of 18 genes in lung and/or blood co-localized with COVID-19 loci. Of these, 12 genes were in suggestive loci (PGWAS < 5 × 10-05). LZTFL1, SLC6A20, ABO, IL10RB and IFNAR2 and OAS1 had been previously associated with a heightened risk of COVID-19 (PGWAS < 5 × 10-08). We identified a causal association between OAS1 and COVID-19 GWAS. Plasma ABO protein, which is associated with blood type in humans, demonstrated a significant causal relationship with COVID-19 in the MR analysis; increased plasma levels were associated with an increased risk of COVID-19 and, in particular, severe COVID-19. In summary, our study identified genes associated with COVID-19 that may be prioritized for future investigations. Importantly, this is the first study to demonstrate a causal association between plasma ABO protein and COVID-19.
Asunto(s)
Proteínas Sanguíneas/metabolismo , COVID-19/epidemiología , Predisposición Genética a la Enfermedad , Pulmón/metabolismo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , SARS-CoV-2/aislamiento & purificación , Sistema del Grupo Sanguíneo ABO/metabolismo , COVID-19/metabolismo , COVID-19/virología , Estudios de Cohortes , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Factores de RiesgoRESUMEN
BACKGROUND: Both ABO blood group antigens and pathogenic immunoglobulin A1 (IgA1) in patients with IgA nephropathy (IgAN) are influenced by modifications of N-acetylgalactosamine and galactose. The purpose of this study was to assess whether ABO blood type is associated with galactose-deficient IgA1 (Gd-IgA1) in the progression of kidney disease in patients with IgAN. METHODS: We enrolled 1313 IgAN patients with a median of 44 months follow-up and measured the plasma Gd-IgA1 levels. Multivariate Cox regression models were used to estimate the association between all variables and adverse outcomes. Using the propensity score matching method, 718 IgAN patients with blood type either A or B were selected, and their data were used to assess the association of blood type and Gd-IgA1/serum complement 3 (sC3) with outcomes. RESULTS: We found that the risk of adverse outcomes was significantly higher in patients with blood type A than in those with type B (hazard ratio = 1.82, 95% confidence interval 1.23-2.71; P = 0.003) after multivariate adjustment. The Gd-IgA1 levels showed trends similar to the multivariate-adjusted event-free curves for the blood types. However, this higher risk of adverse outcomes in type A than in type B patients was no longer significant after the addition of Gd-IgA1/sC3 to the model. CONCLUSIONS: IgAN patients with blood type A had a higher risk of adverse outcomes than those with type B, and this risk was associated with Gd-IgA1/sC3. Thus, the ABO blood type may provide a reference for the prognostic factors for individuals with IgAN.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/metabolismo , Galactosa/deficiencia , Tasa de Filtración Glomerular , Glomerulonefritis por IGA/complicaciones , Inmunoglobulina A/sangre , Proteinuria/patología , Adulto , Femenino , Humanos , Masculino , Pronóstico , Proteinuria/etiología , Estudios RetrospectivosRESUMEN
BACKGROUND: The amino acid substitutions caused by ABO gene variants are usually predicted to impact the glycosyltransferase function. Here, the effect of an amino acid substitution in the vicinity of the catalytic active region of the B-glycosyltransferase was explored in vitro and in silico study, which is important for further recognizing the ABO subgroup. METHODS: The ABO serological tests were performed by the routine methods. The ABO genotype was analyzed by polymerase chain reaction and sequenced bidirectionally. The haplotype of the variant allele was separated using single-strand amplification and sequencing with allele-specific primers. Stably expression cell lines with variant were constructed for study in vitro. 3D structure of the B-glycosyltransferase (GTB) variant was simulated by PyMOL software. The free energy change (ΔΔG) was calculated by FoldX. RESULTS: A variant c.737A > G was identified in a Chinese individual with Bweak phenotype, which led to an amino acid substitution p.Y246C in the vicinity of the catalytic active region of GTB enzyme. The stably expression cell lines with variant and wild type were successfully established and showed that the variant caused a decrease in protein levels and/or enzyme activity. The 3D structural of the GTB modelling found the amino acid substitution p.Y246C caused the hydrogen bond of the protein changes. Meanwhile, the free energy change (ΔΔG) value predicted the destabilizing effect on the variant GTB. DISCUSSION: The p.Y246C variant in the vicinity of the enzyme active centre reduced the antigen expression because of greatly destabilizing effect on the GTB variant.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/genética , Galactosiltransferasas/genética , Modelos Moleculares , Mutación Missense , Fenotipo , Sistema del Grupo Sanguíneo ABO/metabolismo , Adulto , Alelos , Sustitución de Aminoácidos , Pueblo Asiatico/genética , Dominio Catalítico , Simulación por Computador , Femenino , Galactosiltransferasas/metabolismo , Haplotipos , Humanos , Embarazo , Conformación ProteicaRESUMEN
OBJECTIVE: Major ABO incompatible hematopoietic progenitors from bone marrow (HPC(M)) donor collections that are destined for clinical transplantation are typically processed to deplete products of red blood cells (RBCs). The purpose of this study was to compare RBC depletion when using the Spectra Optia® relative to a 2-step method involving a COBE2991 instrument to obtain a buffy coat followed by a hydroxyethyl starch (HES) density gradient (COBE+HES) of the buffy coat. METHODS: Post-processing recoveries of products undergoing 4, 8, and 10 bone marrow processing (BMP) cycles (i.e. 1 cycle=1 volume of HPC(M)) with the Spectra Optia® were determined for volume, RBC content, viable total nucleated cells (vTNC), viable CD34+ cells (vCD34), viable CD3+ cells (vCD3) and colony-forming-cells (CFC). Subsequent RBC depletions with Spectra Optia® were then performed with 10 BMP cycles on additional HPC(M) collections and were compared against a retrospective analysis of historical COBE+HES post-processing data. RESULTS: Ten BMP cycles of HPC(M) (n=6) products were identified as optimal with volume reductions of 81.3±1.6 % and RBC reductions of 97.0±0.6 % with the Spectra Optia®. This also resulted in an average of 0.28 ±0.14 mL of RBC/kg (mean±SD; n=6) with vTNC yields of 65.0±10.9%, vCD34+ yields of 98.5±12.7%, and vCD3+ yields of 90.6±10.0%. Recoveries with the COBE+HES methodology resulted in vTNC recoveries of 62.9±20.5% (mean±SD; n=30) and 0.63±0.71 mL of RBC/kg (mean±SD; n=30). CONCLUSIONS: The Spectra Optia® is a viable option for depleting HPC(M) harvests of contaminating RBC in situations of ABO incompatibility. Target cells from a MNC rich fractionation were preserved through processing while eliminating RBC contaminants.
Asunto(s)
Eliminación de Componentes Sanguíneos/métodos , Eritrocitos/inmunología , Células Madre Hematopoyéticas/metabolismo , Sistema del Grupo Sanguíneo ABO/metabolismo , Médula Ósea/inmunología , Médula Ósea/metabolismo , Trasplante de Médula Ósea/métodos , Separación Celular/métodos , Voluntarios Sanos , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/inmunología , Células Madre Hematopoyéticas/patología , Humanos , Estudios Retrospectivos , Donantes de TejidosRESUMEN
Understanding the genetic architecture of host proteins interacting with SARS-CoV-2 or mediating the maladaptive host response to COVID-19 can help to identify new or repurpose existing drugs targeting those proteins. We present a genetic discovery study of 179 such host proteins among 10,708 individuals using an aptamer-based technique. We identify 220 host DNA sequence variants acting in cis (MAF 0.01-49.9%) and explaining 0.3-70.9% of the variance of 97 of these proteins, including 45 with no previously known protein quantitative trait loci (pQTL) and 38 encoding current drug targets. Systematic characterization of pQTLs across the phenome identified protein-drug-disease links and evidence that putative viral interaction partners such as MARK3 affect immune response. Our results accelerate the evaluation and prioritization of new drug development programmes and repurposing of trials to prevent, treat or reduce adverse outcomes. Rapid sharing and detailed interrogation of results is facilitated through an interactive webserver ( https://omicscience.org/apps/covidpgwas/ ).
Asunto(s)
COVID-19/genética , COVID-19/virología , Interacciones Huésped-Patógeno/genética , Proteínas/genética , SARS-CoV-2/fisiología , Sistema del Grupo Sanguíneo ABO/metabolismo , Aptámeros de Péptidos/sangre , Aptámeros de Péptidos/metabolismo , Coagulación Sanguínea , Sistemas de Liberación de Medicamentos , Femenino , Regulación de la Expresión Génica , Factores Celulares Derivados del Huésped/metabolismo , Humanos , Internet , Masculino , Persona de Mediana Edad , Sitios de Carácter Cuantitativo/genéticaRESUMEN
ABH antigens are histo-antigens, but were first described on the surface of human erythrocytes. They are found in those cells only in great apes and humans, while in more primitive animals they are found in tissues and body fluids. ABH antigens are mainly distributed in tissues that are in contact with the external environment and may serve as ligands for pathogens in tissues or block their connection. Description of the distribution of these molecules in non-human primate tissues is restricted to a few tissues and species. This paper describes the expression of human A, B and H type antigens in different organs from four species of New World Primates, obtained from the Centro Nacional de Primatas, as well as comparing that expression with what has been described for humans. In this study, although the tissue description of the antigens is similar to the genetic model for humans, some differences in expression between some organs from those species and those of humans were found. The differences occurred mainly in endodermal organs that have secretory functions and are probably under the control of the human-type FUT-2 enzyme. In the mesodermal-origin organs there was a reduction or absence of A and B antigen marking, particularly in the H precursor substance, indicating that those organs are under the control of the human-type FUT-1 enzyme. These findings have demonstrated that there is similar ABH antigen reactivity in tissue distribution between the species, although there are some species-specific cases.
Asunto(s)
Sistema del Grupo Sanguíneo ABO/metabolismo , Antígenos/metabolismo , Especificidad de Órganos , Animales , Aotidae , Callithrix , Platirrinos , Saimiri , Sapajus apella , Especificidad de la EspecieRESUMEN
ABO blood group is associated with cardiovascular disease, with significantly lower risk in blood group O individuals. ABO(H) blood group determinants are expressed on different glycoproteins on platelet surfaces. In addition, ABO(H) structures are also present on VWF glycans. These ABO(H) carbohydrates influence both platelet and VWF function. Previous studies have reported that approximately 5-10% of normal blood donors express abnormally high or low levels of A or B blood group antigens on their platelet surfaces (high expresser phenotype, HXP or low expresser phenotype, LXP respectively). In this study, the biological effects of the ABO Expresser phenotype were investigated. ABO(H) expression on platelets and plasma VWF was studied in a series of 541 healthy blood donors. Overall, 5.6% of our study cohort were classified as HXP, whilst 4.4% satisfied criteria for LXP. We demonstrate that genotype at the ABO blood group locus plays a critical role in modulating the platelet HXP phenotype. In particular, A1A1 genotype is a major determinant of ABO high-expresser trait. Our data further show that ABH loading on VWF is also affected by ABO expresser phenotype. Consequently, A antigen expression on VWF was significantly elevated in HXP individuals and moderately reduced in LXP subjects (P < 0.05). Collectively, these findings suggest that ABO expresser phenotype influences primary hemostasis though several different pathways. Further studies will be required to define whether inter-individual variations in ABO(H) expression on platelets and/or VWF (particularly HXP and LXP) impact upon risk for cardiovascular disease.