| 1. |
- Nylander, Anja, et al.
(författare)
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An investigation of the interaction between red blood cells and Streptococcus pyogenes
- 2010
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Konferensbidrag (refereegranskat)abstract
- Blood group antigens may be used as receptors by pathogens when infecting their hosts. Different blood groups therefore can be disease susceptibility factors. Thus, pathogens may have exerted a selection pressure on the evolution of blood group diversity. One aim of our study was to identify red blood cell (RBC) membrane structures that are bound by the common human pathogen. Streptococcus pyogenes, responsible for conditions like pharyngitis, Scarlet fever, necrotizing fasciitis and rheumatic heart disease. We also wanted to explore any differences in the ability of S. pyogenes to agglutinate RBC of different ABO groups and of selected null blood group phenotypes.Solubilized RBC membranes were incubated with different strains of S. pyogenes. RBC proteins that bound to bacteria were eluted and separated by SDS-PAGE. In our initial studies, a strong band at ~58 kDa and a weaker band at ~28 kDa were visualized by Coomassie staining. Subsequent analysis by mass spectrometry and Western blotting revealed the bands to correspond to IgG heavy and light chains. The IgG-related bands were strongest for bacterial strains expressing both protein H and M protein, surface structures known to bind IgG, while weaker or no bands were detected in those strains lacking one or both proteins. Results from subsequent experiments indicated that the interaction between S. pyogenes and RBCs was not limited to IgG, but that a number of other RBC membrane structures appear to bind specifically to S. pyogenes. Those proteins are currently being analysed by mass spectrometry.In agglutination studies of S. pyogenes and RBCs, either sensitised with IgG or stripped of IgG we confirmed that IgG has a role in the binding of RBCs by S. pyogenes. We observed no difference in the ability of S. pyogenes to agglutinate RBCs of different ABO groups, indicating that the ABO-specific differences in RBC surface oligosaccharides are not recognized. When we tested a panel of RBCs with rare null phenotypes we found that cells of the Helgeson phenotype, expressing very low levels of the Knops antigens on complement receptor 1 (CR1), agglutinated more weakly than other common and rare RBCs tested.We are still puzzled by the fact that the hemagglutination is stronger for S. pyogenes strains lacking the M-protein, known to bind both complement and IgG on the surface of the bacteria. Our hypothesis is that there might be some repulsive force acting between the M-protein and surface of RBC, making the interaction stronger when the M-protein is missing. This is supported by agglutination studies with papain-treated RBCs, where the negative charge is reduced.IgG is known to bind senescent cell antigens on erythroid band 3 and thus the amount of IgG increases on the RBC surface as it ages. We speculated that binding to IgG on the RBC surface by S. pyogenes could be a way to selectively target aged RBCs, possibly to acquire heme as a source of iron. Attempts to separate RBCs according to age were made on density gradients, followed by agglutination studies of the different fractions. Our initial results did not demonstrate any conclusive differences. Our data indicate that interactions between S. pyogenes and RBC are mediated at least through IgG and CR1 on the RBC surface. The clinical importance awaits exploration but may be relevant in the identification of resistance factors to infections among humans, and could thus lead to the development of alternative ways to treat infections caused by S. pyogenes.
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| 2. |
- Storry, Jill, et al.
(författare)
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Homozygosity for a null allele of SMIM1 defines the Vel-negative blood group phenotype
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 537-U109
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Tidskriftsartikel (refereegranskat)abstract
- The Vel antigen is present on red blood cells (RBCs) from all humans except rare Vel-negative individuals who can form antibodies to Vel in response to transfusion or pregnancy. These antibodies may cause severe hemolytic reactions in blood recipients. We combined SNP profiling and transcriptional network modeling to link the Vel-negative phenotype to SMIM1, located in a 97-kb haplotype block on chromosome 1p36. This gene encodes a previously undiscovered, evolutionarily conserved transmembrane protein expressed on RBCs. Notably, 35 of 35 Vel-negative individuals were homozygous for a frameshift deletion of 17 bp in exon 3. Functional studies using antibodies raised against SMIM1 peptides confirmed a null phenotype in RBC membranes, and SMIM1 overexpression induced Vel expression. Genotype screening estimated that similar to 1 of 17 Swedish blood donors is a heterozygous deletion carrier and similar to 1 of 1,200 is a homozygous deletion knockout and enabled identification of Vel-negative donors. Our results establish SMIM1 as a new erythroid gene and Vel as a new blood group system.
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| 3. |
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| 4. |
- Kristiansson, Amanda, et al.
(författare)
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The Role of α1-Microglobulin (A1M) in Erythropoiesis and Erythrocyte Homeostasis-Therapeutic Opportunities in Hemolytic Conditions
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 21:19, s. 1-21
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Forskningsöversikt (refereegranskat)abstract
- α1-microglobulin (A1M) is a small protein present in vertebrates including humans. It has several physiologically relevant properties, including binding of heme and radicals as well as enzymatic reduction, that are used in the protection of cells and tissue. Research has revealed that A1M can ameliorate heme and ROS-induced injuries in cell cultures, organs, explants and animal models. Recently, it was shown that A1M could reduce hemolysis in vitro, observed with several different types of insults and sources of RBCs. In addition, in a recently published study, it was observed that mice lacking A1M (A1M-KO) developed a macrocytic anemia phenotype. Altogether, this suggests that A1M may have a role in RBC development, stability and turnover. This opens up the possibility of utilizing A1M for therapeutic purposes in pathological conditions involving erythropoietic and hemolytic abnormalities. Here, we provide an overview of A1M and its potential therapeutic effect in the context of the following erythropoietic and hemolytic conditions: Diamond-Blackfan anemia (DBA), 5q-minus myelodysplastic syndrome (5q-MDS), blood transfusions (including storage), intraventricular hemorrhage (IVH), preeclampsia (PE) and atherosclerosis.
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| 5. |
- Goel, Suchi, et al.
(författare)
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RIFINs are adhesins implicated in severe Plasmodium falciparum malaria
- 2015
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 21:4, s. 314-317
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Tidskriftsartikel (refereegranskat)abstract
- Rosetting is a virulent Plasmodium falciparum phenomenon associated with severe malaria. Here we demonstrate that P. falciparum-encoded repetitive interspersed families of polypeptides (RIFINs) are expressed on the surface of infected red blood cells (iRBCs), bind to RBCs-preferentially of blood group A-to form large rosettes and mediate microvascular binding of iRBCs. We suggest that RIFINs have a fundamental role in the development of severe malaria and thereby contribute to the varying global distribution of ABO blood groups in the human population.
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| 6. |
- Svensson, Lola, 1948, et al.
(författare)
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Forssman expression on human erythrocytes: biochemical and genetic evidence of a new histo-blood group system
- 2013
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 121:8, s. 1459-68
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Tidskriftsartikel (refereegranskat)abstract
- Abstract In analogy with histo-blood group A antigen, Forssman (Fs) antigen terminates with α3-N-acetylgalactosamine and can be utilized by pathogens as a host receptor in many mammals. However, primates including humans lack Fs synthase activity and have naturally-occurring Fs antibodies in plasma. We investigated individuals with the enigmatic ABO subgroup Apae and found them to be homozygous for common O alleles. Their erythrocytes had no A antigens but instead expressed Fs glycolipids. The unexpected Fs antigen was confirmed in structural, serological and flowcytometric studies. The Fs synthase gene, GBGT1, in Apae individuals encoded an arginine to glutamine change at residue 296. Gln296 is present in lower mammals whereas Arg296 was found in six other primates, >250 blood donors and Apae family relatives without the Apae phenotype. Transfection experiments and molecular modelling showed that 296Gln reactivates the human Fs synthase. Uropathogenic E.coli containing prsG-adhesin-encoding plasmids agglutinated Apae but not group O cells, suggesting biological implications. Predictive tests for intravascular hemolysis with crossmatch-incompatible sera indicated complement-mediated destruction of Fspositive erythrocytes. Taken together, we provide the first conclusive description of Fs expression in normal human hematopoietic tissue and the basis of a new histo-blood group system in man, FORS.
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| 7. |
- Westman, Julia, et al.
(författare)
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Identification of the Molecular and Genetic Basis of PX2, a Glycosphingolipid Blood Group Antigen Lacking on Globoside-deficient Erythrocytes
- 2015
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 290:30, s. 18505-18518
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Tidskriftsartikel (refereegranskat)abstract
- The x(2) glycosphingolipid is expressed on erythrocytes from individuals of all common blood group phenotypes and elevated on cells of the rare P/P1/P-k-negative p blood group phenotype. Globoside or P antigen is synthesized by UDP-N-acetylgalactosamine: globotriaosyl-ceramide 3-beta-N-acetylgalactosaminyl-transferase encoded by B3GALNT1. It is the most abundant non-acid glycosphingolipid on erythrocytes and displays the same terminal disaccharide, GalNAc beta 3Gal, as x(2). We encountered a patient with mutations in B3GALNT1 causing the rare P-deficient P-1(k) phenotype and whose pretransfusion plasma was unexpectedly incompatible with p erythrocytes. The same phenomenon was also noted in seven other unrelated P-deficient individuals. Thin-layer chromatography, mass spectrometry, and flow cytometry were used to show that the naturally occurring antibodies made by p individuals recognize x(2) and sialylated forms of x(2), whereas x(2) is lacking on P-deficient erythrocytes. Overexpression of B3GALNT1 resulted in synthesis of both P and x(2). Knockdown experiments with siRNA against B3GALNT1 diminished x(2) levels. We conclude that x(2) fulfills blood group criteria and is synthesized by UDP-N-acetylgalactosamine: globotriaosylceramide 3-beta-N-acetylgalactosaminyltransferase. Based on this linkage, we proposed that x(2) joins P in the GLOB blood group system (ISBT 028) and is renamed PX2 (GLOB2). Thus, in the absence of a functional P synthase, neither P nor PX2 are formed. As a consequence, naturally occurring anti-P and anti-PX2 can be made. Until the clinical significance of anti-PX2 is known, we also recommend that rare P-1(k) or P-2(k) erythrocyte units are preferentially selected for transfusion to P-k patients because p erythrocytes may pose a risk for hemolytic transfusion reactions due to their elevated PX2 levels.
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| 8. |
- Gassner, Christoph, et al.
(författare)
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Two Prevalent ∼100-kb GYPB Deletions Causative of the GPB-Deficient Blood Group MNS Phenotype S-s-U-in Black Africans
- 2020
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Ingår i: Transfusion Medicine and Hemotherapy. - : S. Karger AG. - 1660-3796 .- 1660-3818. ; 47:4, s. 326-336
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Tidskriftsartikel (refereegranskat)abstract
- The U antigen (MNS5) is one of 49 antigens belonging to the MNS blood group system (ISBT002) carried on glycophorins A (GPA) and B (GPB). U is present on the red blood cells in almost all Europeans and Asians but absent in approximately 1.0% of Black Africans. U negativity coincides with negativity for S (MNS3) and s (MNS4) on GPB, thus be called S-s-U-, and is thought to arise from homozygous deletion of GYPB. Little is known about the molecular background of these deletions. Bioinformatic analysis of the 1000 Genomes Project data revealed several candidate regions with apparent deletions in GYPB. Highly specific Gap-PCRs, only resulting in positive amplification from DNAs with deletions present, allowed for the exact genetic localization of 3 different breakpoints; 110.24- A nd 103.26-kb deletions were proven to be the most frequent in Black Americans and Africans. Among 157 CEPH DNAs, deletions in 6 out of 8 African ethnicities were present. Allele frequencies of the deletions within African ethnicities varied greatly and reached a cumulative 23.3% among the Mbuti Pygmy people from the Congo. Similar observations were made for U+var alleles, known to cause strongly reduced GPB expression. The 110- A nd 103-kb deletional GYPB haplotypes were found to represent the most prevalent hereditary factors causative of the MNS blood group phenotype S-s-U-. Respective GYPB deletions are now accessible by molecular detection of homo- A nd hemizygous transmission.
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| 9. |
- Hellberg, Åsa, et al.
(författare)
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A novel nonsense variant in RHAG underlies a Nordic Rhnull phenotype
- 2023
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Ingår i: Vox Sanguinis. - : John Wiley & Sons. - 0042-9007 .- 1423-0410. ; 118:8, s. 690-694
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectivesThe extremely rare Rhnull phenotype is characterized by the absence of all Rh antigens on erythrocytes. It is divided into the regulator and amorph types based on the underlying genetic background. The more common regulator type depends on critical variants silencing RHAG, which encodes RhAG glycoprotein, necessary for RhD/RhCE expression. Rhnull cells have altered expression of glycophorin B and LW glycoprotein.Materials and MethodsFour unrelated Rhnull individuals were investigated. Serological testing was performed according to standard blood bank practice. RHD/RHCE and S/s allele-specific Polymerase chain reaction (PCR) genotyping was done on genomic DNA using in-house PCR assays. RHAG, and in some cases also RHD/RHCE, were sequenced. Initial s phenotyping results triggered additional serological investigation.ResultsAnti-Rh29 was identified in all four individuals. Extended typing with anti-S and anti-s showed that the three samples predicted to type as s+ failed to react with 2 of 5 anti-s. Sequence analysis of all 10 RHAG exons and the immediate intron/exon boundaries revealed a single nucleotide variant in the 3′-end of intron 6, c.946 −2a>g in all samples. RHD/RHCE showed no alterations.ConclusionA novel Nordic Rhnull allele was identified. In addition, it was shown that s+ Rhnull red blood cells are not only U− but also have qualitative changes in their s antigen expression.
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| 10. |
- Lee, Yan Q., et al.
(författare)
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The Xg blood group system : no longer forgotten
- 2020
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Ingår i: Immunohematology. - 0894-203X. ; 36:1, s. 4-6
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- This update of the Xg blood group system (Johnson NC. XG: The forgotten blood group system. Immunohematology 2011;27:68-71) notes the identification of a cis-regulatory element of both XG and CD99 expression, remarkably by two independent groups during 2018, and confirmed by another in 2019. A single nucleotide change at the XG locus (rs311103) abolishes GATA1 binding and suppresses both XG and CD99. The last blood group system to resist elucidation of its genetic basis was thereby resolved. Soon afterwards, it was discovered that the rare anti-Xga response, mainly seen in men, is produced by individuals primarily carrying a large deletion in the X chromosome that truncates XG and leads to the Xgnull phenotype.
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