ABSTRACT
The Working Party has met twice since the last report: in Seoul, South Korea 2014, and in London, UK 2015, both in association with the International Society of Blood Transfusion (ISBT) Congress. As in previous meetings, matters pertaining to blood group antigen nomenclature were discussed. Eleven new blood group antigens were added to seven blood group systems. This brings the current total of blood group antigens recognized by the ISBT to 346, of which 308 are clustered within 36 blood groups systems. The remaining 38 antigens are currently unassigned to a known blood group system.
ABSTRACT
BACKGROUND: Providing adequate transfusion support for alloimmunised patients for whom antigen negative blood is not readily available is hampered by the risk of a haemolytic reaction. The monocyte monolayer assay (MMA) has shown good correlation between the antibody clinical significance and the fate of antigen positive blood. MATERIALS AND METHODS: From 2006 to 2013, the clinical significance of red cell alloantibodies produced by 61 patients was evaluated using a MMA; and antigen positive blood offering the best survival advantage was selected for transfusion following a secondary MMA crossmatch. Post-transfusion, patients were evaluated for clinical signs of haemolysis. RESULTS: Overall, 19 of 61 (31·1%) of our antibodies were potentially clinically significant, with a monocyte index (MI) > 5%. There was no correlation between the clinical significance as showed by the MMA, and the specificity of the antibody or the strength of reactivity at antihuman globulin (AHG) phase. Using the MMA as a secondary crossmatch method, 31 alloimmunised patients (including: eight anti-hr(B), four anti-Yt(a), one each anti-Rg1, -Co(a), Er(a), Le(b), -LW, -Sl1) received 103 antigen positive blood units with no clinical sign of a post-transfusion reaction. For three patients (one each anti-Jo(a), -AnWj, unidentified 'HTLA'), initial MMA was performed as part of an investigation of a suspected haemolytic reaction. In each case, the MMA accurately identified the unit responsible for the reaction. CONCLUSION: Used as a crossmatch surrogate, the MMA provided valuable information in the decision of transfusing antigen positive blood to alloimmunised patients, avoiding delay because of the search of rare antigen negative units.
Subject(s)
Blood Group Antigens/immunology , Blood Group Incompatibility/immunology , Blood Grouping and Crossmatching/methods , Isoantibodies/blood , Transfusion Reaction , Adult , Aged, 80 and over , Anemia, Sickle Cell/blood , Anemia, Sickle Cell/therapy , Complement System Proteins/analysis , Female , Gastrointestinal Hemorrhage/blood , Gastrointestinal Hemorrhage/therapy , Humans , Immunoglobulin G/blood , Immunoglobulin G/classification , Isoantibodies/classification , Isoantibodies/immunology , Kidney Failure, Chronic/blood , Kidney Failure, Chronic/therapy , Male , Monocytes , Transfusion Reaction/etiology , Transfusion Reaction/prevention & controlABSTRACT
The International Society of Blood Transfusion Working Party on red cell immunogenetics and blood group terminology convened during the International congress in Cancun, July 2012. This report details the newly identified antigens in existing blood group systems and presents three new blood group systems.
Subject(s)
Blood Group Antigens/classification , Terminology as Topic , Blood Group Antigens/genetics , Blood Group Antigens/immunology , Humans , Immunogenetics , Societies, ScientificSubject(s)
Blood Group Antigens , Receptors, Complement 3b/blood , Blood Group Antigens/analysis , Blood Group Antigens/classification , Blood Group Antigens/genetics , Blood Group Antigens/immunology , Chromosomes, Human, Pair 1/genetics , Coombs Test , Ethnicity/genetics , Humans , Isoantibodies/immunology , Leishmaniasis/blood , Malaria, Falciparum/blood , Membrane Glycoproteins/blood , Membrane Glycoproteins/immunology , Mycobacterium Infections/blood , Polymorphism, Genetic , Receptors, Complement 3b/genetics , Receptors, Complement 3b/immunology , Rosette Formation , Saliva/chemistry , Sequence Deletion , Urine/chemistryABSTRACT
Mitochondrial DNA (mtDNA) variation was analyzed in Mauritania and Mali, and compared to other West African samples covering the considerable geographic, ethnic and linguistic diversity of this region. The Mauritanian mtDNA profile shows that 55% of their lineages have a west Eurasian provenance, with the U6 cluster (17%) being the best represented. Only 6% of the sub-Saharan sequences belong to the L3A haplogroup a frequency similar to other Berber speaking groups but significantly different to the Arabic speaking North Africans. The historic Arab slave trade may be the main cause of this difference. Only one HV west Eurasian lineage has been detected in Mali but 40% of the sub-Saharan sequences belong to cluster L3A. The presence of L0a representatives demonstrates gene flow from eastern regions. Although both groups speak related dialects of the Mande branch, significant genetic differences exist between the Bambara and Malinke groups. The West African genetic variation is well structured by geography and language, but more detailed ethnolinguistic clustering suggest that geography is the main factor responsible for this differentiation.
Subject(s)
DNA, Mitochondrial/genetics , Ethnicity/genetics , Genetic Variation/genetics , Genetics, Population , Africa, Western , Ethnicity/statistics & numerical data , Geography/statistics & numerical data , Humans , Linguistics/statistics & numerical data , Mali , MauritaniaABSTRACT
This longitudinal study investigates the change of erythrocyte complement receptor (E-CR1) expression in patients with severe acute respiratory syndrome (SARS). Circulating E-CR1 expression was semiquantified by flow cytometric analyses in 54 SARS patients and in 212 healthy individuals as a control. Since E-CR1 expression is influenced by the genetic polymorphisms in the CR1 gene, a major genetic polymorphism located within intron 27 of the CR1 gene was simultaneously analysed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The results showed that the expression level of E-CR1 (referred to as net fluorescence intensity values, NFI) was statistically correlated with the relevant genetic genotypes among the Chinese population including the healthy individuals (NFI: 5.14 +/- 0.82, 3.57 +/- 0.66 and 2.67 +/- 0.32 for HH, HL and LL genotypes, respectively) and SARS patients (NFI: 3.52 +/- 0.91 and 2.63 +/- 0.70 for HH and HL genotypes, respectively). Interestingly, the expression density of E-CR1 was found to fall significantly during the initiation and progressive phases (weeks 1 and 2 after the disease onset) and gradually returned close to normal through their whole convalescent phase (beginning from weeks 2 or 3 to weeks 7 or 8) in SARS patients irrespective CR1 genotype. In conclusion, our findings, at least, suggest that E-CR1 is likely involved in immune pathogenesis of SARS disease.
Subject(s)
Erythrocytes/immunology , Receptors, Complement 3b/immunology , Severe Acute Respiratory Syndrome/immunology , Adolescent , Adult , Age Factors , Aged , Erythrocyte Count , Female , Flow Cytometry/methods , Genotype , Humans , Longitudinal Studies , Male , Middle Aged , Polymerase Chain Reaction/methods , Polymorphism, Restriction Fragment Length , Receptors, Complement 3b/blood , Receptors, Complement 3b/genetics , Severe Acute Respiratory Syndrome/blood , Severe Acute Respiratory Syndrome/mortalityABSTRACT
Complement receptor-1 (CR1) is a ligand for rosette formation, a phenomenon associated with cerebral malaria (CM). Binding is dependent on erythrocyte CR1 copy number. In Caucasians, low CR1 expressors have two linked mutations. We determined the Q981H and HindIII RFLP distribution in differing population groups to ascertain a possible role in adaptive evolution. We examined 194 Caucasians, 180 Choctaw Indians, 93 Chinese-Taiwanese, 304 Cambodians, 89 Papua New Guineans (PNG) and 366 Africans. PCR/RFLP used HindIII for CR1 expression and BstNI for the Q981H mutation. DNA sequencing and pyrosequencing were performed to resolve inconclusive results. Gene frequencies for the L allele were 0.15 in Africans, 0.16 in Choctaws, 0.18 in Caucasians, 0.29 in Chinese-Taiwanese, 0.47 in Cambodians and 0.58 in PNG. Allelic frequency for 981H were 0.07 in Africans, 0.15 in Caucasians, 0.18 in Choctaws, 0.29 in Chinese-Taiwanese, 0.47 in Cambodians and 0.54 in PNG. The Q981H polymorphism correlates with the HindIII RFLP in most groups except West Africans and appears to be part of a low CR1 expression haplotype. The gene frequency for the haplotype is highest in the malaria-endemic areas of Asia, suggesting that this haplotype may have evolved because it protects from rosetting and CM.
Subject(s)
Gene Frequency/genetics , Malaria, Cerebral/genetics , Polymorphism, Restriction Fragment Length , Polymorphism, Single Nucleotide , Receptors, Complement 3b/genetics , Africa , Asia, Southeastern , Endemic Diseases , Female , Humans , Malaria, Cerebral/ethnology , Male , Racial GroupsABSTRACT
BACKGROUND: DNA mutations resulting in the McCoy and Swain-Langley polymorphisms have been identified on complement receptor 1 (CR1)-a ligand for rosetting of Plasmodium falciparum-infected RBCs. The molecular identification of the Kna/Knb polymorphism was sought to develop a genotyping method for use in the study of the Knops blood group and malaria. STUDY DESIGN AND METHODS: CR1 deletion constructs were used in inhibition studies of anti-Kna. PCR amplification of Exon 29 was followed by DNA sequencing. A PCR-RFLP was developed with NdeI, BsmI, and MfeI for the detection of Kna/Knb, McCa/McCb, and Sl1/Sl2, respectively. Knops phenotypes were determined with standard serologic techniques. RESULTS: A total of 310 Malian persons were phenotyped for Kna with 200 (64%) Kn(a+) and 110 (36%) Kn(a-). Many of the Kn(a-) exhibited the Knops-null phenotype, that is, Helgeson. The Kna/b DNA polymorphism was identified as a V1561M mutation with allele frequencies of Kna (V1561) 0.9 and Knb (M1561) 0.1. CONCLUSION: The high frequency (18%) of Knb in West African persons suggests that it is not solely a Caucasian trait. Furthermore, because of the high incidence of heterozygosity as well as amorphs, accurate Knops typing of donors of African descent is best accomplished by a combination of molecular and serologic techniques.
Subject(s)
Blood Group Antigens/genetics , Malaria/genetics , Polymorphism, Single Nucleotide , Receptors, Complement 3b/genetics , Black or African American/genetics , Black People/genetics , Genotype , Humans , Incidence , Malaria/ethnology , Mali/epidemiology , Phenotype , United States/epidemiology , White People/geneticsABSTRACT
The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-value <0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McC(b) have arisen to confer a selective advantage against infectious disease that, in view of these case-control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McC(b) with severe malaria may involve variation in CR1 expression levels.
Subject(s)
Blood Group Antigens/genetics , Malaria, Falciparum/genetics , Receptors, Complement/genetics , Amino Acid Sequence , Case-Control Studies , DNA Primers , Gambia/epidemiology , Gene Frequency/genetics , Humans , Malaria, Falciparum/epidemiology , Molecular Probe Techniques , Molecular Sequence Data , Polymorphism, Single Nucleotide/genetics , Selection, GeneticABSTRACT
Complement receptor 1 (CR1) expression level on erythrocytes is genetically determined, and in Caucasian populations is linked to high (H) and low (L) expression alleles identified by a HindIII restriction fragment length polymorphism (RFLP). Erythrocyte CR1 may be an important factor in determining malaria susceptibility, as low expression of CR1 reduces the rosetting of uninfected erythrocytes with Plasmodium falciparum-infected cells, a process that contributes to malaria pathogenesis. Prior to studying CR1 expression and malaria susceptibility, we have investigated whether the quantity of erythrocyte CR1 correlates with the H and L alleles in an African population. Mean erythrocyte CR1 in 149 Malian adults was 415 molecules per cell, which is comparable to Caucasian populations; however, there was no relationship between erythrocyte CR1 level and genotype for the HindIII RFLP (mean CR1 per erythrocyte HH = 414, HL = 419 and LL = 403, P > 0.1, Student's t-test). The conclusions of a previous study of erythrocyte CR1 expression level and malaria susceptibility in West Africa that was based on HindIII RFLP genotyping may therefore need to be re-evaluated.
Subject(s)
Erythrocytes/metabolism , Genetic Predisposition to Disease , Malaria, Falciparum/genetics , Plasmodium falciparum , Polymorphism, Restriction Fragment Length , Receptors, Complement 3b/blood , Receptors, Complement 3b/genetics , Site-Specific DNA-Methyltransferase (Adenine-Specific)/genetics , Black or African American , Animals , Black People/genetics , Gene Expression Regulation/immunology , Genetic Predisposition to Disease/genetics , Humans , Malaria, Falciparum/metabolism , Mali , Receptors, Complement 3b/biosynthesisABSTRACT
BACKGROUND: Complement receptor type 1 (CR1), which bears the Knops (Kn [KN]) blood group antigens, is involved in the rosetting of Plasmodium falciparum- infected RBCs with uninfected cells. As a first step in understanding this interaction, the molecular basis for the blood group antigens encoded by CR1 was investigated. STUDY DESIGN AND METHODS: An antibody from a white donor who exhibited an apparent anti-Sl(a) was used for population studies of several racial groups. The donor's genomic DNA was sequenced to identify the Sl(a) mutation and other mutations. RESULTS: The donor with anti-Sl(a) typed as Sl(a+) with some sera and had the CR1 genotype AA at bp 4828 (R1601). However, she was homozygous for a new mutation (GG) at bp 4855 changing amino acid 1610 from S1610 to T1610 (S1610T). This mutation occurred in heterozygous form in eight white and one Asian donor. The site is only nine amino acids from the previously described Sl(a) polymorphism and appears to produce a new conformational epitope. CONCLUSION: The antigen formerly known as Sl(a) can now be subdivided. A new terminology is proposed that recognizes both linear and conformational epitopes on the CR1 protein. At amino acid 1601, Sl 1 (Sl(a)) is represented by R, Sl 2 (Vil) is represented by glycine, and Sl 3 requires both R1601 and S1610. Sl 4 and Sl 5 are hypothetical epitopes represented by S1610 and T1610, respectively.
Subject(s)
Antigens, Surface/genetics , Blood Group Antigens/genetics , Receptors, Complement/genetics , Amino Acid Sequence , Antigens, Surface/chemistry , Antigens, Surface/immunology , Asian People , Black People , Blood Group Antigens/immunology , Cloning, Molecular , Consensus Sequence , Epitopes/chemistry , Heterozygote , Homozygote , Humans , Isoantibodies/blood , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Mutation , Nucleic Acid Hybridization , Oligonucleotide Probes , Polymerase Chain Reaction , Receptors, Complement/chemistry , Receptors, Complement/immunology , Repetitive Sequences, Amino Acid , Sequence Analysis, DNA , White PeopleABSTRACT
It has been more than 10 years since the topic of "high-titer, low-avidity" (HTLA) antibodies was reviewed in Immunohematology. We have learned a lot about these antibodies in the past 10 years and that knowledge has helped us to understand some of the unusual characteristics of these antibodies. Furthermore, it has helped us to name and delineate the various associated blood group systems. Although we will begin with a general review of HTLAs, this manuscript will focus on the recent findings in the Knops blood group system.
ABSTRACT
One may wonder why the genes for the class III region are even situated in the human Major Histocompatibility Locus (MHC). However, on closer inspection we find that the genes for the complement components, tumor necrosis factor (TNF) and others may play an important role in host immune defenses. Thus, this region on chromosome six may be more appropriately thought of as an immune response area. Accordingly, there is a high degree of polymorphism in many genes within the MHC, the most notable being the HLA genes. In the class III region C2, factor B (Bf) and C4 are polymorphic in as many populations studied to date. The purpose of this review will be to briefly describe the class III region, identify the genetic polymorphism found in various ethnic groups and define their roles in autoimmune diseases.
Subject(s)
Autoimmune Diseases/ethnology , Autoimmune Diseases/genetics , Major Histocompatibility Complex , Complement C2/genetics , Complement C4/genetics , Humans , Polymorphism, Genetic , Tumor Necrosis Factor-alpha/geneticsSubject(s)
Antigens, Surface/classification , Blood Group Antigens/classification , Erythrocyte Membrane/immunology , Isoantigens/blood , Rh-Hr Blood-Group System/chemistry , Terminology as Topic , Amino Acid Substitution , Antigens, Surface/genetics , Blood Group Antigens/genetics , Carbohydrates/blood , Carbohydrates/immunology , Epitopes/classification , Humans , Rh-Hr Blood-Group System/immunologyABSTRACT
The complement protein C4 is a non-enzymatic component of the C3 and C5 convertases and thus essential for the propagation of the classical complement pathway. The covalent binding of C4 to immunoglobulins and immune complexes (IC) also enhances the solubilization of immune aggregates, and the clearance of IC through complement receptor one (CR1) on erythrocytes. Human C4 is the most polymorphic protein of the complement system. In this review, we summarize the current concepts on the 1-2-3 loci model of C4A and C4B genes in the population, factors affecting the expression levels of C4 transcripts and proteins, and the structural, functional and serological diversities of the C4A and C4B proteins. The diversities and polymorphisms of the mouse homologues Slp and C4 proteins are described and contrasted with their human homologues. The human C4 genes are located in the MHC class III region on chromosome 6. Each human C4 gene consists of 41 exons coding for a 5.4-kb transcript. The long gene is 20.6 kb and the short gene is 14.2 kb. In the Caucasian population 55% of the MHC haplotypes have the 2-locus, C4A-C4B configurations and 45% have an unequal number of C4A and C4B genes. Moreover, three-quarters of C4 genes harbor the 6.4 kb endogenous retrovirus HERV-K(C4) in the intron 9 of the long genes. Duplication of a C4 gene always concurs with its adjacent genes RP, CYP21 and TNX, which together form a genetic unit termed an RCCX module. Monomodular, bimodular and trimodular RCCX structures with 1, 2 and 3 complement C4 genes have frequencies of 17%, 69% and 14%, respectively. Partial deficiencies of C4A and C4B, primarily due to the presence of monomodular haplotypes and homo-expression of C4A proteins from bimodular structures, have a combined frequency of 31.6%. Multiple structural isoforms of each C4A and C4B allotype exist in the circulation because of the imperfect and incomplete proteolytic processing of the precursor protein to form the beta-alpha-gamma structures. Immunofixation experiments of C4A and C4B demonstrate > 41 allotypes in the two classes of proteins. A compilation of polymorphic sites from limited C4 sequences revealed the presence of 24 polymophic residues, mostly clustered C-terminal to the thioester bond within the C4d region of the alpha-chain. The covalent binding affinities of the thioester carbonyl group of C4A and C4B appear to be modulated by four isotypic residues at positions 1101, 1102, 1105 and 1106. Site directed mutagenesis experiments revealed that D1106 is responsible for the effective binding of C4A to form amide bonds with immune aggregates or protein antigens, and H1106 of C4B catalyzes the transacylation of the thioester carbonyl group to form ester bonds with carbohydrate antigens. The expression of C4 is inducible or enhanced by gamma-interferon. The liver is the main organ that synthesizes and secretes C4A and C4B to the circulation but there are many extra-hepatic sites producing moderate quantities of C4 for local defense. The plasma protein levels of C4A and C4B are mainly determined by the corresponding gene dosage. However, C4B proteins encoded by monomodular short genes may have relatively higher concentrations than those from long C4A genes. The 5' regulatory sequence of a C4 gene contains a Spl site, three E-boxes but no TATA box. The sequences beyond--1524 nt may be completely different as the C4 genes at RCCX module I have RPI-specific sequences, while those at Modules II, III and IV have TNXA-specific sequences. The remarkable genetic diversity of human C4A and C4B probably promotes the exchange of genetic information to create and maintain the quantitative and qualitative variations of C4A and C4B proteins in the population, as driven by the selection pressure against a great variety of microbes. An undesirable accompanying byproduct of this phenomenon is the inherent deleterious recombinations among the RCCX constituents leading to autoimmune and genetic disorders.