Turtle-dove ovomucoid, a glycoprotein proteinase inhibitor with P1-blood-group antigen activity.
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ABSTRACT:
SUBMITTER: Francois-Gerard C
PROVIDER: S-EPMC1186419 | biostudies-other | 1979 Feb
REPOSITORIES: biostudies-other
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Project description:BackgroundThe molecular genetics of the P blood group system and the absence of P1 antigen in the p phenotype are still enigmatic. One theory proposes that the same gene encodes for both the P1 and Pk glycosyltransferases, but no polymorphisms in the coding region of the Pk gene explain the P1/P2 phenotypes. We investigated the potential regulatory regions up- and downstream of the A4GALT (Pk) gene exons.ResultsP1 (n = 18) and P2 (n = 9) samples from donors of mainly Swedish descent were analysed by direct sequencing of PCR-amplified 5'- and 3'-fragments surrounding the Pk coding region. Seventy-eight P1 and P2 samples were investigated with PCR using allele-specific primers (ASP) for two polymorphisms previously proposed as P2-related genetic markers (-551_-550insC, -160A>G). Haplotype analysis of single nucleotide polymorphisms was also performed with PCR-ASP. In approximately 1.5 kbp of the 3'-untranslated region one new insertion and four new substitutions compared to a GenBank sequence (AL049757) were found. In addition to the polymorphisms at positions -550 and -160, one insertion, two deletions and one substitution were found in approximately 1.0 kbp of the 5'-upstream region. All 20 P2 samples investigated with PCR-ASP were homozygous for -550insC. However, so were 18 of the 58 P1 samples investigated. Both the 20 P2 and the 18 P1 samples were also homozygous for -160G.ConclusionThe proposed P2-specific polymorphisms, -551_-550insC and -160G, found in P2 samples in a Japanese study were found here in homozygous form in both P1 and P2 donors. Since P2 is the null allele in the P blood group system it is difficult to envision how these mutations would cause the P2 phenotype. None of the novel polymorphisms reported in this study correlated with P1/P2 status and the P1/p mystery remains unsolved.
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Project description:Shiga toxin (STx) is a virulence factor produced by enterohemorrhagic Escherichia coli. STx is taken up by mammalian host cells by binding to the glycosphingolipid (GSL) globotriaosylceramide (Gb3; Galα1-4Galβ1-4Glc-ceramide) and causes cell death after its retrograde membrane transport. However, the contribution of the hydrophobic portion of Gb3 (ceramide) to STx transport remains unclear. In pigeons, blood group P1 glycan antigens (Galα1-4Galβ1-4GlcNAc-) are expressed on glycoproteins that are synthesized by α1,4-galactosyltransferase 2 (pA4GalT2). To examine whether these glycoproteins can also function as STx receptors, here we constructed glycan-remodeled HeLa cell variants lacking Gb3 expression but instead expressing pA4GalT2-synthesized P1 glycan antigens on glycoproteins. We compared STx binding and sensitivity of these variants with those of the parental, Gb3-expressing HeLa cells. The glycan-remodeled cells bound STx1 via N-glycans of glycoproteins and were sensitive to STx1 even without Gb3 expression, indicating that P1-containing glycoproteins also function as STx receptors. However, these variants were significantly less sensitive to STx than the parent cells. Fluorescence microscopy and correlative light EM revealed that the STx1 B subunit accumulates to lower levels in the Golgi apparatus after glycoprotein-mediated than after Gb3-mediated uptake but instead accumulates in vacuole-like structures probably derived from early endosomes. Furthermore, coexpression of Galα1-4Gal on both glycoproteins and GSLs reduced the sensitivity of cells to STx1 compared with those expressing Galα1-4Gal only on GSLs, probably because of competition for STx binding or internalization. We conclude that lipid-based receptors are much more effective in STx retrograde transport and mediate greater STx cytotoxicity than protein-based receptors.
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Project description:In 2014, the membrane-bound protein CD59 became a blood group antigen. CD59 has been known for decades as an inhibitor of the complement system, located on erythrocytes and on many other cell types. In paroxysmal nocturnal haemoglobinuria (PNH), a stem cell clone with acquired deficiency to express GPI-anchored molecules, including the complement inhibitor CD59, causes severe and life-threatening disease. The lack of CD59, which is the only membrane-bound inhibitor of the membrane attack complex, contributes a major part of the intravascular haemolysis observed in PNH patients. This crucial effect of CD59 in PNH disease prompted studies to investigate its role in other diseases. In this review, the role of CD59 in inflammation, rheumatic disease, and age-related macular degeneration is investigated. Further, the pivotal role of CD59 in PNH and congenital CD59 deficiency is reviewed.
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Project description: Not available
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Project description:BACKGROUND:Kell null (K0) individuals can produce anti-Ku, an antibody against many epitopes in the Kell glycoprotein, after transfusion and/or pregnancy. Since sensitized K0 patients are rare, little is known about anti-Ku clinical relevance and in particular about its association to hemolytic disease of the fetus and newborn. CASE REPORT:This work describes a case of neonatal hyperbilirubinemia due to immune-mediated erythrocyte destruction by an alloantibody directed against the Kell glycoprotein. Serologic and molecular approaches identified an anti-Ku alloantibody in maternal serum. A homozygous IVS3 + 1g>a point mutation (KEL*02N.06 allele) was found to be responsible for the lack of Kell antigen expression in the mother's red blood cell and subsequent alloimmunization after a previous pregnancy. Even though in most cases Kell antibodies are clinically severe and may cause suppression of erythropoiesis, in our case the newborn had a moderate anemia and hyperbilirubinemia that was successfully treated with phototherapy without requiring exchange transfusion. Serological and molecular studies performed in the proband's family members allowed us to provide them with proper counseling regarding alloimmunization after transfusion and/or pregnancy. CONCLUSIONS:This case enlarges the understanding of the clinical significance of alloantibodies against Kell blood group antigens.
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Project description:The expression of ABO(H) blood group antigens causes deletion of cells that generate self-specific antibodies to these antigens but this deletion limits adaptive immunity toward pathogens bearing cognate blood group antigens. To explore potential defense mechanisms against such pathogens, given these limitations in adaptive immunity, we screened for innate proteins that could recognize human blood group antigens. Here we report that two innate immune lectins, galectin-4 (Gal-4) and Gal-8, which are expressed in the intestinal tract, recognize and kill human blood group antigen-expressing Escherichia coli while failing to alter the viability of other E. coli strains or other Gram-negative or Gram-positive organisms both in vitro and in vivo. The killing activity of both Gal-4 and Gal-8 is mediated by their C-terminal domains, occurs rapidly and independently of complement and is accompanied by disruption of membrane integrity. These results demonstrate that innate defense lectins can provide immunity against pathogens that express blood group-like antigens on their surface.
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Project description:BackgroundBotswana is among the world's countries with the highest rates of HIV infection. It is not known whether or not this susceptibility to infection is due to genetic factors in the population. Accumulating evidence, however, points to the role of erythrocytes as potential mediators of infection. We therefore sought to establish the role, if any, of some erythrocyte antigens in HIV infection in a cross-section of the population.Methods348 (346 HIV-negative and 2 HIV-positive) samples were obtained from the National Blood Transfusion Service as residual samples, while 194 HIV-positive samples were obtained from the Botswana-Harvard HIV Reference Laboratory. Samples were grouped for twenty three antigens. Chi-square or Fischer Exact analyses were used to compare the frequencies of the antigens in the two groups. A stepwise, binary logistic regression was used to study the interaction of the various antigens in the light of HIV-status.ResultsThe Rh antigens C and E were associated with HIV-negative status, while blood group Jka, P1 and Lub were associated with HIV-positive status. A stepwise binary logistic regression analysis yielded group C as the most significant protective blood group while Lub and P1 were associated with significantly higher odds ratio in favor of HIV-infection. The lower-risk-associated group C was significantly lower in Africans compared to published data for Caucasians and might partially explain the difference in susceptibility to HIV-1.ConclusionThe most influential antigen C, which also appears to be protective, is significantly lower in Africans than published data for Caucasians or Asians. On the other hand, there appear to be multiple antigens associated with increased risk that may override the protective role of C. A study of the distribution of these antigens in other populations may shed light on their roles in the HIV pandemic.
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Project description:The Potyviridae family is a major group of plant viruses that includes c. 200 species, most of which have narrow host ranges. The potyvirid P1 leader proteinase self-cleaves from the remainder of the viral polyprotein and shows large sequence variability linked to host adaptation. P1 proteins can be classified as Type A or Type B on the basis, amongst other things, of their dependence or not on a host factor to develop their protease activity. In this work, we studied Type A proteases from the Potyviridae family, characterizing their host factor requirements. Our in vitro cleavage analyses of potyvirid P1 proteases showed that the N-terminal domain is relevant for host factor interaction and suggested that the C-terminal domain is also involved. In the absence of plant factors, the N-terminal end of Plum pox virus P1 antagonizes protease self-processing. We performed extended deletion mutagenesis analysis to define the N-terminal antagonistic domain of P1. In viral infections, removal of the P1 protease antagonistic domain led to a gain-of-function phenotype, strongly increasing local infection in a non-permissive host. Altogether, our results shed new insights into the adaptation and evolution of potyvirids.
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Project description:Streptococcus pyogenes (group A streptococcus [GAS]) is responsible for over 500,000 deaths worldwide each year. The highly virulent M1T1 GAS clone is one of the most frequently isolated serotypes from streptococcal pharyngitis and invasive disease. The oral epithelial tract is a niche highly abundant in glycosylated structures, particularly those of the ABO(H) blood group antigen family. Using a high-throughput approach, we determined that a strain representative of the globally disseminated M1T1 GAS clone 5448 interacts with numerous, structurally diverse glycans. Preeminent among GAS virulence factors is the surface-expressed M protein. M1 protein showed high affinity for several terminal galactose blood group antigen structures. Deletion mutagenesis shows that M1 protein mediates glycan binding via its B repeat domains. Association of M1T1 GAS with oral epithelial cells varied significantly as a result of phenotypic differences in blood group antigen expression, with significantly higher adherence to those cells expressing H antigen structures compared to cells expressing A, B, or AB antigen structures. These data suggest a novel mechanism for GAS attachment to host cells and propose a link between host blood group antigen expression and M1T1 GAS colonization. There has been a resurgence in group A streptococcal (GAS) invasive disease, which has been paralleled by the emergence of the highly virulent M1T1 GAS clone. Intensive research has focused on mechanisms that contribute to the invasive nature of this serotype, while the mechanisms that contribute to host susceptibility to disease and bacterial colonization and persistence are still poorly understood. The M1T1 GAS clone is frequently isolated from the throat, an environment highly abundant in blood group antigen structures. This work examined the interaction of the M1 protein, the preeminent GAS surface protein, against a wide range of host-expressed glycan structures. Our data suggest that susceptibility to infection by GAS in the oral tract may correlate with phenotypic differences in host blood group antigen expression. Thus, variations in host blood group antigen expression may serve as a selective pressure contributing to the dissemination and overrepresentation of M1T1 GAS.
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Project description:Human histo-blood group A transferase (AT) catalyzes the biosynthesis of oligosaccharide A antigen important in blood transfusion and cell/tissue/organ transplantation. This enzyme may synthesize Forssman antigen (FORS1) of the FORS blood group system when exon 3 or 4 of the AT mRNA is deleted and/or the LeuGlyGly tripeptide at codons 266-268 of AT is replaced by GlyGlyAla. The Met69Ser/Thr substitutions also confer weak Forssman glycolipid synthase (FS) activity. In this study, we prepared the human AT derivative constructs containing any of the 20 amino acids at codon 69 with and without the GlyGlyAla substitution, transfected DNA to newly generated COS1(B3GALNT1 + A4GALT) cells expressing an enhanced level of globoside (Gb4), the FS acceptor substrate, and immunologically examined the FORS1 expression. Our results showed that all those substitution constructs at codon 69 exhibited FS activity. The combination with GlyGlyAla significantly increased the activity. The conserved methionine residue in the ABO, but not GBGT1, gene-encoded proteins may implicate its contribution to the separation of these genes in genetic evolution. Surprisingly, with increased Gb4 availability, the original human AT with the methionine residue at codon 69 was also demonstrated to synthesize FORS1, providing another molecular mechanism of FORS1 appearance in cancer of ordinary FORS1-negative individuals.
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