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At least 19 recordsLinked to original sources
PubMed1982

Haptoglobin biosynthesis in rats. Immunological identification of polysomes synthesizing haptoglobin and quantitation of haptoglobin in the cytoplasm of liver cells.

A quantitative enzyme-linked immunosorbent assay was developed and utilized to study the stimulation of haptoglobin biosynthesis during an acute inflammatory challenge. A 10-fold increase in intracellular haptoglobin was measured at the peak of the inflammatory response. The increase in serum haptoglobin levels was concomitant with the intracellular levels, demonstrating the secretory output is also elevated during the inflammatory period. A monospecific antihaptoglobin was produced and used to detect the specific polysomes involved in haptoglobin synthesis. The amount of radioactively labeled antibody bound to the nascent haptoglobin chain was increased approx. 3-fold during the inflammatory response, indicating that new haptoglobin was being synthesized and suggesting an increase in functional haptoglobin mRNA resulting from the inflammatory signal.

Animals↗
PubMed1985

Nucleotide sequence of the haptoglobin and haptoglobin-related gene pair. The haptoglobin-related gene contains a retrovirus-like element.

Thirty-three kilobase pairs (kb) of human DNA containing the haptoglobin (Hp) and haptoglobin-related (Hpr) gene pair were cloned, and the nucleotide sequence of 21-kb DNA was determined. The two genes are closely linked, with Hpr being 2.2 kb downstream of Hp. Six hundred nucleotides of DNA occur between the two genes that are not found either 5' to the Hp gene or 3' to the Hpr gene. After the duplication event, the first intron of the Hpr gene acquired a 9-kb insert consisting mainly of a retrovirus-like element with a potential primer-binding site homologous to a mouse isoleucine tRNA. The element forms a repeated family in the human genome that I name RTVL-I (retrovirus-like element-isoleucine). In the coding region of the Hpr gene, there are no frameshift or nonsense mutations and its exon-intron splicing sites, 5' flanking and 3' flanking sequences do not show any obvious defects. There are 28 amino acid differences between the decoded amino acid sequences of the Hpr and Hp genes. Sixteen of these differences occur in the hpr beta chain, and all appear to be located on the surface of the molecule in places not thought to be involved in the hemoglobin binding function of haptoglobin. The structure of the Hpr gene suggests that the gene may be expressed and give rise to a functional product.

Amino Acid Sequence↗
PubMed2004

Analysis of haptoglobin and hemoglobin-haptoglobin interactions with the Neisseria meningitidis TonB-dependent receptor HpuAB by flow cytometry.

Neisseria meningitidis expresses a two-component TonB-dependent receptor, HpuAB, which mediates heme-iron (Hm-Fe) acquisition from hemoglobin and hemoglobin-haptoglobin complexes. Due to genetic polymorphisms in the human haptoglobin gene, haptoglobin (and hemoglobin-haptoglobin) exists as three structurally distinct phenotypes. In this study, we examined the influence of the haptoglobin phenotype on the interactions of HpuAB with apo-haptoglobin and hemoglobin-haptoglobin. Growth assays confirmed that HpuAB utilizes hemoglobin-haptoglobin more efficiently than hemoglobin as an Fe source and revealed a preference for human-specific, polymeric 2-2 or 2-1 hemoglobin-haptoglobin complexes. We developed a flow cytometry-based assay to measure the binding kinetics of fluorescein-labeled ligands to HpuAB on live, intact meningococci. The binding affinity of HpuAB for hemoglobin-haptoglobin phenotypes correlated well with the ability of each ligand to support Neisseria meningitidis growth, with higher affinities exhibited for types 2-2 and 2-1 hemoglobin-haptoglobin. Saturable binding of Hb and apo-haptoglobin suggested that HpuAB-mediated utilization of hemoglobin-haptoglobin involves specific interactions with both components. In contrast to previous studies, we detected binding of HpuB expressed alone to hemoglobin, apo-haptoglobin, and hemoglobin-haptoglobin of all three phenotypes. However, in the absence of HpuA, the binding capacity and/or affinity of the receptor was reduced and the dissociation of hemoglobin was impaired. We did not detect binding of HpuA alone to hemoglobin, apo-haptoglobin, or hemoglobin-haptoglobin; however, the lipoprotein is crucial for optimal recognition and use of ligands by the receptor. Finally, this study confirmed the integral role of TonB and the proton motive force in the binding and dissociation of Hb and hemoglobin-haptoglobin from HpuAB.

Apoproteins↗
PubMed2002

Anaphylactic transfusion reactions in haptoglobin-deficient patients with IgE and IgG haptoglobin antibodies.

BACKGROUND: Patients with haptoglobin deficiency associated with haptoglobin IgG antibodies, who experienced severe nonhemolytic transfusion reactions (NHTRs), have been identified in Japan. Haptoglobin deficiency therefore might be a risk factor for NHTRs. STUDY DESIGN AND METHODS: A total of 4138 cases of voluntarily reported NHTRs in Japan, including 367 cases of immediate-onset anaphylactic NHTRs, were examined to identify haptoglobin deficiency. Serum haptoglobin IgG and IgE antibodies were determined in haptoglobin-deficient patients to elucidate the mechanism underlying the transfusion reactions. RESULTS: Seven patients with haptoglobin deficiency were identified. Six of them experienced severe and acute NHTRs. Six of them were identified to be homozygous for the Hpdel allele of the haptoglobin gene. Both haptoglobin IgG and IgE antibodies were detected in serum samples of all the patients. The stimulative effects of blood transfusion on the production of hap- toglobin antibodies in the patients and the relation- ship between the presence of the antibodies and the occurrence of the transfusion reactions were observed. CONCLUSION: Anaphylactic NHTRs in these patients with haptoglobin deficiency associated with serum haptoglobin antibodies were suggested to be prevalent in Japan. In addition to IgG antibodies, IgE haptoglobin antibodies detected in the sera of such patients were suggested to play a role in the occurrence of the reactions.

Adolescent↗
PubMed2006

A unique loop extension in the serine protease domain of haptoglobin is essential for CD163 recognition of the haptoglobin-hemoglobin complex.

Haptoglobin and haptoglobin-related protein are homologous hemoglobin-binding proteins consisting of a complement control repeat (alpha-chain) and a serine protease domain (beta-chain). Haptoglobin-hemoglobin complex formation promotes high affinity binding of hemoglobin to the macrophage scavenger receptor CD163 leading to endocytosis and degradation of the haptoglobin-hemoglobin complex. In contrast, complex formation between haptoglobin-related protein and hemoglobin does not promote high affinity interaction with CD163. To define structural components of haptoglobin important for CD163 recognition, we exploited this functional difference to design and analyze recombinant haptoglobin/haptoglobin-related protein chimeras complexed to hemoglobin. These data revealed that only the beta-chain of haptoglobin is involved in receptor recognition. Substitution of 4 closely spaced amino acid residues of the haptoglobin beta-chain (valine 259, glutamate 261, lysine 262, and threonine 264) abrogated the high affinity receptor binding. The 4 residues are encompassed by a part of the primary structure not present in other serine protease domain proteins. Structural modeling based on the well characterized serine protease domain fold suggests that this sequence represents a loop extension unique for haptoglobin and haptoglobin-related protein. A synthetic peptide representing the haptoglobin loop sequence exhibited a pronounced inhibitory effect on receptor binding of haptoglobin-hemoglobin.

Amino Acid Sequence↗
PubMed2004

Haptoglobin genotypic distribution (including Hp0 allele) and associated serum haptoglobin concentrations in Koreans.

BACKGROUND: Haptoglobin polymorphism is associated with the prevalence of infections, autoimmune diseases, cardiovascular diseases, and other disorders. Congenital haptoglobin deficiency is associated with anaphylactic transfusion reactions in anhaptoglobinaemic patients with antihaptoglobin antibody. AIMS: To investigate haptoglobin genotypic distribution (including the Hp(0) allele) and associated serum haptoglobin concentrations in Koreans. METHODS: Five hundred and nine healthy Korean adults were randomly selected. Two methods were used: haptoglobin genotyping based on a polymerase chain reaction (PCR) system that exploited the structural difference of the Hp(1) and Hp(2 )alleles, and another PCR method that detected haptoglobin gene deletion by amplification of the junctional region of the Hp(0) allele. Serum haptoglobin concentrations were measured by nephelometry. RESULTS: The haptoglobin genotypes of 509 subjects were as follows: Hp(1)Hp(1), 7.1%; Hp(2)Hp(1), 37.7%; Hp(2)Hp(2), 49.3%; Hp(0)Hp(1), 2.2%; Hp(0)Hp(2), 3.5%; Hp(0)Hp(0), 0.2%. The gene frequency of Hp(0) in Koreans was calculated to be 0.031. Significant differences were seen among the concentrations of each haptoglobin genotype (Kruskal-Wallis test). Hp(0)Hp(2), but not Hp(0)Hp(1), was associated with hypohaptoglobinaemia. CONCLUSIONS: PCR methods for differentiating between haptoglobin genotypes, including the Hp(0) allele, may be useful in a broad spectrum of basic studies and clinical examinations.

Adult↗
PubMed1988

Purification of mouse haptoglobin by antibody affinity chromatography and development of an ELISA to measure serum haptoglobin levels.

Mouse haptoglobin was isolated from acute-phase serum initially by affinity chromatography on haemoglobin-Sepharose. This proved inefficient, but sufficient material was obtained for use as an immunogen. Rabbit anti-haptoglobin antibodies were used as immunoabsorbents to isolate larger quantities of haptoglobin. Subsequently, specific anti-haptoglobin antibodies were prepared by affinity chromatography on haptoglobin-Sepharose. A direct sandwich ELISA for mouse serum haptoglobin was developed, using affinity purified reagents. The working range of the haptoglobin standard curve was 0.02-0.5 microgram/ml. The reagents did not cross-react with albumin or haemoglobin and the antibody also recognised rat haptoglobin.

Animals↗
PubMed1984

Structure of haptoglobin and the haptoglobin-hemoglobin complex by electron microscopy.

The human serum protein, haptoglobin, forms a stable, irreversible complex with hemoglobin. Haptoglobin is composed of two H chains, which are connected via two smaller L chains to give a protein of 85,000 Mr. In the complex, each H chain binds an alpha beta dimer of hemoglobin for a total molecular weight of 150,000. The scanning transmission electron microscope has been used to derive new information about the shape and structure of haptoglobin and hemoglobin, and about their relative orientation in the complex. The micrographs of negatively stained images show that haptoglobin has the shape of a barbell with two spherical head groups, which are the H chains. These are connected by a thin filament with a central knob, which corresponds to the L chains. The overall length of the molecule is about 124(+/- 8) A and the interhead distance is 87 (+/- 7) A. In the haptoglobin-hemoglobin complex, the head groups are ellipsoidal and under optimal staining conditions bilobal . Thus, the alpha beta dimers are binding to the H chains, but off the long axis of the barbell by 127 degrees in a trans configuration. This angle considerably restricts the region on the surface of the H chain structure that can contain the hemoglobin binding site. The interhead group distance for complex is 116.5(+/- 6.3) A or 30 A greater than for haptoglobin. The N terminus of the beta chain was located on the trans off-axis configured barbell structure of complex by using a hemoglobin that was crosslinked between the alpha beta dimers in the region of the beta N terminus. The distances and angles that are measured on the micrographs for the native and crosslinked complex molecules permit the directions of two of the alpha beta dimer ellipsoid axes to be assigned. Taken together, these data provide an approximate relative orientation for the binding of the alpha beta dimer to the H chain of haptoglobin.

Binding Sites↗
PubMed1982

Inhibition of cathepsin L and B by haptoglobin, the haptoglobin-hemoglobin complex, and asialohaptoglobin. "In vitro" studies in the rat.

In broadening our research on the inhibition of cathepsin B (EC 3.4.22.1) by rat haptoglobin, we have used the haptoglobin-hemoglobin complex and asialohaptoglobin. The inhibition of cathepsin L (EC 3.4.22.15), another lysosomal thiol proteinase, by haptoglobin and its related molecules has also been investigated. With azocasein as substrate, both enzymes were inhibited by both haptoglobin and its related molecules. When azocasein was used as a substrate, the apparent Michaelis constant (Km, app.) for cathepsin L was 1 X 10(-5) +/- 0.4 X 10(-5) M. When haptoglobin was added, the apparent inhibition constant (Ki, app) was 3 X 10(-8) +/- 2.5 X 10(-8) M. The results suggest that rat haptoglobin specifically inhibits lysosomal thiol proteinases and that it has a regulatory role in tissue proteolysis associated with the inflammatory reaction. On the other hand, these properties would seem to be peculiar to the systems rat haptoglobin-rat liver cathepsin B or L.

Animals↗
PubMed1997

Distribution of lymphocyte subsets in bone marrow and peripheral blood is associated with haptoglobin type. Binding of haptoglobin to the B-cell lectin CD22.

Haptoglobin is an acute phase protein showing a genetic polymorphism with 3 major types: Hp 1-1, Hp 2-1, and Hp 2-2. In this study, flow cytometric analysis demonstrated that all three haptoglobin types bind to CD22 on human B-lymphocytes with equal affinity. Comparison of reference values for lymphocyte subsets in peripheral blood and bone marrow showed significant differences between haptoglobin types. Haptoglobin 2-2 is associated with higher peripheral B-lymphocyte counts (P < 0.001) and CD4+ T-lymphocyte counts (P < 0.05). In bone marrow, CD4+ T-cell percentages were highest (P < 0.001) but B-cell percentages were lowest (P < 0.001) in haptoglobin 2-2 type. A negative correlation between serum haptoglobin 1-1 concentration and peripheral B-cell counts was observed (r = -0.663). Our results suggest that haptoglobin is involved in lymphocyte distribution. The present findings are a potential cause of over- or underestimation of lymphocyte subset counts in the clinical staging of immunodeficiency diseases.

Adult↗
PubMed1981

Catabolism of globin-haptoglobin in liver cells after intravenous administration of hemoglobin-haptoglobin to rats.

The intracellular site of uptake and degradation of globin-haptoglobin, the protein moiety of hemoglobin-haptoglobin, in rat liver cells was investigated in vivo. Hemoglobin-haptoglobin, administered intravenously to rats, is cleared from circulation and incorporated exclusively into liver parenchymal cells through the receptor specific for the molecule (Kino, K., Tsunoo, H., Higa, Y., Takami, M., Hamaguchi, H., and Nakajima, H. (1980) J. Biol. Chem. 255, 9616-9620). Intrahepatocellular distribution of radioactivity was determined after intravenous administration of (125I-hemoglobin)-haptoglobin or hemoglobin-(125I-haptoglobin) to rats. The 125I-labeled hemoglobin-haptoglobin was incorporated first in organelles of low density (density range, 1.05-1.07 g/ml) recovered in Golgi subfractions of the liver cells in a substantially intact form. The organelles progressively acquired a higher density, presumably through fusion with primary lysosomes. In the resulting organelles of high density (density range, 1.07-1.15 g/ml), which are probably secondary lysosomes, hemoglobin-haptoglobin first dissociated symmetrically to yield two 82,000-dalton subunits by a limited proteolysis, and further digestion of the constituent polypeptide chains seemed to proceed thereafter in the organelles during the transport process across the cells.

Animals↗
PubMed1986

Polymorphisms in the human haptoglobin gene cluster: chromosomes with multiple haptoglobin-related (Hpr) genes.

We have found polymorphisms for the number of tandemly arranged haptoglobin-related (Hpr) genes in the haptoglobin gene cluster of Blacks. Genomic mapping and nucleotide sequence analysis indicate that two copies of the Hpr gene first resulted from unequal but homologous crossing-over in a region 3' to the haptoglobin (Hp) and the haptoglobin-related genes. Subsequent increases in the number of Hpr loci have occurred in some chromosomes. Among 25 American Blacks studied (15 were unrelated), 2 related individuals have one extra copy of the Hpr gene and 5 unrelated individuals have more than two extra Hpr genes. None of 26 Whites and one Oriental studied have extra copies. In one of the Blacks, six tandemly arranged Hpr genes were demonstrated in one chromosome by pulsed field gradient electrophoresis. His other chromosome had one Hpr gene. The tandem Hpr genes were found in individuals with the haptoglobin genotypes Hp2/Hp2 (3 of 3 tested) and Hp2/Hp1 (4 of 11 tested), but none were found in the Hp1/Hp1 individuals (11 tested). Fibroblast cell cultures from two Hp2/Hp1 heterozygotes were fused to mouse cells to obtain cell lines retaining a human chromosome 16 on which the haptoglobin gene cluster is located. DNA analysis of the hybrid cells showed that in both individuals the tandemly arranged Hpr genes are linked to the Hp2 allele. These results suggest that the multiple copies are associated with the Hp2 gene.

Base Sequence↗
PubMed1975

Cross-linking of hemoglobin, haptoglobin, and hemoglobin-haptoglobin complex with bifunctional imidoesters.

Dimethyl adipimidate was used to cross-link the polypeptides within hemoglobin, haptoglobin, and hemoglobin-haptoglobin complex. Cross-linked hemoglobin retained considerable ability to bind haptoglobin, although the amounts bound were reduced and the haptoglobin reaction could be used to fractionate the modified hemoglobin. With cross-links limited to intramolecular sites, hemoglobin showed four bands on polyacrylamide gel electrophoresis in sodium dodecyl sulfate, identified, with reference to the subunit polypeptides, as monomer, dimer, trimer, and tetramer. The dimer region consisted of at least two separable species. When hemoglobin-haptoglobin complex was cross-linked, a band of hemoglobin dimer was present, which demonstrates that at least two hemoglobin subunits have a close spatial relation when bound to haptoglobin. Some comparisons with adipimidate-reacted hemoglobin were made using malonimidate and suberimidate and some marked differences were noted.

Animals↗
PubMed1996

Determination of intermediates of hemoglobin-haptoglobin complex of haptoglobin polymers by "Crossed hemoglobin electrophoresis".

We designed a "crossed hemoglobin electrophoresis" to be able to detect the intermediates of a hemoglobin-haptoglobin complex without the need for the purification step of haptoglobin molecules. Native polyacrylamide gel electrophoresis was performed as the first dimensional electrophoresis followed by a cross to hemoglobin as the second dimensional electrophoresis. Using this method, we found that a number of intermediates of normal Hp 2-2, Hp 2-1 polymers, particularly those from the trimer to the pentamer, were detected on a polyacrylamide gel. Each of their polymers combined to the hexamer with at least an equimolar content of hemoglobin. In the process of detecting the haptoglobin serotype of more than 10,000 patients for the clinical utilization of quantitative analytical data, we observed two haptoglobin variants, the Hp Johnson and a haptoglobin serotype similar to the Carlberg type. Using our crossed hemoglobin electrophoresis, we also detected the capacity for combining with hemoglobin of each polymer of these variants.

Electrophoresis, Gel, Two-Dimensional↗
PubMed1979

Canine haptoglobin: a unique haptoglobin subunit arrangement.

1. Isolated canine haptoglobin behaved identically to the alpha 2 beta 2 structure typical of human haptoglobin type 1-1 on alkaline polyacrylamide gel electrophoresis and on gel filtration. 2. In the presence of urea or sodium dodecyl sulphate canine haptoglobin dissociated into alpha beta subunits that separated into alpha and beta chains after reduction with 2-mercaptoethanol. 3. Compositional analysis identified one less half-cystine in canine alpha chain when compared to human alpha 1 chain. 4. These results provide evidence that there is no inter alpha chain disulphide in canine haptoglobin comparable to the alpha 1 20-alpha 1 20 disulphide in human haptoglobin that links the two alpha beta subunits.

Amino Acids↗
PubMed1991

Monoclonal antibody to human haptoglobin reacts with goat haptoglobin.

1. Monoclonal antibody 2.36.71.41 produced to human haptoglobin forms precipitates with goat haptoglobin in double immunodiffusion and electroimmunodiffusion. 2. Solid-phase immunoenzymatic assay (ELISA) based on the reaction of the monoclonal antibody 2.36.71.41 with goat haptoglobin can be used for quantitative estimation of haptoglobin content in goat sera. 3. The minimum detectable concentration of goat haptoglobin is 0.03 micrograms/ml.

Animals↗