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PubMed1998

Semiautomatic and robotic methods for determining serum haptoglobin levels.

The assay of Makimura and Suzuki for serum haptoglobin has been adapted to use one tube with both semiautomated and robotic methods. The adaptation permits the determination of haptoglobin in several hundred serum samples per day. Both methods were strongly correlated with the original two-tube method and had within-assay variability of 4.4% for the semiautomated and 4.8% for the robotic method. Day-to-day variability averaged 6.0% for the semiautomated and 5.5% for the robotic method. The y-intercepts for both assays were higher than that of the original two-tube method, and thus, reference values are higher than those reported previously.

Journal Article↗
PubMed2026

Cryo-EM provides insight into how the Staphylococcus aureus IsdH receptor removes hemin from the hemoglobin:haptoglobin complex.

Staphylococcus aureus extracts hemin from human hemoglobin (Hb) to overcome host-imposed iron limitation. How it recovers Hb-bound hemin from the hemoglobin:haptoglobin (Hb:Hp) complex, the major circulating form of Hb outside red blood cells, remains unclear. Here we use cryo-electron microscopy, biophysical measurements, and solution kinetics to define how the S. aureus IsdH surface receptor extracts hemin from Hb:Hp. A 3.1 Å cryo-EM structure of Hb:Hp bound by full-length IsdH reveals that its N-terminal NEAT domain (N1) anchors it to αHb, whereas its downstream N2N3 extraction unit engages βHb to remove its hemin. The receptor engages Hb:Hp differently than isolated Hb, because N-linked glycans on haptoglobin bias the extraction unit toward βHb, sterically occluding its access to αHb while still permitting engagement by N1. Kinetic assays show that IsdH actively accelerates hemin release from Hb:Hp. Three-dimensional variability analysis indicates that this likely occurs via a dynamic interface in which receptor motions reposition the extraction unit relative to βHb, collectively supporting a model in which IsdH transiently perturbs the F-helix to promote hemin extraction. Alignment of that model with a previously determined CD163:Hb:Hp structure shows how IsdH may disrupt Hb:Hp recognition by macrophage and monocyte CD163 receptors, helping to explain how it may hinder clearance of Hb:Hp from circulation. In aggregate, these results help define the structural basis for hemin extraction from Hb:Hp and how IsdH may subvert receptor-mediated clearance of the Hb:Hp complex.

Journal Article↗
PubMed1964

HAPTOGLOBIN BINDING CAPACITY OF CERTAIN ABNORMAL HEMOGLOBINS.

Hemoglobins H and Bart's failed to bind human haptoglobin. The binding of hemoglobins A(1), F, I, and Lepore was comparable to that of hemoglobin A. These findings suggest that configurational differences or the absence of alpha chain dimers was responsible for the lack of binding of hemoglobins H and Bart's.

Blood Protein Electrophoresis↗
PubMed1964

ESTIMATION OF SERUM HAEMOGLOBIN-BINDING CAPACITY (HAPTOGLOBIN) ON SEPHADEX G.100.

A method is described for the estimation of serum haptoglobin as ;haemoglobin-binding capacity'. The method relies on column chromatographic separation of the haemoglobin/haptoglobin complex from excess added free haemoglobin on the dextran gel Sephadex G.100. The method is simple and reproducible, and correlates well with another method of estimating haemoglobin-binding capacity over a wide range of values.

Chromatography↗
PubMed1965

DIAGNOSTIC VALUE OF SERUM HAPTOGLOBIN.

Serum haptoglobin has been estimated quantitatively in 25 patients with haemolytic disease, and its diagnostic value assessed by comparing the levels with those obtained in 110normal subjects, in 149 patients with other forms of anaemia, and in 37 patients with non-haematological disorders. The normal range was found to be 33 to 213 mg./100 ml.; subnormal levels were found in 80% of patients with haemolytic disease or megaloblastic anaemia, patients with haemorrhage into the tissues, and occasionally in association with other diseases. When taken in conjunction with other clinical and laboratory features this simple biochemical estimation can be of diagnostic value.

Adolescent↗
PubMed1996

A new approach to fecal occult blood testing based on the detection of haptoglobin.

BACKGROUND: Colorectal carcinoma is a common disease, occurring in 1 in 20 adults in Western society, and there is a compelling need for an effective early diagnostic test. Several serum tests, including carcinoembryonic antigen have been used, but none are sufficiently sensitive for the early diagnosis of the disease. METHODS: In a novel approach using fecal extracts from patients with colorectal cancer as the antigen for immunization, several MoAbs were produced. One (FE14.1) was found to react with the feces from patients with colon cancer, but not with those from normal subjects. A sandwich enzyme-linked immunoadsorbent assay was developed, and its ability to diagnose colorectal carcinoma evaluated. RESULTS: Of the patients with colorectal carcinoma, 91.5% (43/46) were positive compared with 1.9% of normal individuals (4/211). Analysis of the N-terminal amino acid sequence of a subunit of the molecule detected by FE14.1 shows it to be the beta chain of haptoglobin. CONCLUSIONS: The assay developed in this study has several advantages compared with current fecal occult blood tests, including no requirement for dietary restriction and the ability to distinguish between upper and lower gastrointestinal bleeding, while retaining the sensitivity and specificity of the current tests. Furthermore, the sensitivity of the tests increases to 100% if the FE14.1 and HemeSelect are combined. In addition, the study shows the potential to produce anticancer agents by immunizing with fecal material.

Adult↗
PubMed1989

Genetic variation of haptoglobin and transferrin in relation to DNA content and stage in renal cell carcinoma.

Four genetic marker systems were investigated in 102 patients with renal cell carcinoma. The previously observed excess of the transferrin (TF) variant C3 among male patients was confirmed. Interestingly, an excess of TFC3 and a deficit of the haptoglobin heterozygote, HP2-1, were associated with diploid tumor DNA content and Stage I, particularly in male patients. The results are discussed in terms of a possible genetic influence on tumor progression.

Carcinoma, Renal Cell↗
PubMed1975

Anthropological studies among Libyans. Erythrocyte genetic factors, serum haptoglobin phenotypes and anthropometry.

Anthropological studies were done on 1276 Libyans from the Mediterranean cities of Tripoli and Benghazi, and from Sabha southward in The Sahara. The incidences of hemoglobin (Hb)-S and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency were low in the coastal areas and significantly high in Sabha. Hb-C occurred sporadically in Tripoli and Sabha, and was absent from Benghazi in the east. One case of Hb-J Benghazi was noted. There were no sigificant differences in the ABO blood group and Rh0 (D) type distributions in the three localities. G-6-PD gene GdAfrequency was significantly high in Sabha. The lowest value of 6-phosphogluconate dehydrogenase (6-PGD) gene PGDA frequency and highest value of the gene PGDC were in Sabha. Adenylate kinase (AK) gene AK2 was only detectable in Tripoli. Acid phosphatase (AP) gene Pa frequency in Sabha was more than twice that in Tripoli and Benghazi, while pc was distinctly lower in Sabha than in the northern cities. Haptoglobin gene Hp1 frequency was almost identical in all areas. Anthropometric measurements revealed overall homogeneity of the three samples, closer similarity in the coastal region to adjacent North African populations, and Negroid influence in the Sahara Libyans. Anthropometry substantiated findings from blood markers.

ABO Blood-Group System↗
PubMed1992

Haptoglobin-stimulated bone resorption in neonatal mouse calvarial bones in vitro.

OBJECTIVE: To study the in vitro effects of human haptoglobin (Hp) on bone resorption and prostanoid formation. METHODS: Parietal bones were dissected out from neonatal mice that had been injected with 45Ca, and were cultured in chemically defined medium with or without test substances. Bone resorption was assessed by analysis of 45Ca release. Prostanoid formation was quantified by analysis of the amount of prostaglandin E2 (PGE2) in culture medium. RESULTS: Hp phenotype 2-1, in quantities greater than or equal to 0.17 mg/ml, stimulated the release of 45Ca and the biosynthesis of PGE2, in a time- and dose-dependent manner. Hp-induced PGE2 formation was abolished by indomethacin and flurbiprofen, whereas the stimulation of 45Ca release was only partially reduced. CONCLUSION: These observations suggest that the acute-phase reactant Hp may contribute, by a humoral mechanism, to the bone resorption seen in chronic inflammatory processes.

Animals↗
PubMed2006

Regulation of surface CD163 expression and cellular effects of receptor mediated hemoglobin-haptoglobin uptake on human monocytes and macrophages.

Local dysregulation of iron metabolism is suggested to contribute to atherosclerotic lesion development through hemoglobin scavenging pathways. We evaluated the effects of CD163-mediated uptake of hemoglobin-haptoglobin (HbHp) complexes on surface CD163 and intracellular heme oxygenase-1 expression and the secretion of pro- and antiinflammatory cytokines by macrophages. We found that increased availability of HbHp complexes triggers the upregulation of surface CD163, and also results in a dose-dependent secretion of IL-6 and IL-10.

Antigens, CD↗
PubMedDate not supplied

Increased renal hypertrophy in diabetic mice genetically modified at the haptoglobin locus.

BACKGROUND: The human haptoglobin (Hp) gene is polymorphic with two functional classes of alleles, denoted 1 and 2. We have demonstrated in three longitudinal studies and several cross-sectional studies that the Hp genotype is an independent risk factor for diabetic vascular disease. These studies have presented a compelling argument that diabetic individuals homozygous for the Hp 1 allele are at decreased risk of vascular complications as compared to diabetic individuals with the Hp 2 allele. METHODS: The naturally occurring (wild type) mouse Hp is a class 1 Hp allele. We examined renal hypertrophy in wild-type mice, Hp knockout mice (Hp 0), and in mice with the Hp 2 allele (Hp 2) with and without diabetes. RESULTS: In the absence of diabetes, we found that renal hypertrophy was significantly increased in Hp 0 mice and that this could be prevented with vitamin E. There was no difference between wild type and Hp 2 mice with regard to renal hypertrophy in the absence of diabetes. However, in the presence of diabetes, Hp 2 mice demonstrated a significant increase in renal hypertrophy as compared to wild-type mice. CONCLUSIONS: These results support a direct linkage between diabetic vascular disease and the Hp genotype. These Hp-modified mice may serve as a platform on which to test a variety of pharmacological agents in order to decrease diabetic vascular disease.

Animals↗
PubMed2007

Retinal capillary basement membrane thickness in diabetic mice genetically modified at the haptoglobin locus.

BACKGROUND: Individuals with diabetes mellitus (DM) homozygous for the haptoglobin (Hp) 1 allele are at decreased risk of retinopathy as compared to DM individuals with the Hp 2 allele. We sought to recapitulate these findings in DM mice genetically modified at the Hp locus. METHODS: An early morphological characteristic of the microangiopathy seen in diabetic retinal disease is retinal capillary basement membrane (RCBM) thickening. RCBM thickness as assessed by electron microscopy was performed on a total of 12 eyes taken from three mice in each of the four study groups (three eyes from C57Bl/6 Hp 1 and C57Bl/6 Hp 2 mice with and without streptozotocin-induced diabetes). RESULTS: The non-parametric Kruskal-Wallis ANOVA test demonstrated that there was a highly significant difference between the four groups of mice (P < 0.0001). Mann-Whitney tests for specific pair-wise comparisons demonstrated that there was no significant difference in the RCBM thickness between Hp 1 and Hp 2 mice (p = 0.70) or between DM Hp 1 and non-DM Hp 1 mice (p = 0.42). However, induction of diabetes resulted in a marked increase in RCBM thickness in Hp 2 mice compared to non-DM Hp 2 mice (p = 0.0004) and compared to DM Hp 1 mice (p = 0.0005). CONCLUSIONS: A highly significant increase in RCBM thickness was observed in DM mice with the Hp 2 genotype. These data provide important support for association studies done in humans showing an increased prevalence of diabetic retinopathy in individuals with the Hp 2 genotype.

Animals↗
PubMed1990

Haptoglobin subtype determination by isoelectric focusing in agarose gel: application to paternity testing and presentation of a new alpha 2-variant.

Haptoglobin subtyping of a Danish population sample (n = 2184) by a modified isoelectric focusing/immunoblotting method, using agarose gel and visualization by an alkaline phosphatase conjugated antibody, is presented. The allele frequencies were: Hp*1F 0.151; Hp*1S 0.241; Hp*2FS 0.565; Hp*2SS 0.040; Hp*2FF 0.002; Hp J*0.0002. Based on these data the theoretical change of exclusion of nonfathers in paternity cases was calculated to be 35%. Examination of 51 families with 120 children and of 648 mother/child pairs showed no exceptions from Mendelian inheritance. The results obtained by application of Hp subtyping to 405 paternity cases are given and the reliability of the method is discussed. A new alpha 2-variant occurring in the father and in two of three siblings of a Danish family is presented.

Alleles↗
PubMed1990

Haptoglobin subtyping by isoelectric focusing in miniaturized polyacrylamide gels rehydrated in presence of 2-mercaptoethanol.

A fast isoelectric focusing method for routine haptoglobin (Hp) subtyping is presented. This method is based on isoelectric focusing, under reducting conditions, of neuraminidase-treated plasma samples by using dry miniaturized (interelectrode distance: 55 mm) polyacrylamide gel, rehydrated in presence of 2-mercaptoethanol and a mixture of pharmalyte carrier ampholytes (pH 4-6.5 and pH 6-8) followed by immunoblotting. The presence of 2-mercaptoethanol in the gel prevented refolding of the Hp alpha and Hp beta chains during focusing, making it possible to obtain a sharp Hp band pattern with a clear separation of the different Hp alpha allelic products (1S, 1F, 2FS, 2SS and 2FF). A population study carried out with 250 unrelated individuals living in Central Spain is also presented.

Acrylic Resins↗
PubMed1986

Progress toward resolving the possible linkage of multiple endocrine neoplasia type 2A to haptoglobin and group-specific loci: use of restriction fragment length polymorphisms extends exclusion region.

In an earlier paper, positive but nonsignificant lod scores were found in pair-wise linkage tests between multiple endocrine neoplasia type 2A (MEN-2A) and both the haptoglobin (HP) locus on chromosome 16 and group-specific component (GC) locus on chromosome 4. Recently discovered restriction fragment length polymorphisms for HP and for metallothionein 2 processed pseudogene 1 (MT2P1) near GC have made it possible to carry out a more powerful set of linkage tests with MEN-2A. This paper reports the results of such linkage analyses employing both pair-wise and multipoint tests. Close linkage of HP on chromosome 16 and MEN-2A is excluded. Linkage of MEN-2A on chromosome 4 with GC is excluded on the MT2P1 side of GC in a 7-centimorgan interval around MT2P1.

Blood Protein Electrophoresis↗
PubMed1998

Acute-phase induced phosphorylation of rat liver nucleoprotein p70 modulates its binding affinity for the haptoglobin gene.

An increase in the binding affinity of rat liver trans-acting nucleoprotein p70 for the hormone responsive element of the rat haptoglobin gene in acute-phase reactions has implicated a posttranslational modification. This investigation examines the proposed acute-phase related structural alterations of p70 using an in vitro phosphorylation/dephosphorylation assay and selective digestion of p70 with Staphylococcal aureus V8 protease. The results show that p70 requires phosphorylation to express its DNA-binding ability. Selective proteolysis of p70 provided evidence that acute-phase induced phosphorylation of this protein alters its conformation in such a way that its DNA-binding ability is increased.

Acute-Phase Reaction↗
PubMed1983

Molecular cloning of human haptoglobin cDNA: evidence for a single mRNA coding for alpha 2 and beta chains.

Human haptoglobin (Hp) is a plasma glycoprotein composed of alpha and beta polypeptide chains that are covalently associated by disulfide bonds. It had been suggested that alpha and beta polypeptides could be synthesized via a common precursor polypeptide. We report the molecular cloning of DNA complementary to human Hp mRNA. One of the clones, pULB1148, carries a full length copy coding for both alpha 2 and beta polypeptides. In vitro translation of human liver mRNA hybridizing with this cDNA gives a protein mol. wt. of 49000 daltons. The sequence of the alpha 2 beta cDNA shows the presence of a single Arg residue between Gln 142 of the alpha 2 chain and Ileu 1 of the beta chain. With a few minor exceptions, the DNA sequence fits the previously published amino acid sequences. The differences are the presence of an Asp residue at position 52 of alpha 2 instead of Asn, the existence in beta of only one Lys residue between Gly 65 and the following Gln, the presence of Ser and Cys at positions 218-219 instead of Cys-Ser, and of Asp residues at positions 205 and 235 instead of Asn.

Amino Acid Sequence↗
PubMed2001

Haptoglobin inhibits lecithin-cholesterol acyltransferase in human ovarian follicular fluid.

The activity of the enzyme lecithin-cholesterol acyltransferase (LCAT; E.C. 2.3.1.43) is involved in the removal of cholesterol excess from peripheral cells. This activity is stimulated by the HDL (high density lipoprotein) apolipoprotein A1 (ApoA1). Haptoglobin (Hpt) was previously found to be associated with ApoA1 in ovarian follicular fluid. LCAT activity was analyzed in follicular fluids, collected from an IVF program, containing different amounts of Hpt or Hpt/ApoA1 ratio. Addition of purified Hpt to follicular fluid caused a decrease in the enzyme activity, which was measured as the rate of synthesis of cholesteryl esters. In the fractions of fluid proteins, as obtained by gel filtration chromatography, Hpt and HDL were titrated by ELISA while the LCAT activity was assayed by using radioactive cholesterol and purified HDL. When isolated LCAT was incubated with fractions containing different Hpt/ApoA1 ratios, the enzyme activity was found negatively correlated with the Hpt/ApoA1 ratio (P < 0.01). LCAT kinetic parameters were measured in two fractions with the same amount of ApoA1 (5 microg/ml) but different amounts of Hpt (0.69 or 3.77 microg/ml): the V(max) did not change while the K(m) values were 24.1 or 78.6 microM in the presence of the low or high Hpt level, respectively. The analysis of fluids associated with cytoplasmically mature MII oocytes, in a cross-sectional study, confirmed that a negative correlation exists between the Hpt/ApoA1 ratio and the LCAT activity (P < 0.01). The results suggest that Hpt inhibits the reverse transport of cholesterol by preventing ApoA1 stimulation of the LCAT activity.

Apolipoprotein A-I↗