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PubMed1976

Reaction of haptoglobin with hemoglobin covalently cross-linked between the alpha beta dimers.

Hemoglobin tetramers which cannot split into alphabeta dimers, because they are covalently cross-linked between the beta chains across the polyphosphate binding site, form complexes with haptoglobin. The reaction is biphasic as measured by fluorescence quenching and peroxidase activity. A complex in which one of the alpha beta dimers of the cross-linked hemoglobin is bound to one of the sites in the divalent haptoglobin molecule, is formed reversibly during the initial fast phase. In the subsequent slower step, this product then either polymerizes, adds another cross-linked hemoglobin molecule or, in the presence of excess haptoglobin, combines with a second haptoglobin molecule. This latter complex, in which two haptoglobin molecules are bridged by a cross-linked hemoglobin tetramer, can still combine with normal alpha beta dimers at the vacant haptoglobin combining sites. In spite of the very low oxygen affinity of the cross-linked hemoglobin, combination with haptoglobin shifts if oxygen affinity to the very high value of the normal hemoglobin-haptoglobin complex.

Binding Sites↗

PubMed1991

Haptoglobin and ceruloplasmin as determinants of inflammation in dogs.

Assay procedures for determining serum haptoglobin concentration and ceruloplasmin oxidase activity in dogs were validated, and reference values were established. Serum haptoglobin concentration is reported as milligrams per deciliter of cyanmethemoglobin binding capacity, whereas serum ceruloplasmin oxidase activity was determined by use of p-phenylenediamine as substrate. Both assays were used to analyze serum samples from 288 dogs. In each dog's case record, clinical history and final diagnosis were evaluated to determine whether the dog had an inflammatory condition. Complete blood cell counts were performed in 265 dogs, using simultaneously collected blood samples. Plasma fibrinogen concentration was determined for 161 dogs. A positive correlation (P less than 0.01) for serum haptoglobin concentration and for ceruloplasmin oxidase activity, compared with WBC counts, segmented neutrophil and band neutrophil counts, and plasma fibrinogen concentration. Ceruloplasmin oxidase activity and haptoglobin concentration were up to 6 times more sensitive than fibrinogen concentration or leukocyte counts in detecting inflammation. Specificity of ceruloplasmin oxidase activity was comparable to fibrinogen concentration and leukocyte counts, whereas haptoglobin concentration was found to be slightly less specific. Specificity of haptoglobin concentration improved slightly (from 0.82 to 0.88) when dogs with a history of glucocorticoid administration were excluded from analysis. Predictive value of a negative test result (haptoglobin concentration less than 125 mg/dl; ceruloplasmin oxidase activity less than 20 IU/L) and predictive value of a positive test result for haptoglobin concentration and ceruloplasmin activity were comparable to or better than fibrinogen concentration or various oxidase leukocyte counts in detection of inflammation in a variety of disease conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

[Immunochemical characteristics of the ovine polymeric haptoglobin HpC].

It was found that haptoglobins of camel, cattle, horse, pig, rat, guinea pig and man form upon immunoelectrophoresis precipitation arcs with antibodies against polymeric sheep haptoglobin C, corresponding to alpha 2-globulins. The immunocrossreactivity of haptoglobins of man and various animal species towards antibody to sheep haptoglobin (100, 88.0, 75.2, 72.1, 56.3, 51.0, 41.3 and 28.0% for haptoglobin of sheep, camel, pig, cattle, man, rat, guinea pig and horse, respectively) was determined. The intensity of crossreactions between sheep haptoglobin and the proteins under study towards antibody to haptoglobin C reflects the similarity of their primary structure and, consequently, the immune homology of their molecules. Using quantitative titration, the antigenic valency values for human (6), sheep (5), cattle (4) and horse (3) haptoglobins were determined.

Animals↗

PubMed1987

An analogy between fetal haptoglobin and a potent immunosuppressant in cancer.

In spite of the numerous reports indicating the presence of humoral immunosuppressive factors in cancer patients, only a few of these factors have been biochemically identified. Furthermore, their role as effective immunosuppressors in vivo remains to be established. Our laboratory has attempted to isolate and identify the major immunosuppressive factor in the malignant effusions derived from ovarian and lung cancer patients. We have previously demonstrated that the Mr 52,000 immunosuppressive factor isolated from the ascites fluid of an ovarian cancer patient inhibited T-dependent immune responses in vivo and in vitro including the inhibition of E-rosetting. Thus, this immunosuppressive factor was named "suppressive E-receptor" (SER). Our current study demonstrates that this SER factor purified from malignant effusions derived from ovarian, lung, or head and neck cancer patients had a common component which dissociated equally into Mr 38,000-42,000 and 17,000-19,000 moieties on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under vigorous reducing conditions. Electroelution of these two components followed by a limited amino acid sequence determination revealed these two components to have N-terminal amino acid sequences identical to the beta and alpha 2 subunits of normal adult haptoglobin. Immunoelectrophoresis of SER using a polyclonal antiserum to neonatal cord blood demonstrated that SER, unlike normal haptoglobin, has slower electrophoretic mobility than the normal adult haptoglobin. Western blotting analysis of SER separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis under denaturing conditions failed to recognize a monoclonal antibody directed specifically to SER. However, this monoclonal antibody exclusively reacted with the SER separated by an analytical polyacrylamide gel electrophoresis gel under nondenaturing conditions while normal adult haptoglobins or purified but denatured haptoglobin obtained from the same malignant fluid as SER all failed to react with this antibody. Thus, SER appears to bear an additional epitope(s) that is absent in normal adult haptoglobin. Since the SER as well as the neonatal haptoglobin have at least 100 to 1000-fold more potent immunosuppressive activity than the normal adult haptoglobin, this additional epitope(s) present in SER may be responsible for the potent immunosuppressive property of SER.

Amino Acid Sequence↗

PubMed1982

Hemoglobin binding site and its relationship to the serine protease-like active site of haptoglobin.

Haptoglobin forms a stable, irreversible complex with hemoglobin. The H chain of haptoglobin, which is the subunit that binds hemoglobin, shows strong sequence homology with the serine protease family. This raises the question of whether hemoglobin binds to the protease-like active site pocket of H chain as the protease inhibitors do with serine proteases. This question can be tested by binding proflavin and thionin to haptoglobin because these dyes are known to interact specifically with serine proteases at the peptide binding site. A single, specific binding site, characteristic of the serine proteases, was found for haptoglobin with association constants for proflavin or 1.4 x 10(3) at pH 7.1 and 8.2 x 10(3) at pH 9.5 and for thionin of 3.5 x 10(3) at pH 7.1. In order to confirm that these dyes are indeed binding to the specificity pocket of haptoglobin, competition experiments with classical serine protease substrates and inhibitors were performed. The results showed that trypsin-specific substrates and inhibitors did compete with proflavin binding, as expected from the homology, and that reagents of a chymotryptic specificity did not. When the dye titrations were performed on haptoglobin-hemoglobin complex, the same binding constants were obtained as for haptoglobin alone. This demonstrates that the active site-like region of haptoglobin and the hemoglobin binding site are mutually exclusive and do not interact in any way.

Binding Sites↗

PubMed1994

Dexamethasone-induced haptoglobin release by calf liver parenchymal cells.

Parenchymal cells were isolated from the liver of male calves, and monolayer cultures formed were treated with glucocorticoids to examine whether haptoglobin, appearance of which is associated with hepatic lipidosis (fatty liver) in cattle, is induced by steroid hormones. Without addition of dexamethasone, only trace amounts of haptoglobin were detected in culture medium. With addition of dexamethasone (10(-12) to 10(-4) M), considerable amounts of haptoglobin were released into the medium. Maximal release was observed at concentrations of 10(-8) to 10(-6) M dexamethasone. Haptoglobin release was similarly induced by cortisol, although the effect was less potent than that of dexamethasone. Actinomycin D (a known protein synthesis inhibitor) dose-dependently reduced amounts of haptoglobin released in response to 10(-8) M dexamethasone. Dexamethasone also induced annexin I, which is known to be synthesized in response to glucocorticoids. Dexamethasone treatment resulted in reduced protein kinase C activity in the cell cytosol, which has been shown to be an early event in dexamethasone-treated cells. Other than glucocorticoids, estradiol induced haptoglobin release, whereas progesterone was less effective. The association of haptoglobin with hepatic lipidosis can be reasonably explained by the fact that haptoglobin production by the liver is induced by glucocorticoids and estradiol, and these steroid hormones are triggers for development of hepatic lipidosis in cattle.

Animals↗

PubMed1993

[Causes of anomalous patterns of haptoglobin using polyacrylamide gel electrophoresis].

We could observe several anomalous electrophoretic patterns of haptoglobin during serotype analysis. We classified these anomalous patterns of haptoglobin into two major classes. The first is the change of number of haptoglobin bands, and the second is the shift from the normal serotype patterns. The change of number of haptoglobin bands was caused by unsaturation of haptoglobin in binding with hemoglobin, mixing of different serotypes by blood transfusion or injection of haptoglobin and serotype variants of haptoglobin. The shift of haptoglobin PAGE pattern was occurred from a large amount of M-protein or lipoproteins in serum.

Electrophoresis, Polyacrylamide Gel↗

PubMed1993

[Decrease of haptoglobin serum level in patients with chronic viral hepatitis C].

Serum levels of haptoglobin, an acute phase protein, in usually increased in patients with inflammation and decreased in patients with intravascular hemolysis. Changes in haptoglobin serum levels were also observed in patients with liver disease. The aim of this study was to evaluate the serum level of haptoglobin in patients with chronic viral hepatitis C. Haptoglobin serum levels were measured by rate nephelometry in 34 patients with histologically proven chronic viral hepatitis C and in 30 controls. Haptoglobin serum levels were lower in patients than in controls (0.56 +/- 0.36 versus 0.90 +/- 0.35 g/L, P < 0.001). In patients with chronic hepatitis but without cirrhosis, haptoglobin serum levels were decreased as well. Haptoglobin serum levels were positively correlated to prothrombin index (P < 0.001) and negatively correlated to the histology activity index of Knodell (P < 0.001), and especially to scores of fibrosis (P < 0.001) and periportal necrosis (P < 0.05). Red cell count, indirect bilirubin level, and reticulocyte count, as markers of hemolysis, were similar in patients and controls. We conclude that determination of haptoglobin serum levels may be useful in the evaluation and the follow-up of patients with chronic viral hepatitis C.

Adult↗

PubMed1993

The effect of exploratory laparotomy on the serum and peritoneal haptoglobin concentrations of the pony.

Serum haptoglobin concentration was used as an indicator of the acute phase response in ponies undergoing exploratory laparotomy. Preoperative, 1 h intraoperative, 3 h, 6 h, 12 h and 24 h postoperative blood samples and 48 h postoperative peritoneal fluid samples were obtained for haptoglobin analysis. A spectrophotometric assay based on cyanmethemoglobin binding capacity (CyanBC) was used to determine haptoglobin concentrations. The preoperative reference range for serum haptoglobin concentrations in these ponies was 25-60 mg CyanBC/dL. Intraoperative and 3 h postoperative blood samples had decreased haptoglobin concentrations when compared to preoperative values. Serum haptoglobin concentrations began to rise by the 6 h postoperative sample and were generally elevated above preoperative values by the 24 h postoperative sample. Two of the ten ponies had mild signs of postoperative colic which were associated with twofold elevations in serum haptoglobin concentrations and fivefold elevations in peritoneal fluid haptoglobin concentrations.

Acute-Phase Reaction↗

PubMed1999

Effect of multiple mutations in the hemoglobin- and hemoglobin-haptoglobin-binding proteins, HgpA, HgpB, and HgpC, of Haemophilus influenzae type b.

Haemophilus influenzae requires heme for growth and can utilize hemoglobin and hemoglobin-haptoglobin as heme sources. We previously identified two hemoglobin- and hemoglobin-haptoglobin-binding proteins, HgpA and HgpB, in H. influenzae HI689. Insertional mutation of hgpA and hgpB, either singly or together, did not abrogate the ability to utilize or bind either hemoglobin or the hemoglobin-haptoglobin complex. A hemoglobin affinity purification method was used to isolate a protein of approximately 120 kDa from the hgpA hgpB double mutant. We have cloned and sequenced the gene encoding this third hemoglobin/hemoglobin-haptoglobin binding protein and designate it hgpC. Insertional mutation of hgpC did not affect the ability of the strain to utilize either hemoglobin or hemoglobin-haptoglobin. An hgpA hgpB hgpC triple mutant constructed by insertional mutagenesis showed a reduced ability to use the hemoglobin-haptoglobin complex but was unaltered in the ability to use hemoglobin. A second class of mutants was constructed in which the entire structural gene of each of the three proteins was deleted. The hgpA hgpB hgpC complete-deletion triple mutant was unable to utilize the hemoglobin-haptoglobin complex and showed a reduced ability to use hemoglobin. We have identified three hemoglobin/hemoglobin-haptoglobin-binding proteins in Haemophilus influenzae. Any one of the three proteins is sufficient to support growth with hemoglobin-haptoglobin as the heme source, and expression of at least one of the three is essential for hemoglobin-haptoglobin utilization. Although the three proteins play a role in hemoglobin utilization, an additional hemoglobin acquisition mechanism(s) exists.

Amino Acid Sequence↗

PubMed1993

Ascites levels of haptoglobin in patients with ovarian cancer.

BACKGROUND: Haptoglobin is an acute-phase reactant protein involved in immune regulation. It has been isolated from malignant ovarian ascites and has been shown to be capable of mediating nonspecific immune suppression in vitro in humans and in vivo in experimental animals. The range of concentrations under which such a nonspecific suppression is observed lies well within concentrations of haptoglobin observed in vivo. This immune suppression could adversely affect patient outcome. METHODS: Based on this information, ascites haptoglobin levels of 21 consecutive patients with ovarian cancer who underwent initial surgical debulking were determined. After the patients received chemotherapy, they were divided into those having a positive and those have a negative second-look operation. RESULTS: Seventeen patients with positive pathology at second look had an initial mean ascites haptoglobin level of 99 +/- 49 mg/dl. The mean haptoglobin level in the four patients with negative findings was 67 +/- 42 mg/dl. The difference in these mean haptoglobin levels is not statistically significant (P > 0.05). CONCLUSION: Although the number of patients in this study is small, the wide range of values documented in both groups make it doubtful that an initial absolute ascites haptoglobin level will prove clinically prognostic of eventual disease status at the time of second look laparotomy.

Adenocarcinoma↗

PubMed1990

Reduced serum haptoglobin values in hemophiliacs receiving monoclonally purified factor VIII concentrates.

Hemophiliacs often have mild anemia, and hemolysis has been suggested as the likely mechanism on the basis of the reduced serum haptoglobin values frequently observed in these patients. It has been suggested that hypohaptoglobinemia results from isohemagglutinins or other contaminating proteins in the infused factor concentrates. The advent and increased utilization of Factor VIII concentrates that are highly purified by use of monoclonal antibodies have provided the opportunity to study whether proteins other than Factor VIII contained in the concentrate induce hemolysis. Of 49 consecutively studied Factor VIII-deficient hemophiliacs, 19 (39%) had a reduced serum haptoglobin level (less than 27 mg/dl). In particular, 16 of 35 (46%) of patients receiving only monoclonally purified Factor VIII products (Monoclate or Hemofil-M) had a reduced serum haptoglobin value. Haptoglobin measurements were variable on repeat measurement in 8 patients. Haptoglobin levels did not correlate with type or severity of hemophilia, hemoglobin value, or alterations in liver function. Low serum haptoglobin values were also observed in children with leukemia, without apparent hemolysis, who had extensive cutaneous hemorrhage associated with thrombocytopenia. We propose that reduced serum haptoglobin values in hemophiliacs do not result from immune-mediated hemolysis due to contaminating proteins in the concentrate. Moreover, hypohaptoglobinemia may not be due to hemolysis at all but may instead result from dissolution of hematomas and other foci of internal hemorrhage.

Adolescent↗

PubMed2004

Mass spectrometric protein structure characterization reveals cause of migration differences of haptoglobin alpha chains in two-dimensional gel electrophoresis.

Haptoglobin belongs to the major constituents of plasma and acts as hemoglobin-binding and acute-phase protein. Due to the occurrence of three major allelic variants and further structural modifications, the alpha chains of haptoglobin form varying spot patterns in two-dimensional gel electrophoresis (2-DE) gels, which is generally observed in differential proteome analyses using plasma or related body fluids of humans. In the present study plasma samples from 10 donors of initially unknown haptoglobin phenotype were separated by 2-DE and tryptic digests of excised haptoglobin alpha chain spots were analyzed by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) and MALDI-quadrupole ion trap TOF-MS. Haptoglobin alpha1S, alpha1F, as well as alpha2 chains were found to occur each with at least three structurally differing protein species: (i) the unmodified form, which corresponds to the sequence database entries; (ii) derivatives, in which asparagine at position five is deamidated to aspartic acid; and (iii) derivatives with an additional C-terminal arginine residue. These structural variants account for the most commonly observed spot patterns of haptoglobin alpha chains in Coomassie-stained gels. Additionally, a minor derivative of the haptoglobin alpha2 chain carrying both modifications, deamidation at position five and the C-terminal arginine residue, was identified. Theoretical pI values of the characterized structural variants are, consistent with their observed migration in the 2-DE gels.

Amino Acid Sequence↗

PubMed1981

Haptoglobin and albumin synthesis in isolated rat hepatocytes. Response to potential mediators of the acute-phase reaction.

Incorporation of [3H]leucine into haptoglobin and albumin by isolated rat hepatocyte suspensions was studied to assess the role of potential mediators of the acute-phase reaction in promoting haptoglobin synthesis. In vitro, in the presence of insulin, the addition of a hormone mixture containing hydrocortisone, glucagon, somatotropin, and triiodothyronine resulted in a 70% increase in leucine incorporation into haptoglobin relative to albumin at 48 h incubation. A variety of agents, selected because they are considered to play some part in the acute-phase reaction, were added to the medium, and similar measurements of leucine incorporation were made. The specific binding to hepatocytes by asialo- and asialo, agalacto-derivatives of haptoglobin or orosomucoid did not affect synthesis of haptoglobin or albumin. Epinephrine, prostaglandins E1 and E2, bacterial lipopolysaccharide, and sera containing active complement components also failed to stimulate relative haptoglobin synthesis. A partially purified preparation of human leukocytic pyrogen, however, caused a 70% increase in leucine incorporation into haptoglobin relative to albumin in the present of the hormone mixture, suggesting that this substance may affect acute-phase protein synthesis.

Albumins↗

PubMed1991

Diabetic BB/Wor rat haptoglobin exhibits a probable structural abnormality in Asn-linked oligosaccharides.

In this study we demonstrate that haptoglobin, a serum glycoprotein secreted by the liver, has altered structure in the BB/Wor diabetic rat. SDS-PAGE of haptoglobin (a tetramer composed of two glycosylated beta-chains each containing two sites for Asn-linked oligosaccharides connected by disulfide bonds with two nonglycosylated alpha-chains) clearly shows that the beta-chain of haptoglobin from diabetic rats is smaller than normal, with a molecular mass of 39 instead of 40 kDa. Both acute and chronic diabetic rats exhibit the defect. Defective haptoglobin appears in the serum within 4 days of onset of the disease, but insulin therapy prevents the defect. Removal of Asn-linked oligosaccharides with peptide: N-glycosidase F from Flavobacterium meningosepticum abolished the size difference between the beta-chains from normal and diabetic haptoglobin, with the molecular mass in both cases shifting to 30 kDa. Haptoglobin from both normal and diabetic rats was resistant to digestion by endoglycosidase H from Streptomyces griseus, which cleaves high mannose-type chains. Removal of sialic acid with neuraminidase treatment resulted in a reduction in the molecular mass in both cases, but without eliminating the size difference between the two. These results demonstrate that haptoglobin from diabetic BB/Wor rats contains a structural abnormality which correlates with onset of the disease. The defect is most likely due to an alteration in Asn-linked oligosaccharides, probably involving a change in the neutral sugars of complex-type oligosaccharide chains. This finding represents the first example of an altered Asn-linked oligosaccharides in diabetes.

Animals↗

PubMed1993

Haptoglobin polymorphism and the immune response after hepatitis B vaccination.

One hundred healthy Caucasian medical students (age 22 +/- 1 years) were vaccinated with a recombinant hepatitis B vaccine and their haptoglobin types were determined. A relationship between haptoglobin type and immune response to the vaccine was observed. Subjects with a 2-2 haptoglobin phenotype produced significantly lower hepatitis B antibody titres than those having a 1-1 or 2-1 haptoglobin phenotype. The haptoglobin phenotypes not only influenced the magnitude but also the kinetics of the anti-HBs response. For all haptoglobin types, haptoglobin concentration and immune response to the vaccine behaved independently.

Adult↗

PubMed2005

Serum vitamin C concentration is influenced by haptoglobin polymorphism and iron status in Chinese.

BACKGROUND: Vitamin C is a powerful antioxidant (free radical scavenger). Apart from the diet, other factors regulating its catabolism may affect its serum concentration. Haptoglobin (Hp) is a plasma protein participating in iron metabolism. It shows a genetic polymorphism which shows marked geographical differences. We investigated the relationship between vitamin C, iron status and haptoglobin polymorphism in Chinese men and women. METHODS: Iron status markers were compared according to Hp phenotypes determined by chemiluminescence detection in 110 healthy Chinese subjects. The concentration of haptoglobin was determined using an immunoturbidimetric method. Serum vitamin C was tested by a 2,4-dinitrophenylhydrazine based method. RESULTS: In Chinese, the haptoglobin phenotype distribution was 10.0% Hp 1-1, 33.6% Hp 2-1, and 56.4% Hp 2-2. In the study group, serum vitamin C concentration was associated with haptoglobin type, showing lowest values in serum from Hp 2-2 subjects in males (p=0.028, ANOVA). In contrast to Hp phenotype, Hp concentration did not affect vitamin C concentration. Hp 2-2 shows higher haptoglobin (p=0.002 (ANOVA)) than individuals with the other types. Furthermore, vitamin C was influenced by (log)ferritin levels. In Chinese, vitamin C is influenced by haptoglobin polymorphism and iron status. CONCLUSION: The present findings support the role of non-nutritional factors in vitamin C status.

Ascorbic Acid↗

PubMed1998

Disease-related variations of the glycosylation of haptoglobin in the dog.

Haptoglobin phenotypes have been shown in human medicine to be related to the prevalence of various diseases. Furthermore, abnormal glycosylation of haptoglobin has been reported as a consequence of liver disease, cancer and immunological disorders in man. To our knowledge, similar findings have not, so far, been reported in canine disease. The present paper describes a method for investigation of canine haptoglobin phenotypes and of microheterogeneity caused by altered glycosylation. The method consisted of isoelectric focusing (IEF) of dog serum, followed by immunoblotting. The results indicated the existence of only one canine haptoglobin phenotype with a characteristic microheterogeneity pattern in healthy dogs. Changes in this pattern were found in serum from dogs with liver disease, predominantly chronic progressive hepatitis, and with different kinds of anaemia. Pretreatment of serum with neuraminidase or glycopeptidase F (PNGase F) resulted in identical IEF patterns of haptoglobin from healthy and diseased dogs. Moreover, a fucose-specific lectin was capable of binding to some of the abnormal haptoglobin fractions, mainly those found in association with anaemia. The changes described were interpreted as alterations of the carbohydrate content, with or without fucosylation, of some haptoglobin fractions.

Amidohydrolases↗