[The distribution of haptoglobin-phenotypes and haptoglobin-alleles in pulmonary tuberculosis].
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Alleles↗
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[Haptoglobin subtypes and the haptoglobin streptococcal effect].
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Agglutination↗
[Haptoglobin type, serum concentration of haptoglobin and agglutinating titre against T4-antigen of Streptococcus pyogenes in erysipelas (author's transl)].
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Agglutination Tests↗
[Serum haptoglobin in the diagnosis and prognosis of colonic cancer. Its quantification with immune serum and 1-1 anti-haptoglobin].
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Colonic Neoplasms↗
Increased arterial expression of a glycosylated haptoglobin isoform after balloon dilation.
OBJECTIVE: Haptoglobin is a novel cell migration factor that is expressed in arteries after sustained flow changes and involved in arterial restructuring. Arterial restructuring is the major determinant of arterial shrinkage after balloon dilation. Although the function of extrahepatic haptoglobin expression is not yet understood, local haptoglobin expression may provide the tissue with functionally different haptoglobin due to post-translational modifications. We hypothesized that haptoglobin expression is increased during arterial restructuring after balloon dilation and compared glycosylation patterns between arterial and liver haptoglobin. METHODS: Arterial haptoglobin expression was studied in rabbits at 0, 2, 7, 14 and 28 days after balloon dilation (n=36) using real-time polymerase chain reaction, Western blotting and in situ hybridization. Two-dimensional gel electrophoresis and lectin affinity blotting were used to identify liver and arterial haptoglobin glycoforms. RESULTS: Arterial haptoglobin mRNA (5.7-fold, P=0.01) and protein levels (1.4-fold, P=0.01) were increased after balloon dilation whereas liver haptoglobin expression remained constant. Haptoglobin was expressed in the adventitia of balloon dilated rabbit arteries, which was confirmed in human atherosclerotic arteries. Comparison between liver and arterial haptoglobin demonstrated the expression of artery-specific haptoglobin glycoforms. CONCLUSIONS: This study demonstrates that arterial haptoglobin expression is increased early after balloon dilation whereas liver haptoglobin expression does not change. Furthermore, arterial haptoglobin consists of an unique set of glycoforms compared to haptoglobin produced in the liver.
Animals↗
Expression of haptoglobin mRNA in the liver and oviduct during the oestrous cycle of cows (Bos taurus).
Recent evidence supports involvement of the acute phase protein haptoglobin in numerous events of mammalian reproduction. The objective of this study was to determine whether haptoglobin mRNA was expressed in the bovine ovary and oviduct, and to evaluate whether expression of haptoglobin mRNA in reproductive tissues and liver was associated with a specific phase of the bovine oestrous cycle. Oestrus was synchronized in Holstein cows by prostaglandin injection and tissues were collected during the luteal and peri-oestrous stages of the oestrous cycle. Total RNA was isolated and reverse-transcription polymerase chain reaction (RT-PCR) was performed using primers designed against regions of similarity in human, rat and mouse haptoglobin sequences. Haptoglobin mRNA expression was detected in oviductal cells and liver, during both stages of the oestrous cycle, but not in ovarian follicular cells. The 302 bp PCR product was determined to share 82-83% identity with reported primate haptoglobin sequences. Analysis by Northern blotting revealed 1.2 and 1.4 kb haptoglobin mRNA transcripts in the oviduct and liver, and indicated that hepatic haptoglobin mRNA expression was elevated above basal levels in a greater proportion of peri-oestrous cows (4/4) than luteal cows (1/5). Haptoglobin cDNA was cloned and in vitro transcribed to generate probes for in situ hybridization. Haptoglobin mRNA was detected in the liver, but not in the ovary or oviduct. We conclude that haptoglobin mRNA expression in the bovine liver is up-regulated during the peri-oestrous phase of the oestrous cycle, and that the bovine oviduct expresses a low level of haptoglobin mRNA constitutively. This temporal pattern of haptoglobin mRNA expression would expose reproductive tissues to elevated concentrations of serum haptoglobin during the peri-oestrous stage, and suggests that haptoglobin may be important in reproductive events occurring during this time period.
Animals↗
Rat haptoglobin: method of quantitation and response to antiarthritic therapy in collagen arthritis.
Concentrations of the acute phase reactant haptoglobin were quantitated in the serum of rats using a commercially available antihuman haptoglobin radial immunodiffusion kit. That this antiserum reacted with rat haptoglobin was shown through the techniques of Ouchterlony immunodiffusion and immunoelectrophoresis. Haptoglobin levels were increased seven days after immunization of rats with type II collagen plus incomplete Freund's adjuvant (ICFA) and peaked on day 14. However, even six weeks post-immunization the concentration of haptoglobin was elevated in arthritic rats. A significant correlation was observed between the concentration of serum haptoglobin and the severity of disease (arthritic index) in rats immunized six weeks previously with type II collagen plus ICFA. The effects of antiinflammatory and antirheumatic therapy on arthritic index and serum haptoglobin concentration were determined using a therapeutic dosing protocol. Under these conditions, the known antiarthritic effects of nonsteroidal antiinflammatory drugs, steroids and immunosuppressive agents in this model were confirmed. Of these agents, only the nonsteroidal drugs reduced serum haptoglobin; hydrocortisone, cyclophosphamide and azathioprine elevated haptoglobin. Aurothioglucose, auranofin, and chloroquine, members of the class of disease-modifying antirheumatic drugs, had a general tendency to exacerbate disease, but had minimal effect on serum haptoglobin. D-Penicillamine had little effect on arthritic index and haptoglobin. These results suggest that, while haptoglobin levels do correlate with the intensity of hindpaw swelling, measurement of haptoglobin may not be an accurate indicator of the underlying disease processes in the collagen arthritis model.
Animals↗
Haptoglobin and the development of cerebral artery vasospasm after subarachnoid hemorrhage.
BACKGROUND: Vasospasm is a prolonged constriction of a cerebral artery that is induced by hemoglobin after subarachnoid hemorrhage (SAH). The subarachnoid blood clot also contains the protein haptoglobin, which acts to neutralize hemoglobin. Because the haptoglobin alpha gene is dimorphic, a person can expresses only one of three types of haptoglobin (alpha1-alpha1, alpha1-alpha2, or alpha2-alpha2) depending on the alpha subunit genes he or she inherits. Each of these three haptoglobin types has different antihemoglobin activities; therefore, haptoglobin may influence the development of vasospasm differently in various patients with SAH. OBJECTIVE: To determine whether SAH patients who have haptoglobin containing the alpha2 subunit would be more likely to develop vasospasm than would be SAH patients who have haptoglobin alpha1-alpha1. METHODS AND RESULTS: A total of 32 patients with Fisher Grade 3 SAH were enrolled in this study. Haptoglobin type was determined by polyacrylamide gel electrophoresis. The primary measure for vasospasm was increased blood flow velocities as detected by daily transcranial Doppler ultrasonography (TCD). The authors found that only 2 of 9 patients with haptoglobin alpha1-alpha1 (22%) had development of "possible" vasospasm as measured by TCD, whereas 20 of 23 patients with the haptoglobin alpha2 subunit (either the alpha1-alpha2 or alpha2-alpha2 haptoglobin types) had development of "possible" vasospasm (87%). The secondary measure for vasospasm was cerebral angiography performed between 3 and 14 days after SAH. Similar results (17% vs 56%) were seen between these groups in those patients who underwent cerebral angiography, although its inconsistent use limited the strength of the statistical comparison. CONCLUSIONS: Haptoglobins containing the alpha2 subunit seem to be associated with a higher rate of vasospasm than is haptoglobin alpha1-alpha1.
Brain↗
Haptoglobin expression and release by rabbit oviduct and endometrium, its localization in blastocyst extra-embryonic matrix and fluid during preimplantation time.
BACKGROUND: Evidence is emerging that haptoglobin, an acute phase protein with immunomodulatory properties, is expressed by the endometrium of various species. The present study describes an in-depth investigation of haptoglobin expression and release in the rabbit reproductive tract and in preimplantation embryos. METHODS: The full-length cDNA sequence of rabbit haptoglobin was determined by rapid amplification of cDNA ends PCR. Haptoglobin expression was studied in the oviductal ampull, and isthmus, endometrium and embryos from the time of ovulation up to adhesion. These results were completed by western blot analysis of reproductive tract secretions and embryonic tissues. RESULTS: cDNA sequencing showed a high homology between rabbit and human haptoglobin (84.1%). In oviductal tissues haptoglobin mRNA is clearly expressed from 6 h post-conception (p.c.) to day 3, and in the uterus on days 5 and 6. In the oviductal fluid highest haptoglobin protein content was found between 6 h p.c and day 2, and in the uterine fluid on days 5 and 6 p.c. Embryos do not express haptoglobin mRNA during preimplantation development. However, considerable amounts of maternal haptoglobin protein were detected in the blastocyst coverings and in blastocyst fluid. CONCLUSIONS: Already during periovulatory time and oviductal passage, high amounts of haptoglobin are present in the microenvironment surrounding the oocyte/embryo. Two days before implantation, again, high haptoglobin levels are detectable in the embryo's environment. The incorporation of haptoglobin into the extra-embryonic matrix may be of particular functional significance.
Amino Acid Sequence↗
Seasonal childhood anaemia in West Africa is associated with the haptoglobin 2-2 genotype.
BACKGROUND: Anaemia is a major cause of morbidity and mortality for children in Africa. The plasma protein haptoglobin (Hp) binds avidly to free haemoglobin released following malaria-induced haemolysis. Haptoglobin polymorphisms result in proteins with altered haemoglobin-binding capacity and different antioxidant, iron-recycling, and immune functions. Previous studies examined the importance of haptoglobin polymorphism in malaria and iron homeostasis, but it is unknown whether haptoglobin genotype might be a risk factor for anaemia in children in a malaria-endemic area. METHODS AND FINDINGS: A cohort of 780 rural Gambian children aged 2-6 y was surveyed at the start and end of the malaria season. Samples were taken to assess haemoglobin (Hb) concentration, iron status (ferritin, zinc protoporphyrin, transferrin saturation, and soluble transferrin receptor concentration), haptoglobin concentration, alpha-1-antichymotrypsin (a measure of inflammation), and malaria parasites on blood film. We extracted DNA and genotyped for haptoglobin, sickle cell, and glucose-6-phosphate (G6PD) deficiency. Mean Hb levels fell over the malaria season. Children with the haptoglobin 2-2 genotype (17%) had a greater mean drop in Hb level over the malaria season (an 8.9 g/l drop; confidence interval [CI] 5.7, 12.1) compared to other children (a 5.1 g/l drop; CI 3.8, 6.4). In multivariate regression analysis, controlling for baseline Hb level, age group, village, malaria parasites on blood film, iron status, haptoglobin concentration, and G6PD deficiency, haptoglobin genotype predicted Hb level at the end of the malaria season (p = 0.0009, coefficient = -4.2). Iron status was not influenced by haptoglobin genotype. CONCLUSIONS: The finding that haptoglobin 2-2 genotype is a risk factor for anaemia in children in a malaria-endemic area may reflect the reduced ability of the Hp2-2 polymer to scavenge free haemoglobin-iron following malaria-induced haemolysis. The magnitude of the effect of haptoglobin genotype (4 g/l Hb difference, p = 0.0009) was comparable to that of G6PD deficiency or HbAS (3 g/l difference, p = 0.03; and 2 g/l difference, p = 0.68, respectively).
Anemia↗
Evolution of haptoglobin concentration in serum during the early phase of acute myocardial infarction.
Haptoglobin (Hp) is a haemoglobin-binding acute phase protein with three genetic types: Hp 1-1, Hp 2-1, Hp 2-2. We investigated 45 patients during the first 48 hours of acute myocardial infarction, and studied determinant factors and clinical correlates. Upon hospital admission, serum haptoglobin concentration was increased (1.95 +/- 0.94 g/l, mean +/- SD, P < 0.001) versus the reference population (0.97 +/- 0.46 g/l, n = 107), independent of haptoglobin type: 1.84 +/- 0.64 g/l (Hp 1-1, n = 11) (P < 0.01), 1.98 +/- 0.79 g/l (Hp 2-1, n = 25) (P < 0.001), 1.98 +/- 1.58 g/l (Hp 2-2, n = 9) (P < 0.001). Moreover, during the first hours of hospitalization, a temporal lowering of haptoglobin was observed suggesting acute haemolysis, independent of the haptoglobin type. Minimal serum haptoglobin was reached 9.6 +/- 5.8 hours after admission. The amplitude of the haptoglobin decrease correlated with initial serum haptoglobin (r = 0.78) and was more pronounced (P < 0.05) in men (0.53 +/- 0.57 g/l) than in women (0.18 +/- 0.17 g/l). Decrease of serum haptoglobin did not correlate with infarct size (based on creatine kinase-MB release). Out of the other acute phase proteins measured upon admission, only C-reactive protein was significantly increased (P < 0.05). During the next 36 hours, haptoglobin increased as a result of the acute phase response to myocardial injury. Our findings suggest that acute myocardial infarction is also preceded by an acute phase response, characterized by an initial high haptoglobin and followed by a temporal haptoglobin decrease due to haemolysis.
Aged↗
Identification of haptoglobin as an alternative ligand for CD11b/CD18.
Haptoglobin is an acute phase protein with presumed anti-inflammatory activities. We report that purified fluorescein-labeled haptoglobin 1-1 binds to THP1 and U937 promonocytic cell lines, to monocytes, to granulocytes, and to a subset of CD8+ T cells and to NK cells. Studies with radioiodinated haptoglobin on THP1 cells were consistent with specific binding to one class of receptors with a density of 1.7 x 10(5) binding sites per cell and a low affinity of 6.5 x 10(-6) Kd. Binding was increased by Ca2+ and by Ca2+ and ADP. Binding to THP1 and U937 cells could be inhibited by preincubation with nonfluoresceinated haptoglobin and by fibrinogen, but not by albumin, transferrin, or alpha1-acid glycoprotein. Fibrinogen binds to the CD11b/CD18 integrin. We therefore examined whether haptoglobin has the same receptor. The anti-CD11b mAb44 indeed inhibited the binding of fluoresceinated haptoglobin to THP1 and U937 cell lines, and haptoglobin inhibited the binding of the anti-CD11b mAb anti-Leu15 and mAb44 to both cell lines. An anti-CD18 mAb partly inhibited the binding of fluoresceinated haptoglobin to THP1 and U937, indicating that the beta-chain of MAC-1 is also involved in haptoglobin binding. There was no interference between the binding of anti-CD4, anti-CD11a, or anti-CD11c mAb and haptoglobin binding to THP1 cells. Binding of haptoglobin to purified CD11b/CD18 indicates that it binds directly to the receptor. Haptoglobin is an alternative low affinity ligand for the CD11b/CD18 integrin, suggesting that this acute phase protein might regulate MAC-1-dependent cell function in vivo.
Adenosine Diphosphate↗
Endometriotic haptoglobin binds to peritoneal macrophages and alters their function in women with endometriosis.
OBJECTIVE: To evaluate the effects of endometriotic haptoglobin on peritoneal macrophage function. DESIGN: Prospective laboratory study. SETTING: School of medicine. PATIENT(S): Twenty-three women with and without endometriosis. INTERVENTION(S): Peritoneal macrophages cultured without or with haptoglobin. MAIN OUTCOME MEASURE(S): Peritoneal macrophage haptoglobin immunoreactivity, adhesion, and interleukin-6 (IL-6) production. RESULT(S): In vivo, significantly more peritoneal macrophages from women with endometriosis bound haptoglobin and exhibited reduced adhesion compared to women without endometriosis. In vitro, haptoglobin treatment significantly decreased peritoneal macrophage adherence only in women without endometriosis; this effect was not seen in women with endometriosis, probably owing to in vivo haptoglobin saturation. Conversely, haptoglobin treatment robustly increased IL-6 production only by macrophages from women with endometriosis, suggesting differential immune response in these women. CONCLUSION(S): Endometriotic lesions synthesize and secrete a unique form of haptoglobin (endometriosis protein-I) that is up-regulated by IL-6. This study shows that haptoglobin adheres to peritoneal macrophages; decreases adhesion, which may influence phagocytic function; and up-regulates IL-6 production. Hence, a feed-forward loop is proposed whereby endometriotic lesion haptoglobin decreases macrophage phagocytic function while increasing IL-6 production, which in turn increases endometriotic haptoglobin and promotes establishment of endometriosis.
Adult↗
Covalent structure of human haptoglobin: a serine protease homolog.
The complete amino acid sequences and the disulfide arrangements of the two chains of human haptoglobin 1-1 were established. The alpha 1 and beta chains of haptoglobin contain 83 and 245 residues, respectively. Comparison of the primary structure of haptoglobin with that of the chymotrypsinogen family of serine proteases revealed a significant degree of chemical similarity. The probability was less than 10(-5) that the chemical similarity of the beta chain of haptoglobin to the proteases was due to chance. The amino acid sequence of the beta chain of haptoglobin is 29--33% identical to bovine trypsin, bovine chymotrypsin, porcine elastase, human thrombin, or human plasmin. Comparison of haptoglobin alpha 1 chain to activation peptide regions of the zymogens revealed an identity of 25% to the fifth "kringle" region of the activation peptide of plasminogen. The probability was less than 0.014 that this similarity was due to chance. These results strongly indicate haptoglobin to be a homolog of the chymotrypsinogen family of serine proteases. Alignment of the beta-chain sequence of haptoglobin to the serine proteases is remarkably consistent except for an insertion of 16 residues in the region corresponding to the methionyl loop of the serine proteases. The active-site residues typical of the serine proteases, histidine-57 and serine-195, are replaced in haptoglobin by lysine and alanine, respectively; however, aspartic acid-102 and the trypsin specificity, residue, aspartic acid-189, do occur in haptoglobin. Haptoglobin and the serine proteases represent a striking example of homologous proteins with different biological functions.
Amino Acid Sequence↗
Influence of clinical factors on the haemolysis marker haptoglobin.
BACKGROUND: Plasma haptoglobin determination is clinically used as parameter for haemolysis. To date, however, the influence of the mode of haemolysis (extravascular vs. intravascular) and of nonhaemolytic conditions on haptoglobin concentration and its reliability as a haemolysis marker remain poorly defined. MATERIALS AND METHODS: In a total of 479 individuals, the influence of haemolytic and nonhaemolytic conditions on plasma haptoglobin levels was investigated. RESULTS: All studied types of haemolytic disease (n = 16) were associated with markedly decreased plasma haptoglobin levels, without significant differences between intravascular vs. predominantly extravascular haemolysis. Diminished haptoglobin values were also observed in patients with liver cirrhosis, which normalized after liver transplantation. In contrast, markedly increased haptoglobin levels were found in patients with inflammation. In patients with haemolysis and a concomitant acute-phase response, however, haemolysis-dependent haptoglobin depletion was not attenuated. Interestingly, patients with a strongly positive direct antiglobulin test or high cold agglutinin titre but no further evidence for haemolysis had normal haptoglobin values. Likewise, anaemia owing to bone marrow failure, acute gastrointestinal or chronic diffuse blood loss, and end-stage kidney disease were associated with normal haptoglobin levels. CONCLUSIONS: Plasma haptoglobin depletion is a reliable marker for the instant diagnosis of accelerated red cell destruction irrespective of the site of haemolysis or the presence of inflammation. The capacity of this parameter to predict haemolysis appears to be limited in patients with liver cirrhosis and decreased haptoglobin production only.
Acute-Phase Reaction↗
Haptoglobin phenotypes and gene frequencies in unipolar major depression.
OBJECTIVE: Studies from the authors' laboratory have shown that major depression is accompanied by significantly increased plasma concentrations of positive acute-phase proteins such as haptoglobin. Haptoglobin is characterized by a molecular variation with three known phenotypes (Hp 1-1, Hp 2-1, and Hp 2-2). This study investigated haptoglobin plasma levels and phenotype and gene frequencies in unipolar major depression. METHOD: Haptoglobin plasma levels of 22 healthy volunteers, 32 patients with minor depression, and 72 patients with major depression were determined by means of a laser nephelometric method. Haptoglobin phenotyping of these 126 subjects and 200 healthy blood donors was also carried out. RESULTS: The patients with major depression exhibited significantly higher haptoglobin plasma levels than the healthy comparison subjects and the patients with minor depression. Subjects with the haptoglobin phenotype Hp 2-2 had significantly lower haptoglobin levels than the phenotype Hp 1-1 and Hp 2-1 carriers. The frequencies of haptoglobin phenotypes Hp 2-1 (61.1%) and Hp 2-2 (20.8%) in the patients with major depression were significantly higher and lower, respectively, than the frequencies in the normal population (i.e., the blood donors: 48.0% and 37.0%, respectively). The frequency of the Hp-1 gene was significantly greater in the patients with major depression (48.6%) than in the normal population (39.0%). CONCLUSIONS: Major depression is characterized by a hyperhaptoglobinemia that is largely independent of haptoglobin phenotypes. This altered distribution of haptoglobin phenotypes and genes suggests that genetic variation on chromosome 16 may be associated with that illness.
Adult↗
Identification and immunohistochemical localization of a haptoglobin-like protein in the tissues and fluids of the bovine (Bos taurus) ovary and oviduct.
The objective of this study was to establish the identity of a 40 kDa bovine oviductal fluid protein as a haptoglobin-like protein and to evaluate the association of the haptoglobin-like protein with ovarian and oviductal tissues and fluids. An oviductal fluid protein band corresponding to a molecular mass of 40 kDa was excised and electroeluted from SDS-PAGE gels. Sequence analysis revealed an N-terminal region sharing 81% identity with the beta-subunit of bovine haptoglobin. The 40 kDa oviductal fluid protein crossreacted on immunoblots with antiserum against rabbit endometrial haptoglobin and with an anti-human haptoglobin polyclonal antibody. Two-dimensional PAGE revealed four protein variants ranging in pI from 7.7 to 8.6, which appeared identical, with respect to molecular weight, number of isoforms and pI, to bovine haptoglobin in acute phase serum. The haptoglobin-like protein was localized using immunohistochemistry to the lumina of blood vessels and to the extracellular matrix of ovarian and oviductal tissues. Immunostaining for the haptoglobin-like protein was also detected in the oviductal lumen, in the mucosa of the ampullary oviduct but not the isthmic oviduct, and in intermittent ampullary epithelial cells. Within the ovary, the haptoglobin-like protein was localized to the avascular granulosa cells and follicular fluid of antral follicles, but not in the theca cells or in preantral follicles of any developmental stage. It was concluded that the haptoglobin-like protein is a normal constituent of bovine ovarian and oviductal tissues and fluids, and it was hypothesized that the haptoglobin-like protein contributes to ovarian follicular development and oviductal function.
Animals↗
[The change of acute phase protein haptoglobin in cattle during spontaneous labor and Caesarean section with or without torsio uteri intrapartum].
The change of haptoglobin concentration in cattle with dystocia after torsio uteri which lead to Caesarean section is regarded in contrast to haptoglobin concentrations in cattle at parturitions with undisturbed puerperium and Caesarean section without torsio uteri intra partum. Animals with natural parturition had low haptoglobin concentrations with slight changes, for a slightly increased haptoglobin concentration was seen as physiologic. Also surgical treatment such as Caesarean section did not result in changes of haptoglobin concentration. Thus, the curve of animal patients with anomalies concerning position or with a too large fetus (relatively or absolutly) was nearly identical to the curve of animals with regular parturitions over the first four days after surgery. Not before the fifth day after surgery, a moderate increase of haptoglobin could be observed. Animals with dystocia after torsio uteri intra partum showed significantly higher haptoglobin concentrations in contrast to controls over the time of investigation. The correlation of haptoglobin concentrations in animal patients with torsio uteri bin concentration shortly after surgery an additionally significant increase of haptoglobin concentration could be observed in later fertile cattles but not in later infertile cattle with torsio uteri. In two cows with torsio uteri and ovariohysterectomy haptoglobin concentrations decreased rapidly. Haptoglobin concentration may serve as an indicator for the degree of impairment of the uterus during a parturition as well as a predictor for regenerative potential.
Animals↗