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Eur J Clin Chem Clin Biochem 1997; 35(9):647-654 © 1997 by Walter de Gruyter · Berlin - New York REVIEW Biological Functions of Haptoglobin - New Pieces to an Old Puzzle Wanda Dobryszycka Department of Biochemistry, Faculty of Pharmacy, Wroclaw University of Medicine, Wroclaw, Poland Summary: Haptoglobin, an "acute phase" protein, has different functions, which display genetic polymorphism. The complex of haptoglobin with haemoglobin is metabolized in the heaptic reticuloendothelial system. Biosynthesis of haptoglobin occurs not only in the liver, but also in adipose tissue and in lung, providing antioxidant and antimicrobial activity. Changes in the measured concentrations of haptoglobin in serum may help to assess the disease status of patients with inflammations, infections, malignancy etc. (increases) as well as in haemolytic conditions (decreases). Haptoglobin plays a role in stimulation of angiogenesis and has highly potent cholesterolcrystallization-promoting activity. Probably the most important biological function of haptoglobin consists in the host defence responses to infection and inflammation, acting as a natural antagonist for receptor-ligand activation of the immune system. Introduction Haptoglobin is a genetically determined a2-acidic glycoprotein with haemoglobin-binding capacity, present in most body fluids of humans and other mammals. A positive acute-phase reactant, its plasma level is increased in inflammation, infections of different aetiology, trauma, tissue damage and malignant proliferation, but decreased in haemolytic conditions and in severe hepatocellular deficiency. Thus, changes in the measured concentrations of haptoglobin have been used in the diagnosis and evaluation of treatment response under various pathological conditions (for reviews see I.e. (1-5)). Despite years of investigations and a variety of the known biological activities, the physiological functions of haptoglobin have remained enigmatic. Haptoglobin Phenotypes and Functional Properties Essentially, three major phenotypic forms of human haptoglobin, designated Hp 1-1, Hp 2-2, and Hp 2-1 are due to two alleles HP 1 and HP 2. In its simplest form Hp 1-1 is a tetrachain structure composed of two a1 (light, Μτ 9100, each 83 residues) and two β (heavy, Mr 40 000, each 245 amino acids, containing carbohydrate) chains linked by disulphide bridges. Haptoglobin 2-2 and 2-1 are polymerized forms of higher molecular mass, showing multiple bands in polyacrylamide gel electrophoresis. The polymorphism of haptoglobin was found to be related to the α subunits (the a2-chain comprising 142 residues is almost a duplicate of the c^-chain, although in a cross-over event some amino acid residues have been deleted). Hp 2-1 forms a linear polymeric series which may be represented as (α1β)2(α2β)η, where η = 0,1,2 ... The formula of the Hp 2-2 polymeric series is (a2 )m, where m = 3,4, 5 ... Figure 1 shows the structure and subunit arrangements in Hp 2-1 (4). Ν « κ 1 ι 15 Ά 1 S 68 93 127 1 ?A8 I 179 J90 I I 2« 24, c β .·. r α2 ι · Ί 'i^i/*- form SH polymers ..HHrs·2Π 7? 105 -S-S~ 83 Γ α 7 chain 179190 219 s-S- (α'· β)2· (α*. β)π where π = 0,1,2.... Fig. 1 Scheme of the structure and subunit arrangements in haptoglobin phenotype 2-1 (4). 648 A method called "crossed haemoglobin electrophoresis" (6) has been designed for the study of haemoglobin binding with some of the individual polymeric molecules of haptoglobin subtypes and variants. The oligosaccharide moiety of haptoglobin consists of N-acetylglucosamine, mannose, galactose, fucose and sialic acid. There are 8 sites of glycosylation, forming bi- and triantennary N-linked glycans, which are present in equal proportions (7). Additional allelic variation of the HP 1 allele is due to the HP IF and HP IS alleles, where F indicates fast and S indicates slow migration during electrophoresis (8). Homologous crossing over between HP 2 and either the HP IF or the HP IS allele in HP 2/HP 1 heterozygotes can change the usual type of HP 2 to three other forms: HP 2SS, HP 2FF, and HP 2SF (9). There is still no generally accepted satisfactory mechanism explaining the maintenance of genetic polymorphism in human populations. Interactions between single- or multilocus genetic systems have been extensively examined in the search for evidence of selection in humans. Recently, several functional differences between haptoglobin phenotypes have been demonstrated, which appear to have important biological and clinical consequences (10). These include inter alia the reaction of haptoglobin with haemoglobin (11), the antioxidant activity towards haemoglobin-stimulated lipid peroxidation (12), and the inhibitory effect on prostaglandin synthesis (13). In all these cases the strongest activity was shown by haptoglobin type 1-1, in comparison with 2-1 and 2-2 types. Haptoglobin Biosynthesis Haptoglobin is known to be produced mainly in the liver. Its expression is regulated at three different levels: [a] developmental control for lack of expression in foetal liver, [b] tissue-specific control for selective expression in hepatocytes, and [c] modulation of expression during the acute phase reaction (14). Maximal expression of haptoglobin synthesis in the liver requires cytokines (interleukins IL-1 and IL-6 type, tumour necrosis factor TNF- , transforming growth factor TGF-ß, leukaemia inhibitory factor LIF and others), and glucocorticoids, alone or in various combinations (15). Elevation of the haptoglobin gene transcription rate in acute phase liver relies essentially on an increase in the binding affinity of hepatocyte regulatory DNA-binding proteins. These include the family of Dobryszycka: Biological functions of haptoglobin nuclear factors and CCAAT-enhancer binding protein. Isoform ß of the latter has been identified as a ligand to the hormone response elements of haptoglobin (16). Haptoglobin is expressed in specific cells of non-hepatic origin, including adipocytes and lung cells. After inflammation had been induced in vivo, transcription of the haptoglobin gene rose four-fold in lung (in mouse and baboon), and six-fold in adipose tissue (in mouse), an increase similar to that observed in the normal livers (17, 18). Unique exposure of the lung to the atmosphere and a large number of potential injuries from chemical agents, microorganisms, organic and inorganic dusts makes it particularly vulnerable. Locally synthesized haptoglobin provides a major source of antioxidant and/or antimicrobial activity in the mucous blanket as well as in the alveolar fluid in the lung. This indicates a protective role of haptoglobin against infection and in repairing injured tissues. Haptoglobin-Haemoglobin Complex Haptoglobin combines specifically with haemoglobin, the complex showing peroxidase activity in vitro. The binding of haptoglobin to haemoglobin is one of the strongest known non-covalent interactions in biology, the association constant being greater than 10~15 mol/1 (4). The haptoglobin-haemoglobin complex in plasma is rapidly cleared by the reticuloendothelial system in the liver. Hence, iron from haemoglobin remains available for further metabolic use. In haemolytic states (especially intravascular), haptoglobin levels are reduced. It should be pointed out that such a decrease is considered to be a secondary phenomenon, whereas a primary decrease occurs during severe chronic hepatocellular deficiency (a failure in biosynthesis or in secretion by hepatocytes). Moreover, hypohaptoglobinaemia may result from dissolution of haematomas and other foci of internal haemorrhage (19). Haptoglobin cannot be considered as a regular transport protein, but is regarded as a suicidal one. On the other hand, haemoglobin binding is apparently not an essential function, since the condition of ahaptoglobinaemia is clinically silent. Moreover, under normal conditions there is more than enough circulating haptoglobin to bind the intravascular free haemoglobin that is formed daily. Some animals (e. g. cattle) synthesize haptoglobin only in response to inflammation. Formation of the haptoglobin-haemoglobin complex in vivo can play a role in preventing the haemoglobindriven generation of hydroxyl radical and lipid peroxide in areas of inflammation. On the other hand, haptoglobin may bind analogous iron-binding proteins of microbial origin and thus provide a novel microbicidal mechanism Dobryszycka: Biological functions of haptoglobin to augment the destruction of intracellular pathogens. The haptoglobin-haemoglobin complex bound within the phagolysosomes of phagocytic cells may generate reactive oxygen species that are directly microbicidal (20). The complex was found to display an inhibitory effect on the endothelium-derived relaxing factor (nitric oxide) (21). Relevance of Haptoglobin in Clinical Medicine Haptoglobin is present in most body fluids (serum, urine, saliva, cerebrospinal fluid, amniotic fluid, ascites etc.). Serum haptoglobin may be measured by determining the peroxidase activity of haptoglobin-haemoglobin complex (the method of Jayle, who first described this property (22)), electrophoresis (23), crossed affinoimmunoelectrophoresis with wheat germ agglutinin (24), afrlnity-chromatography (25), immunodifrusion (26), differential acid denaturation of haemoglobin and its complex with haptoglobin (27), laser-immunonephelometry (28), ELISA system based on streptococcal haptoglobin receptors (29) etc. However, some of the methods are insufficiently precise for small amounts of haptoglobin, while others are based on arduous and expensive techniques which makes them of limited practical value in clinical laboratories. In our laboratory two immunosorbent ELISA systems were developed, based either on the reaction with haemoglobin (Hb-Hp ELISA) (30) or with the lectin, concanavalin A (Con A-Hp-ELISA) (31). In both the systems, antihaptoglobin antibodies (polyclonal or monoclonal) are conjugated with horse-radish peroxidase. In the HbHp-ELISA, haemoglobin is bound to the β chain of haptoglobin; in the Con A-Hp-ELISA, the binding also occurs on the β chain, but the oligosaccharide moiety (mannobiosyl core) is involved in the binding. These methods enable the measurement of haptoglobin in concentrations higher than 5 μg/l. By means of another ELISA test, it is possible to determine 10~10 mol/1 of haptoglobin in biological fluids (32). Such highly sensitive methods are of special significance in measurements of haptoglobin levels in biological fluids of low haptoglobin content, i. e. in cord sera and amniotic fluids (diagnosis of intrauterine foetal infections), effusions of different aetiology (discrimination of transudative vs. exudative ascites), in sera from haemolytic anaemias, in the diagnosis of ahaptoglobinaemia, etc. 649 haptoglobin are significantly related to those of fibrinogen, absolute number of leukocytes, neutrophils, CD4+ Τ cells and the CD4+/CD8+ Τ cell ratio, and soluble receptors of interleukins 6 and 2 (35). Ahaptoglobinaemia is common in the newborn but is present in 8090% of infants up to 3 months of age. This has been attributed both to the haemolysis of foetal red cells and to immaturity of the parenchymal cells and reticuloendothelial system of the liver, with respect to the biosynthesis and catabolism of haptoglobin, respectively. Profound changes in serum haptoglobin level occur hi a great variety of disease states. Haptoglobin should be considered as a protein undergoing two pathophysiological phenomena: an increase in production during an inflammatory reaction and a decrease (as a primary phenomenon) in production during severe hepatocellular deficiency (either a failure in biosynthesis or in the secretion by hepatocytes), or a decrease (as a secondary phenomenon) under haemolytic conditions (19, 36). The haptoglobin serum level is increased up to 3—8 fold in response to injury, i. e. surgery and burns, bacterial or parasitic infections, ischaemic necrosis, connective tissue diseases, chemical irritants, malignancy (10, 33, 37). Haptoglobin measurement may help hi these cases to assess the disease status of patients, and to monitor the effects of therapy. This has been applied satisfactorily in serial analyses of serum haptoglobin in patients with ovarian carcinoma receiving chemotherapy, indicating duration of remission and/or recurrence of malignancy (38). Pretreatment haptoglobin levels were correlated positively with initial size of the ovarian tumour obtained during laparotomy (39). In diabetic patients under different metabolic control (retinopathy, nephropathy), haptoglobin levels were parallel to the cut-off value (10%) of glycated haemoglobin (40). Evolution of the haptoglobin concentration in serum has been observed during the early phase of acute myocardial infarction (41). Even localized infections, resulting in increased inflammation and tissue loss in the periodontium, elicit systemic changes manifested by increases in haptoglobin levels (42). Low levels of haptoglobin are found in intra- or extravascular haemolysis, ineffective erythropoiesis, severe liver disease, genetic factors in seemingly normal individuals, and in a number of abnormal haemoglobin diseases such as sickle cell anaemia, haemoglobin C disMean values of haptoglobin concentrations in normal ease and thalassaemias; also after adverse transfusion human serum obtained from various laboratories differ reactions and autoimmune haemolysis as in acquired significantly (0.5-1.5, 0.75-1.75, 0.7-1.3, 0.5-2.2 haemolytic anaemia. In an acute haemolytic crisis all of g/1). In part these variations are explained by the differ- the haptoglobin is usually depleted because of the one ences in levels of the haptoglobin types as well as by way transit of the complex with haemoglobin to the the dependence on sex (5, 10, 33). Recently, the IFCC- liver, where it is catabolized. The cut-off level of haptostandardized reference range of haptoglobin in serum globin (0.2 g/1) has been used in the differential diagno(0.3-2.0 g/1) was reported (34). Mean values in plasma sis of a variety of primary and secondary haemolytic 650 processes vs. anaemias without haemolysis (43). In patients exhibiting haemolysis and concurrent acute phase reaction, it should be taken into account that the decline in serum haptoglobin concentration occurs significantly faster than the serum haptoglobin increase in the acute phase (44). Also, evaluation of intravascular haemolysis by haptoglobin administration followed by measurement has been used in surgery for prosthetic valve replacement (45). Patients with unipolar major depression exhibited significantly higher haptoglobin plasma levels than healthy subjects and patients with minor depression. Subjects with the haptoglobin phenotype 2-2 had significantly lower haptoglobin levels than the Hp 2-1 and Hp 1-1 carriers. The frequency of phenotypes of the Hp-1 gene was significantly higher in patients with major depression (46, 47). Major depression is characterized by hyperhaptoglobinaemia, which in turn is largely dependent on the haptoglobin phenotype, being significantly related to activation of cell-mediated immunity. This altered distribution of haptoglobin phenotypes and genes suggests that genetic variation on chromosome 16 may be associated with that illness. Moreover, depressed patients showed significantly lower basal hypothalamic pituitary-thyroid levels than patients with normal haptoglobin levels (48-50). Abnormal changes in the fucosylation of haptoglobin may reflect early stages in the development of liver disease, and they can be used as a marker for alcoholic liver disease, but not for excessive alcohol consumption or non-alcoholic liver disease (7, 51). Similar changes in the fucose content in haptoglobin were found in patients with rheumatoid arthritis (52). A possible therapeutic application of human haptoglobin consists of the selective removal of free haemoglobin (exceeding 2.3—3.5 g/1) from the blood of patients suffering from severe traumatic shocks. This has been applied in the control of acute bleeding from oesophageal varices caused by treatment with ethanolamine oleate sclerosant, thereby successfully protecting against renal damage (53). Prophylactic haptoglobin infusion has been used in peripheral blood stem cell transplantation in order to avoid the elevation of free haemoglobin and haemoglobinuria (54). The haptoglobin polymorphism has been used in paternity cases in forensic science for several years. Now, thanks to modern laboratory techniques, haptoglobin subtyping can also be carried out in dried blood stains (55). The occurrence of polymorphism of the haptoglobin locus motivated many investigations directed at the determination of possible associations between haptoglobin phenotype distribution and different disorders. Identifi- Dobryszycka: Biological functions of haptoglobin cation of persons at high risk for a disease on the basis of haptoglobin phenotype could have been a rather stimulating goal of preventive medicine. Since a report on the significant increase of haptoglobin type 1-1 among leukaemia patients, compared with other cancer patients as well as normal controls (56), numerous reports have appeared (for comprehensive review see I.e. (10)). Some examples follow: association of haptoglobin types with serum lipids and apolipoproteins (increase of cholesterol and low density lipoprotein levels with an excess of HP 2 gene) (57), with sarcoidosis (excess of HP 1 gene) (58), cirrhosis of the liver (excess of HP 1 gene) (59), chronic hepatitis C (excess of HP 1 gene) (60), essential arterial hypertension (increase of Hp 2-2 phenotype) (61), haemoglobinopathies (increase in Hp 1-1 phenotype (62), immune response after hepatitis B vaccination (decrease of immune response in subjects with Hp 2-2), etc. (63). Some of these investigations clearly show a significant association, while others provide contradictory results. For the time being, such inconclusive reports indicate that the haptoglobin phenotype has little if any practical use in clinical science. Some Biological Activities Recent data suggest that haptoglobin may have temporary but specific physiological activity, distinct from its role in haemoglobin metabolism. Haptoglobin is known to inhibit viral haemagglutination and prostaglandin H synthase (64), to suppress lectinand polysaccharide-produced proliferation of lymphocytes and B-cell mitogenesis and to modulate macrophage function (65). Haptoglobin was found to agglutinate Group A of Streptococcus pyogenes, which possesses surface antigen T4. The reaction was phenotypedependent, i. e. haptoglobin 2-2 type showed higher activity than 2-1, while 1-1 type was inactive (29, 66). A novel function of haptoglobin and the haptoglobinhaemoglobin complex is the induction of apoptosis of hepatocarcinomatous Hep 3B cells (DNA fragmentation, increase of transglutaminase expression). The antiproliferative cytotoxic effect of the complex is exerted via the typical apoptotic pathway (67). Stimulation of angiogenesis is a newly recognized biological function of haptoglobin. In experiments in vitro and in vivo, the angiogenic effects of haptoglobin 2-2 was much more expressed than that of the 1-1 type, while 2-1 type exhibited an intermediate activity. The increased levels of haptoglobin found in chronic inflammatory conditions may play an important role in tissue repair. In systemic vasculitis haptoglobin may also compensate for ischaemia by promoting development of collateral vessels (68). 651 Dobryszycka: Biological functions of haptoglobin Biliary haptoglobin at its physiological concentration has a highly potent cholesterol-crystallization-promoting activity and thus becomes a candidate for major attention in understanding gallstone pathogenesis (69). Trypanosomes are protozoan parasites of medical and veterinary importance. Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense infect humans, causing African sleeping sickness. However, man is protected from T. brucei brucei, which can only infect animals, causing the disease Nagana in cattle. It was suggested that the protective factor may be "haptoglobinrelated protein" (70). However, recent data suggest that the trypanolytic activity of normal human serum is due to a second, less well-defined factor of high molecular mass (71). Haptoglobin may contribute by a humoral mechanism to the bone resorption seen in chronic inflammatory lesions such as rheumatoid arthritis, periodontitis and osteomyelitis (72). It has been shown that, beside paracrine stimulators of osteoclasts (e.g. IL-1, TNF, bradykinin, thrombin), humoral factors induced by the inflammatory process also participate in the resorption of bone. Haptoglobin stimulates prostaglandin E2 biosynthesis hi isolated osteoblasts, and it synergistically potentiates the effect of bradykinin and thrombin. Thus it may contribute to the destruction of bone by inducing the formation of prostanoids capable of stimulating bone resorption (73). Haptoglobin as a Ligand of Immune Cells Exogenous haptoglobin is concentrated within granulocytes and monocytes in considerable quantities. It is not synthesized de novo and is exocytosed following neutrophil activation. Neutrophils possess two specific binding sites for haptoglobin with an affinity similar to that for binding of the lectin, concanavalin A. Native haptoglobin blocks the human neutrophil response to a variety of agonists with defined plasma membrane receptors. Of the various functional parameters assessed, neutrophil respiratory burst activity (superoxide production) and the rise in intracellular calcium were inhibited by haptoglobin. This suggests that haptoglobin may act as a natural antagonist for receptor-ligand activation of the immune system (74). Normal haptoglobin binds to granulocytes and monocytes. Among lymphocytes, haptoglobin predominantly binds to cells that express CD lib/CD 18 receptor (NK cells) and to a minor extent CD4+ and CD8+ cells (75). The MAC-1 or CD lib/CD 18 molecule belongs to the integrin family. These integrins play a major role in numerous biological processes such as inflammation and immune function. Patients deficient for such receptors suffer from persistent neutrophilia, pyogenic infections and wound healing. Modulation of granulocyte activity by haptoglobin is especially interesting when considering the existence of a feedback loop among monocytes and hepatocytes in the control of inflammatory response. Therefore, one of the likely roles of haptoglobin seems to be in the host defence responses to infection and inflammation. CD22 is a cell-surface receptor of resting mature B cells that recognizes sialic acid (Sia) in the natural structure, Sia(a2-6)Gal(ßl-4)GlcNAc. It probably directs potential interactions between mature B cells during inflammatory states. High affinity CD22 ligands are subunits of immunoglobulin M and haptoglobin. Such a mechanism may be biologically relevant (76). The membrane carbohydrate antigen, sialyl Lewisx [Sia(a2-3)Gal(ßl-4)Fuc(al-3)GlcNAc], is involved in cellular adhesive interactions, in leukocyte trafficking, inflammation, thrombosis and probably in the metastasis of some tumour cells. Expression of this antigen in haptoglobin structure may modify disease processes or reflect some pathological changes (77). Oncofoetal Haptoglobins Analysis of the genomic clones for haptoglobin has resulted in the identification of a "haptoglobin-related protein" (Hpr) gene, which contains a number of retroviruslike sequences and is adjacent to the haptoglobin gene. Hpr synthesis is not restricted to the liver: alternative sites of synthesis were found to be the placenta or decidua, and breast cancer cells (5). Recently it was shown that the Hpr gene is expressed in the human hepatoma G2 and leukaemia molt-4 cell lines (78). A macromolecular form of haptoglobin from ascitic fluid of ovarian cancer patients (a haptoglobin gene modified by the effect of malignant growth?) has been shown to possess potent immunosuppressive properties (79, 80). It might serve as a negative feedback regulator of immune response produced by activated macrophages. Its production would be responsible for dysfunction of the immune system in cancer patients. Oncofoetal haptoglobins display similar functions in pregnancy and neoplasia, aiding development of the placenta and foetus while facilitating tumour invasion and metastasis (modulating the host response to a malignancy so as to enable it to survive and expand clonally). Specific changes in the degree of branching of the carbohydrate moiety hi "neoplastic" haptoglobin have been used in measurements of concanavalin -bound haptoglobin in the differentiation of malignant from non-malignant ovarian tumours (81). Despite over 50 years of research and the discovery of multiple aspects of haptoglobin structure and function, 652 gaps and inconsistencies in our knowledge of this protein are readily apparent. Biological activities described in the present article may give an impression of embarras de richesse. Haptoglobin seems to function in association with the immune system, i. e. to protect the host Dobryszycka: Biological functions of haptoglobin against all the dangers of an acute phase reaction. This appears to be the most important function of this protein. Our knowledge of this complex area continues to evolve, but we are still arranging many pieces of the puzzle. References 1. Pintera J. 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