Occurrence and possible function of inflammation-induced expression of sialyl Lewis-x on acute-phase proteins.
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Acute-Phase Proteins↗
Biomedical subjects
E C Havenaar
Publications and source records attributed to E C Havenaar.
Severe rheumatoid arthritis prohibits the pregnancy-induced decrease in alpha3-fucosylation of alpha1-acid glycoprotein.
Patients suffering from rheumatoid arthritis (RA) may experience a temporary reduction of disease symptoms during pregnancy. As indicated by the occurrence of RA-disease symptoms during pregnancy, three categories of patients were defined, namely, remission, relapse and unchanged. In all three categories changes in the plasma level and glycosylation of alpha1-acid glycoprotein (AGP) were determined longitudinally in comparison to those occurring in pregnancy of healthy women. In healthy pregnancy, we observed: (i) a peak in the plasma concentration at week 18 and a minimum at week 30; (ii) a continuous increase in the degree of branching of the glycans during the entire pregnancy period, and (iii) a decrease in the degree of alpha3-fucosylation of AGP-glycans with a minimum occurring at week 25. Comparable pregnancy-induced changes in glycosylation were found for two other acute-phase proteins alpha1-protease inhibitor (PI) and alpha1-antichymotrypsin (ACT). Increased oestrogen levels, known to occur during pregnancy, may be one of the factors that induce these changes, because the increased branching and decreased alpha3-fucosylation is in agreement with our earlier findings regarding an involvement of this hormone in the regulation of acute phase protein glycosylation in oestrogen-treated males as well as females. In all three clinical categories in RA, pregnancy also induced a continuous increase in the degree of branching of the glycans of AGP. However, similar changes in concentration and fucosylation were only found during remission of the disease symptoms. In the relapse and unchanged categories in RA, the degree of fucosylation and the plasma concentration of AGP remained constant throughout pregnancy. This indicates a relationship between changes in alpha3-fucosylation of AGP and RA disease activity.
Arthritis, Rheumatoid↗
Inflammation-induced expression of sialyl LewisX is not restricted to alpha1-acid glycoprotein but also occurs to a lesser extent on alpha1-antichymotrypsin and haptoglobin.
Acute and chronic inflammation-induced expression of sialyl LewisX has already been shown to occur on alpha1-acid glycoprotein. We now demonstrate that this phenomenon is not restricted to alpha1-acid glycoprotein but also occurs on two other acute-phase proteins. ie on alpha1-antichymotrypsin and on haptoglobin. The level of expression of sialyl LewisX on these proteins was lower than on alpha1-acid glycoprotein, in all likelihood because alpha1-acid glycoprotein is the only acute-phase protein containing tetraantennary glycans. No expression of sialyl LewisX was detectable on alpha1-protease inhibitor, a protein with a high diantennary glycan content. Non-sialylated LewisX was not detectable on these major acute-phase proteins in any of the conditions studied. This indicates that the majority of the a3-linked fucose residues are present as sialyl LewisX on alpha1-acid glycoprotein, alpha1-antichymotrypsin and haptoglobin. The absolute contribution to the total phenotype in plasma of protein containing this determinant in a multivalent form was highest for alpha1-acid glycoprotein. This leads us to propose that alpha1-acid glycoprotein is, among the acute-phase proteins studied, the one with the highest potential for interference with the extravasation of leukocytes by binding to the selectins.
Acute-Phase Proteins↗
Sialyl Lewis(x) epitopes do not occur on acute phase proteins in mice: relationship to the absence of alpha3-fucosyltransferase in the liver.
Mice are frequently used in models for the study of immunological processes related to inflammation. Since it is known that the degree of fucosylation of human acute phase proteins (APPs) is altered as a consequence of an inflammatory response, we have undertaken this study to gain more insight into the fucosylation of acute phase proteins as it occurs in mouse liver. Mice carrying the cluster of the three genes encoding human alpha1-acid glycoprotein (AGP), one of the well known APPs, were used and the fucosylation of AGP was assessed. A complete absence of fucosylation on the transgenic human AGP was found, which is in sharp contrast to AGP in human serum, of which a major proportion is normally alpha3-fucosylated. Remarkably, a large proportion of mouse AGP did contain fucose residues. Fucosylation was also detected on another APP, mouse protease inhibitor (PI). Alpha3-fucosylation of the transgenic human AGP can be achieved in vitro, using an alpha3/4-fucosyltransferase (alpha3/4-FucT) isolated from human milk, showing that the glycoprotein is not intrinsically resistant to fucosylation. Upon subsequent measurement of the activities of the possible fucosyltransferases present in liver membranes of parent and transgenic mice, only an N-linked-core alpha6-FucT and no alpha2-, alpha3- or alpha4-FucT activity was detected. This indicates that fucose residues found on the mouse serum proteins AGP and PI, which are synthesized in the liver, are most probably in alpha6-linkage to the core chitobiosyl unit. Interestingly, both alpha6- and alpha3-FucT activity was detectable in human liver membranes. None of the above mentioned findings were influenced by the induction of an acute phase response by administration of bacterial lipopolysaccharide. This study shows that: (a) alpha6-FucT is probably a protein specific-glycosyltransferase, since mouse AGP, but not human AGP, may be used as an acceptor; (b) in contrast to human liver, mouse liver does not express any alpha3-FucT-activity, thereby making the mouse incapable of producing the Sialyl Lewis(x) epitope on APPs, which is an important part of the inflammatory reaction in humans. This last finding indicates that the mouse is not suitable as a model for the study of those phenomena related to inflammation in humans, in which glycosylation of acute phase proteins could play a significant role.
Acute-Phase Proteins↗
Do synovial fluid acute phase proteins from patients with rheumatoid arthritis originate from serum?
This study was performed in order to gain insight into the occurrence, glycosylation and the possible origin of the acute-phase proteins alpha1-acid glycoprotein (AGP) and alpha1-protease inhibitor (PI) in sera and synovial fluid from patients with rheumatoid arthritis (RA). Therefore paired sera and synovial fluid samples from patients with RA, and paired synovial fluid samples from right and left knees of patients with varying degrees of arthritis were studied. Crossed affinity immunoelectrophoresis (CAIE) was used with concanavalin A and Aleuria aurantia lectin for the detection of the degree of branching and fucosylation, respectively, and the monoclonal CSLEX-1 for the detection of Sialyl Lewis(X) (SLe(X)) groups on AGP. For PI, not only CAIE, but also high-pressure-anion-exchange chromatography with pulsed amperometric detection was used to study the glycosylation. It was established that the concentrations of AGP and PI were increased in the serum of RA patients compared to normal healthy controls, but that the concentration of both proteins, as well as albumin, was significantly lower in synovial fluid than in serum. Furthermore, the type of glycosylation of both AGP and PI found in RA was significantly different from that found in normals, with increased fucosylation, but there were no major differences in the degree of branching of AGP- or PI-glycans in RA, compared to normals. No differences in glycosylation could be established between serum and synovial fluid in RA. For PI an increased fucosylation was found, both in serum and synovial fluid, using both methods of detection, and it could be established that only the alpha1-->3- and not the alpha1-->6-fucosylation of PI was affected by RA. The increased fucosylation of AGP resulted in an increased expression of SLe(X) on AGP-glycans. Since the alpha1-->3-fucosylation of AGP was significantly increased in both serum and synovial fluid from RA patients, and this correlated with systemic but not with local disease parameters, it can be suggested that acute phase proteins in synovial fluid are most probably of hepatic origin.
Adult↗
Oral estrogen treatment induces a decrease in expression of sialyl Lewis x on alpha 1-acid glycoprotein in females and male-to-female transsexuals.
The effect of estrogen on the glycosylation of alpha 1-acid glycoprotein was studied in women using oral contraceptives and in male-to-female transsexuals receiving oral or transdermal estrogen treatment. Oral estrogen treatment induced an increase in degree of branching and a decrease in fucosylation and sialyl Lewis x expression on alpha 1-acid glycoprotein compared to individuals receiving no estrogens or transdermal estrogen treatment. The effect on the glycosylation of alpha 1-acid glycoprotein was less in the male-to-female transsexuals receiving oral estrogens in combination with cyproterone acetate, a blocker of the androgen receptor with progestagen-like effects. This was of comparable magnitude as in women using oral contraceptives containing both estrogen and progestagen. We conclude that oral estrogens have an identical effect on the hepatic glycosylation of alpha 1-acid glycoprotein in both males and females and that progestagen reduces this effect. These results show that oral estrogens induce an effect on the glycosylation of alpha 1-acid glycoprotein opposite to that induced by inflammation. Oral estrogens can therefore modulate the glycosylation dependent inflammatory actions of alpha 1-acid glycoprotein, while this is not the case with transdermal estrogens. In all likelihood, estrogen receptors on the hepatocyte must play a significant role in the observed effect.
Administration, Oral↗
Elevated serum level and altered glycosylation of alpha 1-acid glycoprotein in hyperimmunoglobulinemia D and periodic fever syndrome: evidence for persistent inflammation.
Crossed affinoimmunoelectrophoresis using concanavalin A and Aleuria aurantia lectin as diantennary glycan- and fucose-specific affinocomponents, respectively, was applied to study changes in the concentration and glycosylation of the acute phase protein alpha 1-acid glycoprotein (AGP) in sera obtained from patients with hyperimmunoglobulinemia D and periodic fever syndrome. Increases in concentration of AGP compared to control values were found not only during attacks, but also during remissions. Compared to healthy controls, the presence of diantennary glycan-containing glycoforms of AGP also increased during febrile attacks, while no changes were found during remissions. A continuous high degree of alpha 1-->3 fucosylation was accompanied by a continuous high expression of sialyl Lewisx on AGP. Despite the clinical picture of recurrent febrile attacks with asymptomatic intervals, these studies indicate that hyperimmunoglobulinemia D should be considered a condition of persistent inflammation.
Adolescent↗
Alpha 1-acid glycoprotein (orosomucoid): pathophysiological changes in glycosylation in relation to its function.
The aim of this review is to summarize the research efforts of the last two decades with respect to (i) the determination and characterization of the changes in glycosylation of AGP under various physiological and pathological states; and (ii) the effects of such changes on its possible anti-inflammatory functions. It will become clear that the heterogeneity observed in the glycosylation of AGP in serum, represents various so-called glycoforms of AGP, of which the relative amounts are strictly determined by the (patho) physiological conditions.
Acute Disease↗
Selective liver targeting of antivirals by recombinant chylomicrons--a new therapeutic approach to hepatitis B.
Hepatitis B virus (HBV) infection is the world's most important chronic virus infection. No safe and effective treatment is available at present, and clinical exploration of promising antiviral agents, such as nucleoside analogues is hampered because of significant side-effects due to their aspecific body distribution. We are exploring the possibility of the selective delivery of antiviral active drugs to liver parenchymal cells, the main site of infection and replication of HBV. Chylomicrons, which transport dietary lipids into the liver via apolipoprotein E-specific receptors, could serve as drug carriers. However, their endogenous nature hampers their application as pharmaceutical drug carriers. We report here that incorporation of a derivative of the nucleoside analogue iododeoxyuridine into recombinant chylomicrons leads to selective targeting to liver parenchymal cells. Potentially effective intracellular drug concentrations of 700 nM can be achieved, and we therefore anticipate that these drug carrier complexes represent a conceptual advance in the development of an effective and safe therapy for hepatitis B.
Animals↗