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Alpha-1-acid antitrypsin, C – reactive proteins, mannose

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Alpha-1-acid glycoprotein (AGP-1) or orosomucoid
(ORM)was first described in 1950 by KarlSchmid 1,2 and Richard J. Winzler and
colleagues3, and turned out to be a very unusual protein: a very low pI of 2.8
– 3.8 and a very high carbohydratecontent of 45%. For about 30 years, AGP-1 was
consideredto be the protein with the highest carbohydrate content. In 1980, galactoglycoprotein
that had a carbohydrate moiety of 76% was described 4,5.Although numerous
articles were devoted to AGP-1since 1950, its exact biological function remains
obscure.However, numerous activities of potential physiological significance
have been described, suchas various immunomodulatingproperties, the ability
tobind basic drugs and many other molecules like steroidhormones, the latter
leading to the suggestion that AGP-1 might be a member of the lipocalin family.
In addition, AGP-1 serum concentrations that remain stable in physiological
conditions (about 1 g/l in humans and 0.2 g/l in rats) increase several-fold
during acute-phase reactions and AGP-1 is considered as a major member of the
positive acute phase protein family.In
this current project, the focus will be majorly on the role of ? – 1 – acid
glycoprotein during inflammatory response and its functions.

Acute Phase
Response (APR):In response to injury,
local inflammatory cells secrete a number of cytokines into
the bloodstream, most notable of which are
the interleukins IL1, IL6 and IL8, and TNF?.
The liver in response produces a large number of acute-phase reactants/ proteins called as
“positive” acute phase proteins (? – 1 – acid glycoprotein, ? – 1 –
antitrypsin, C – reactive proteins, mannose binding lectins,complement factors, ferritin, ceruloplasmin, Serum amyloid A and haptoglobin) 7, 8 and
the production of a number of other proteins is reduced; these are, therefore,
referred to as “negative” acute-phase reactants (albumin and transferrin) (Fig 1). Increased acute phase proteins
from the liver may also contribute to the promotion of sepsis9.The table 1 illustrates the
classification of Acute Phase Proteins (APP).? – 1 – Acid glycoprotein (AGP-1)/ Orosomucoid
(ORM):Alpha-1-acid
glycoprotein (AGP-1) or Orosomucoid was first identified as a ‘reddish-brown
residue that remained in solution’in 1882 13. AGP-1
is a constitutively expressed positive APP i.e. hepatic synthesis is increased
during the APR, potentially amplifying its concentration by over 25% 14. It
has been suggested that a marked increase in AGP-1 concentration may limit
adverse reactions such as inflammation by providing a form of negative feedback
14.Like
other APPs, the AGP-1 is mainly produced by hepatocytes but there have been
studies indicating that extra-hepatic origin of AGP-1, although generally
infrequent and less well understood than hepatic expression, can occur from
human breast epithelial cells, lymphocytes, monocytes and granulocytes 15,16.Minor
microheterogeneity was shown 17 to be altered during acute and chronic
inflammation when there is an increase in ?1-3 fucosylation of AGP-1;
sialylation was also reported to decrease 18. Additionally, glycosylation
patterns might be useful when determining the stage of a patient’s multiple
sclerosis (MS) 16; however – despite its sensitivity – they were especially
of its specificity. The degree of branching (major microheterogeneity) has
often been reported to alter during pathological conditions 19.AGP-1 is one of the APPs which can
undergo extensive post-translational modification. It is involved in the
regulation of inflammation; perhaps through the acquisition of Slex containing
glycans which help AGP-1 bind to leukocyte and endothelial cell (ETC)
selectins, suppressing inflammation by preventing the movement of leukocytes,
keeping the inflammatory response localized 17.Like
other APPs, its mRNA expression is influenced by cytokines and steroid hormones20.
It is known that various factors act to influence AGP-1 glycosylation including
the inflammatory state 21, pregnancy 22, drug or glucocorticoid use 23
and oral contraceptives 24. Table 2 shows the basal plasma AGP-1 levels and
their altered levels during inflammation in different mammals.Structure of
AGP-1 protein back bone:AGP-1
is comprised of a single polypeptide chain of 201-207 residues,depending on the
species, two disulphide bridges linking cysteine pairs 5-147 and 72-165 4
which play a crucial role for its correct folding and intramolecular and
intermolecular interactions26. The aa backbone of human AGP-1 has been
resolved to 1.8 Å and was found to fold in a typical lipocalin tertiary
conformation 27. This structure is comprised of 1) an eight stranded
beta-barrel as a central folding motif, 2) a flanking ?-helix, and 3) four
loops connecting the ?-strands to form the entrance to a ligand-binding pocket
at the open end of the ?-barrel (Fig 2).AGP-1 is a one of the highly
glycosylated APPs. Approximately 45% of its 43kDa molecular mass can be
attributed to attached sugar chains, presenting 5 N-glycosylation sites
(Asn-15, -38, -54, -75, -85) that are not conserved across species lines. These
glycans contain a wide range of sialo-oligosaccharides, being one of the few
serum glycoproteins that can express di-, tri- and tetra-antennary N-linked
glycans11,25. (Fig. 3)10-12% of the glycan structure of AGP-1 terminates
with sialic acid residue (NeuAc), each coupled through ?(2-3) or ?(2-6)
linkages to a subterminalgalactose residue. This high sialylation state is
responsible for the low pI (2.8-3.8) of AGP-1 11.Although,
such a high diversity of glycan expression would predict more than 105
distinct glycoforms of AGP-1, only 12-20 different glycoforms can be detected
in healthy human serum 11. The glycosylation pattern is strongly influenced
by the pathophysiological condition of the host, including acute inflammation,
pregnancy, severe rheumatoid arthritis, and alcoholic liver cirrhosis or
hepatitis 25. The glycosylation site Asn-38 is located in the ?-helix. A
change in its glycosylation, might influence the tertiary conformation of the
molecule and thus, its ligand-binding activity 11.Additionally
AGP-1 also contains 8 potential phosphorylation sites, that vary in number and
position depending on the species 11. Surprisingly, very little is known about the phosphorylation state of AGP-1
and whether it regulates its biological function. Moreover, kinases that
performs this action are also unknown.Proposed functions
of AGP-1:1. Role of AGP-1
in Immunomodulation:Human AGP-1 was found to
significantly inhibit the proliferative response of human peripheral blood
lymphocytes to phytohemagglutinin (PHA). The inhibitory effect of AGP-1 in the
mixed lymphocyte reaction was probably directed against a subset of T-cells,
since 100% inhibition could not be achieved 13. It was suggested that the
effect of AGP-1 could be due to an interaction with and a possible alteration
of the lymphocyte surface or by modulating intracellular factors or pathways,
like protein tyrosine kinase 28, known to be associated with the
proliferative response of these cells.AGP-1, but not its asialo-derivative,
was shown to displace an anionic surface probe from synthetic phosphatidylcholine
vesicles. AGP-1 was speculated to alter lymphocyte membrane fluidity and
receptor capping at the level of membrane-bound phospholipase 29 or membrane
glycosyltransferase. Inhibition of lymphocyte proliferation by AGP-1 was
demonstrated to correlate with a decrease in interleukin (IL)-2 syntheses by
the lymphocytes 30.2. Pro- and
Anti- Inflammatory effects of AGP-1:In
humans, two distinct isoforms of AGP-1 can be found. One highly glycosylated
AGP-1 isoform has a high MW (50-60 kDa) and is synthesized in myeloid cells in
the bone marrow where they are stored in secondary granules 31. Another far
less abundant AGP-1 isoform has a much lower MW (42-45 kDa) and after its
release from the liver is endocytosed by neutrophils where it is stored in
secretory vesicles 32. The different molecular forms of AGP-1 are attributed
not only by the physiological state but also on the tissue that expresses the
protein.Although the
source of AGP-1 used previously are different, the fact that different
glycoformsof  AGP-1 acts contradicting
during different pathophysiological conditions cannot be ruled out. In vivo effects of AGP-1:Transgenic mice over-expressing AGP-1
have an increased susceptibility to dextran sodium sulfate (DSS)-induced
colitis, compared to wild-type mice. Exogenously administered AGP-1 to
wild-type mice had a comparable effect 33. Macrophages probably play an
important role in this model, since they can phagocytose DSS, leading to their
activation 33. AGP-1 augments the production of the pro-inflammatory
cytokines by macrophages, which injures the tissue. Further, a positive feedback
could be created whereby even more macrophages and other inflammatory cells,
such as neutrophils, are activated and contribute to tissue damage.

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Local MPO levels were
increased in AGP-1-transgenic mice, and that this effect was dose-dependent
(homozygous transgenic mice having higher MPO levels compared to heterozygous
transgenic mice). These results suggest that high levels of AGP-1 can have a
synergistic effect with stimuli that can cause colitis 33.

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