Download Haptoglobin, inflammation and disease

Transactions of the Royal Society of Tropical Medicine and Hygiene (2008) 102, 735—742
available at www.sciencedirect.com
journal homepage: www.elsevierhealth.com/journals/trst
REVIEW
Haptoglobin, inflammation and disease
Isaac K. Quaye ∗
Department of Medical Biochemistry, University of Ghana Medical School, Korle-Bu-Accra, Ghana
Received 2 November 2007; received in revised form 3 April 2008; accepted 3 April 2008
Available online 16 May 2008
KEYWORDS
Haptoglobin;
Haemoglobin;
Phenotype;
Immune response;
Inflammation;
Infectious diseases
Summary Haptoglobin is an acute phase protein that scavenges haemoglobin in the event
of intravascular or extravascular haemolysis. The protein exists in humans as three main phenotypes, Hp1-1, Hp2-2 and Hp2-1. Accumulated data on the protein’s function has established
its strong association with diseases that have inflammatory causes. These include parasitic
(malaria), infectious (HIV, tuberculosis) and non-infectious diseases (diabetes, cardiovascular
disease and obesity) among others. Phenotype-dependent poor disease outcomes have been
linked with the Hp2-2 phenotype. The present review brings this association into perspective
by looking at the functions of the protein and how defects in these functions associated with
the Hp2 allele affect disease outcome. A model is provided to explain the mechanism, which
appears to be largely immunomodulatory.
© 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights
reserved.
1. Introduction
Haptoglobin (Hp) is a unique acute phase protein that
primarily scavenges haemoglobin (Hb) released into the
circulation by haemolysis or normal red blood cell (RBC)
turnover. The protein was first discovered by Polonovski
and Jayle (1938) while Smithies determined the polymorphism in the protein (Smithies and Walker, 1955). The plasma
concentration of Hp increases several fold in the event
of an inflammatory stimulus such as infection, injury or
malignancy, whether local (vascular) or systemic (extravascular). IL-6, produced through the activities of the primary
cytokines TNF-␣ and IL-1, is the major inducer of the expression of the protein (Oliviero et al., 1987).
∗
Tel.: +233 21 661311.
E-mail addresses: [email protected], [email protected].
In human populations three common phenotypes are
represented: Hp1-1, Hp2-2 and the heterozygous Hp2-1,
which is determined by two alleles HP1 and HP2 (Smithies
and Walker, 1955). The HP2 allele contains a partial duplication of approximately 1.7 kb from an unequal crossing
over event between HP1 alleles (Maeda et al., 1984).
The Hp gene transcript yields ␣ and ␤ protein subunits
interconnected by disulfide bridges after post-translational
processing. Inherited variations in the ␣ subunit give rise
to the alleles that define the common phenotypes (Bowman
and Kurosky, 1982). A less common phenotype is Hp2-1 modified (Hp2-1M), which has been observed in Africans and
African-Americans and results from an A-61C mutation in the
promoter region of the Hp gene (Maeda, 1991). This mutation causes decreased gene expression in subjects with the
Hp2-1M phenotype. The mutation is also present in the Hp0
phenotype, characterized by significantly reduced (hypohaptoglobinaemia) or null expression (ahaptoglobinaemia)
of the protein (Grant and Maeda, 1993; Teye et al., 2003). In
0035-9203/$ — see front matter © 2008 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.trstmh.2008.04.010
736
Southeast Asian populations, the Hp0 phenotype arises from
a deletion in the promoter region of the Hp gene that gives
rise to the HPdel allele (Koda et al., 1998). Subjects homozygous for the HPdel allele are ahaptoglobinaemic whilst those
heterozygous are hypohaptoglobinaemic.
Hp has been reported to be involved in modulating the
immune response, autoimmune diseases and major inflammatory disorders (Delanghe et al., 1999; Eaton et al.,
1982; Levy, 2003; Oh et al., 1990; Quaye et al., 2006).
These observations appear to stem from its inherent antioxidant property, its unique role in binding Hb and its ability
to stimulate cells of the monocyte/macrophage lineage.
This review summarizes current knowledge of the role of
Hp in relation to inflammation and major diseases with
inflammatory causes. An attempt is made to examine these
relationships in terms of cause (the biochemical activities
of the protein) and effect (the disease that results from
dysregulation of these activities).
2. Hp tissue expression
Human Hp cDNA was originally cloned from hepatocytes,
where Hp gene expression is most abundant (Yang et al.,
1983). Currently, the transcript has been detected in many
tissues, including white adipose tissue, brown adipose tissue, ovary, lungs, testis, arteries and placenta (Friedrichs
et al., 1995; Kalmovarin et al., 1991; Yang et al., 1995).
In humans, the induction of Hp gene expression is mediated primarily by IL-6, which is the common cytokine
mediator for Hp gene expression in the liver of all
species studied. Three IL-6-responsive regulatory regions
are present on the Hp gene promoter, A-(157), B (-111) and
C (-61), which together constitute the binding site for hormones released during the acute phase response (Baumann
et al., 1990). The binding of hormones and cytokines to the
regulatory regions promotes the transcription of the Hp gene
and increases the synthesis of the protein.
3. Hp function
3.1. Antioxidant/anti-inflammatory role
Under conditions of compromised oxygen supply, such as
occurs in injury, infection or malignancy, oxygen species with
free unpaired electrons are generated during mitochondrial
electron transport. Referred to as highly reactive oxygen
species (ROS), their production causes damage to cell membranes and macromolecules (lipids, proteins and DNA) (Valko
et al., 2007). In addition, cells of the immune system generating ROS also produce reactive nitrogen species (RNS), for
example peroxynitrite (ONOO-) by the interaction between
nitric oxide and superoxide, which are equally damaging to
cell membranes and DNA.
Cellular non-enzymatic antioxidants, which include vitamin C, vitamin E, glutathione and others, maintain cellular
redox homeostasis in order to prevent or control cellular damage in the event of an inflammatory response. Hp
possesses an innate phenotype-dependent antioxidant activity that exceeds by far that of vitamin C (ascorbic acid)
(Tseng et al., 2004) and contributes significantly to this process, particularly at extravascular sites. Both in vitro and in
I.K. Quaye
vivo studies have established that subjects with the Hp1-1
phenotype are more likely to resist cellular oxidative stress
than those with the Hp2-2 phenotype, with Hp2-1 being
intermediate (Tseng et al., 2004). The specific antioxidant
functions of the protein at extravascular sites are: activation
of neutrophils; maintenance of reverse cholesterol transport; inhibition of cyclooxygenase (COX) and lipooxygenase
(LOX); and other antioxidant activities, and are described
below.
3.1.1. Activation of neutrophils
During exercise, injury, trauma or infection, the target
cells secrete the primary pro-inflammatory cytokines IL-1␤
and TNF-␣, which send signals to adjacent vascular cells
to initiate activation of endothelial cells and recruitment
of neutrophils. The activated neutrophils, which are first
in the line of defence, then aid in the recruitment of
other inflammatory cells following extravasation (Kushner,
1993). Neutrophils engage in generating ROS as well as
recruiting other defence cells, particularly monocytes and
macrophages. Hp is synthesized during granulocyte differentiation and stored for release when neutrophils are activated
(Theilgaard-Monch et al., 2006). Neutrophil activation can
occur in the absence of patent injury (during exercise)
(Quindry et al., 2003). By quenching the respiratory burst,
Hp assists in mitigating potential damage to the surrounding
tissues. In a recent study on ischaemia/reperfusion injury
and myocardial infarct size in mice, it was shown that the
Hp2 allele was associated with a higher level of lipid peroxidation products than the Hp2 allele, which also boosted the
expression of the antioxidant cytokine IL-10 (Blum et al.,
2007). The Hp2-2 phenotype has consistently been observed
to be a risk factor in inflammatory diseases (Delanghe et
al., 1999; Levy, 2004; Papp et al., 2007), attributed to its
compromised antioxidant role compared to the Hp2 allele.
3.1.2. Maintenance of reverse cholesterol transport
Elevated levels of low density lipoproteins (LDL) constitute
a major risk for atherosclerosis. Oxidized LDL readily infiltrates into the arterial intima, where it is endocytosed by
macrophages and eventually leads to formation of foam cells
and fatty streaks (Hovingh et al., 2005). On the other hand,
high density lipoproteins (HDL) play a key role in reverse
cholesterol transport, together with the enzyme lecithin
cholesterol acyl-transferase (LCAT). HDL in the form of Apo
A-1 stimulates LCAT and serves as the acceptor for the esterified cholesterol/phospholipid released by the enzyme. In
this way, Apo A-1 sustains cholesterol transport for degradation in the liver, preventing its accumulation in macrophages
to form foam cells. In a recent report, it was shown that Hp
binds to Apo A-1 to protect it from free radical-mediated
damage and also prevents HDL from forming adducts with
other lipoprotein molecules (Salvatore et al., 2007). This
has an important health benefit in cardiovascular disease.
3.1.3. Inhibition of COX and LOX
Arachidonic acid is the substrate for the synthesis of
leukotrienes and prostaglandins (PGE) by the enzymes LOX
and COX, respectively. COX is made up of two isoforms, COX1
that is constitutively expressed and COX2 that is induced by
stimuli including inflammation and hypoxia. Over-expression
Haptoglobin, inflammation and disease
of COX2 leads to synthesis of PGE and its metabolites, thromboxane (vasoconstrictor) and prostacyclins (vasodilator).
Leukotrienes and prostaglandins participate in immunomodulation, upregulation of apoptotic genes, tissue growth and
repair, among others. LOX is also known to participate in
oxidizing LDL, which can lead to the generation of lipid peroxides (Palmer and Henrich, 1995). Hp has been shown to
inhibit both COX and LOX (using commercial Hp in guinea
pigs), which provides a means to modulate responses to
inflammation or infection that may be harmful to tissues
(Saeed et al., 2007).
3.1.4. Other antioxidant activities
As a molecular chaperone, Hp inhibits the inappropriate selfassociation of proteins induced by oxidation or heat. This
function puts Hp alongside clusterin as major extracellular
proteins that protect against protein misfolding, assisting in
the preservation of cell function (Yerbury et al., 2005). Hp
is persistently elevated in pregnancy, myocardial infarction
and obesity (Berkova et al., 2001; Blum et al., 2007; Chiellini
et al., 2004). These conditions are characterized by tissue
growth and repair that require anti-inflammatory responses.
Hp performs this role both as a ligand for Mac-1 (complement
receptor type 3, CD11b/CD18) and a required factor for cell
migration (de Kleijn et al., 2002) and angiogenesis (Cid et
al., 1993). Tissue repair and regeneration are accomplished
by collagen turnover and the movement of fibroblasts within
the extracellular matrix. Hp inhibits the activities of the
matrix metalloproteinases (MMP-2, MMP-9) required for the
breakdown of gelatin and directly promotes the migration
of fibroblasts needed for tissue regeneration (de Kleijn et
al., 2002). At extravascular sites, Hp undertakes significant anti-inflammatory activities that are important for the
maintenance of redox homeostasis while augmenting tissue
repair (de Kleijn et al., 2002).
3.2. Hb binding
Hb is critical for life, providing cells with oxygen for their
energy needs. However, outside of the confines of the erythrocytes (RBCs), Hb is highly toxic (Alayash, 2004). Its
prosthetic group, haem, is lipophilic and readily intercalates into cell membranes to disrupt the lipid bilayers. Iron
present in haem catalyzes the generation of ROS through
the Fenton and Haber-Weiss reactions (Figure 1) (Sadrzadeh
et al., 1984). Additionally, Hb avidly binds to nitric oxide,
depleting the cell of a major modulator of vascular tone,
resulting in changes in vasomotor constriction and endothelial damage (Minneci et al., 2005). The presence of free
Hb is therefore a danger signal that is very rapidly attenuated by mechanisms that enable rapid and efficient removal
of the protein in circulation or at the site of injury. Hp
Figure 1 Reactions associated with the generation of reactive
oxygen species.
737
binds Hb to prevent Hb-related oxidative damage and also
limits the release of haem, which exacerbates oxidative
stress. Hb may therefore act as a secondary modulator of
the anti-inflammatory role of Hp.
In general, Hb removal from the circulation following
intravascular and extravascular haemolysis is accomplished
by three major mechanisms: high affinity binding of Hb
to Hp; high affinity binding of haem to hemopexin (Hpx);
and low affinity binding of Hb to CD163. The mechanisms
involving Hpx and CD163 appear to function during massive
or localized haemolysis, where Hp concentration is overwhelmed or limited, and this review will focus on Hp-Hb
interactions.
Both Hp and Hb are made up of ␣/␤-dimers but interaction to form the Hp-Hb complex occurs mostly through the
␤ chain of Hb and the ␤ chain of Hp (Ettrich et al., 2002).
Equimolar amounts of Hp bind to Hb, although Hp is normally present in serum in a >400 molar excess compared to
free Hb (Bowman and Kurosky, 1982). After forming a Hp-Hb
complex, the scavenger receptor CD163 expressed on the
surface of monocytes and tissue macrophages enables the
endocytosis of the complex, which is followed by degradation in the liver and spleen (Kristiansen et al., 2001). Both
the Hb binding capacity (HBC) and affinity of the Hp-Hb complex for CD163 are phenotype dependent (Kristiansen et al.,
2001). The HBC measures the capacity of an Hp phenotype to
protect against a haemolytic episode (Hb-related cell damage and release of haem). This activity, which is ranked in
the order Hp1-1>Hp2-1>Hp2-2, partially explains the ability of the phenotypes to prevent Hb-related oxidative stress
(Saeed et al., 2007).
3.3. Immunomodulation
In general, an immune response may be classified as innate
or adaptive (Chaplin, 2006). Innate immunity predominantly
carries out the post-injury response, while the innate and
adaptive arms are integrated in the post-infection response
(Medzhitov and Janeway, 2000). In immune modulation, cells
of both arms of the immune system, upon contact with danger signals, stimulate the generation of anti-inflammatory
and pro-inflammatory factors to repair injured tissue or
eliminate an infection, while ensuring that local cellular
damage is minimized (Matzinger, 2002; Shi et al., 2003). The
effectors of the immune response are cellular (phagocytes
and dendritic cells) and humoral (cytokines, complement,
acute phase proteins and leukotrienes) (Pillay et al., 2007).
Hp has numerous roles in both the cellular and humoral
activities of the innate and adaptive systems, including
prostaglandin synthesis, leukocyte recruitment and migration, the generation of cytokine patterns following injury
and infection, and tissue repair.
In the event of an injury or trauma, the acute inflammatory response leads to the recruitment of neutrophils as
the first line of defence, through activated endothelial cells
and platelets (Pillay et al., 2007). The endothelial cells activate COX-2, which synthesizes prostaglandin E2, increasing
vasodilation and so enabling neutrophil migration. Simultaneously, platelets increase expression of chemokines,
platelet derived growth factor (PDGF), TGF-␤ and cytokines
(IL-1, TNF-␣) for the recruitment of additional neutrophils
as well as monocytes and macrophages in the chronic phase
738
(Kaplanski et al., 2003). This early process involves the
active participation of Hp as a ligand for Mac-1 (El-Ghmati
et al., 1996). Although Hp is involved in the initial recruitment of neutrophils, it also dampens sustained neutrophil
activity by inhibiting both LOX and COX (observed in guinea
pigs using commercial Hp) and attenuates the respiratory
burst. Since LOX is also involved in producing lipoxins, which
reduce the effect of the respiratory burst (Wada et al.,
2006), Hp exhibits a potent immunomodulatory role in minimizing cellular damage in the inflammatory response. As a
p53-like protein, Hp promotes the apoptosis of neutrophils
as monocytes and macrophages are attracted to the site of
injury (Kim et al., 1995).
During the repair phase, macrophages express the
chemo-attractants PDGF, MCP-1, TNF-␣, IL-1 and IL-6. These
stimulate the recruitment of more macrophages and fibroblasts to contain the inflammation and begin the wound
healing process (Eming et al., 2007). Increased secretion
of IL-6 and TNF-␣ further enhances Hp expression and augments its activities, which also include inhibition of gelatin
deposition and a direct effect on fibroblast migration needed
for wound healing and repair (Gabay, 2006). Lymphocytes
are the final arm of the cellular immune response that
contribute to achieving wound repair with limited cellular damage. Specifically, the secretion of cytokines by CD4+
TH 1 (pro-inflammatory) and TH 2 (anti-inflammatory) cells is
orchestrated to achieve efficient and effective wound healing. A high TH 1 response could cause cellular damage, while
a high TH 2 response could lead to tissue fibrosis or, in some
cases, allergy (Meneghin and Hogaboam, 2007).Thus proper
TH 1/TH 2 balance is an important mechanism for ensuring
effective elimination of injury or an infecting organism while
maintaining excellent tissue regeneration.
Hp is an established suppressor of T cell proliferation,
exhibiting strong inhibition of TH 2 cytokine release and weak
inhibition of TH 1 cytokine release (Arredouani et al., 2003).
This immunomodulatory role has been found to be phenotype dependent. In a recent publication it was shown that
macrophages, activated by phagocytosis of Hp2-2-Hb complex through CD163, shift the T helper cell response towards
TH 1 cytokines, while those activated by Hp1-1-Hb complex
generate TH 2 cytokines with an increased IL-6 and IL-10
cytokine release (Guetta et al., 2007). The balance of the
T cell response may be particularly important at extravascular sites, where the local expression of Hp would play
a role in reducing damage to the surrounding tissues. At
extravascular sites, immature dendritic cells interact with
antigens or danger signals. Danger signals can be biomolecular metabolites, including advanced glycation end products
(AGEs), membrane components, uric acid and ROS (Valko et
al., 2007; Bianchi, 2007) or infectious signals such as cell
wall components of bacteria and single stranded and double
stranded RNA of viruses (Eisenacher et al., 2008). Dendritic
cells are subsequently activated to mature by mast cells and
move into the lymph nodes to present antigens to naı̈ve
T cells, which differentiate to induce TH 2 or TH 1 cytokine
responses (Wen et al., 2008). The instruction signals from
mast cells tend towards TH 2 cytokine responses. Hp acting
as a ligand for mast cells (El-Ghmati et al., 2002) may have
a significant role in the dendritic cell activation process. It
appears that the default cytokine profile stimulated by Hp
is TH 2. However, the evolution of the HP2 allele seems to
I.K. Quaye
have modulated this function by shifting the cytokine profile
towards a TH 1 dominant phenotype. Such an important evolutionary function must have been acquired following severe
environmental challenges that have continued to sustain the
selection of the HP2 allele.
4. Inflammation and Hp
Inflammation describes the processes involved in the disturbance of tissue homeostasis as a result of acute or chronic
stimuli from an infection, stress, autoimmune reaction or
mechanical injury (Gabay, 2006). The homeostatic immune
surveillance is largely mediated by polymorphonuclear leucocytes (PMN), with the disturbance eliciting PMN migration
through the TH 1/TH 2 cytokine profile (Kato and Kitagawa,
2006). Hp actively participates in all the processes from
PMN recruitment and free radical quenching, to tissue repair
and regeneration. Not surprisingly, the reduction or absence
of Hp protein, as occurs in hypohaptoglobinemia or ahaptoglobinemia, is associated with allergic (skin and lungs) and
anaphylactic transfusion reactions, respectively (Gilstad,
2003; Larsen et al., 2006; Shimada et al., 2002).
A model for the role of Hp in inflammation is depicted
in Figure 2. In this model, danger signals stimulate Hp
expression through the activity of IL-6. In Hp1-1 subjects,
Hp significantly reduces ROS generation through its potent
antioxidant, Hb-binding and anti-inflammatory role as previously elaborated. This activity then triggers a TH 2-dominant
response initiating healing and repair. In Hp2-2 subjects,
however, weak ROS quenching would allow the persistence
of the inflammatory stimulus, leading to aTH 1 response and
increased oxidative stress. Hb in this model is a modulator, as
its binding to Hp reduces the generation of ROS by preventing haem and iron release and also depletes the available
Hp in circulation. This model could explain the effect of
Hp phenotype on the progression and outcome of parasitic
diseases, infectious diseases and non-infectious diseases as
outlined below.
5. Hp and disease associations
The gene frequencies of the HP1 and HP2 alleles differ geographically (Langlois and Delanghe, 1996). In West Africa,
East Africa and South America, the HP1 allele is predominant, while North America, Europe, Asia and Australia have a
predominant HP2 allele. The HP2 allele appears to be gaining
a selective advantage, having derived from the HP1 allele in
India (Langlois and Delanghe, 1996). Hp gene polymorphism
has been investigated in case-control and cross-sectional
studies of several diseases in relation to their incidence and
clinical expression. In particular, diseases of parasitic origin
(malaria) (Atkinson et al., 2007; Elagib et al., 1998; Minang
et al., 2004; Quaye et al., 2000), infectious diseases (pulmonary tuberculosis, HIV) (Delanghe et al., 1998; Kasvosve
et al., 2000) and non-infectious diseases (diabetes, coronary
artery disease and obesity, among others) (Chiellini et al.,
2004; Levy, 2004; Quaye et al., 2006) have been studied.
These studies provide some insights into the role of Hp2 and
Hp2 alleles in susceptibility/protection against infectious
and non-infectious diseases and the selective advantage of
the Hp2 allele in various populations.
Haptoglobin, inflammation and disease
739
Figure 2 Model of the role of haptoglobin (Hp) in the inflammatory response. Danger signals from stressed cells induce expression
of IL-6 which in turn induces expression of Hp. The strong haemoglobin (Hb) binding, antioxidant, and anti-inflammatory activity of
Hp1 leads to a TH 2 dominant cytokine expression. The corollary holds for the Hp2 phenotype. ROS: reactive oxygen species.
In principle, host-pathogen interaction is defined by resistance to (the ability to limit pathogen burden) or tolerance
of (the ability to resist disease severity) a given pathogen
(Raberg et al., 2007). This interaction leads to the evolution of both the host and pathogen for survival. In the recent
history of the evolution of the human genome, malaria has
been identified as the strongest known selective pressure
(Kwiatkowski, 2005). The role of Hp gene polymorphism
in malaria disease has been controversial. Some studies
(cross-sectional and case-control) suggest that the Hp2-2
phenotype is protective against severe Plasmodium falciparum infection and placental parasite burden (Cox et al.,
2007; Elagib et al., 1998; Minang et al., 2004; Quaye et
al., 2000). Other case-control studies did not find significant
associations (Aucan et al., 2002; Bienzle et al., 2005). Two
recent prospective cohort studies have also supported the
view that the Hp2-2 phenotype affords protection against
malaria that increases significantly in children 3 years or
older (Atkinson et al., 2007; Cox et al., 2007).
It has been suggested that the presence of the A-61C
mutation in the Hp promoter region, which is associated
with the HP2 allele, may confound genotyping for Hp0 or
Hp2-2 phenotypes (Cox et al., 2007). This might explain,
in part, the controversy over the role of the HP2 and HP1
alleles in malaria protection and susceptibility. These issues
notwithstanding, two questions of interest are: how might
homozygosity for the HP2 allele confer protection in P. falciparum infection, while posing a risk in the predominantly
inflammation-related disease states described previously
and how might these influence HP2 allele selective advantage? Functionally, the HP2 allele is a weaker antioxidant,
promotes iron retention, has a weaker HBC, is lower in concentration in circulation, and in immunomodulatory function
promotes a TH 1-dependent cytokine profile. The cumulative
effect of all of these factors could be a more pro-oxidant
environment, arising from decreased quenching of ROS
following infection or injury. In malaria disease, persistent
haemolysis, which is also associated with the Hp2-2 phenotype (Atkinson et al., 2006) could increase ROS burden
and decrease antioxidants. Eventually, sustained ROS generation, to which the Plasmodium species is vulnerable,
could lead to a reduction in parasite burden. This initial
respiratory burst and parasite destruction might promote
an accelerated processing of parasite antigens for presentation to naı̈ve T cells. In a malaria-endemic environment,
this activity could boost host immunity over an extended
period and prevent severe disease or afford immunological tolerance. In a study relating malarial anaemia and Hp
genotype, it was also observed that the Hp2-2 phenotype
was associated with asymptomatic malaria at the end of the
malaria season (Atkinson et al., 2006). Thus, the increasing
prevalence of the HP2 allele in both Africa and Asia (Teye
et al., 2006) may be largely attributed to selective pressure
from malaria, as has been the case for HbS, HbC and ␣ and
␤ thalassaemia. Additionally, the added shift towards TH 1
cytokine profiles contributed by the HP2 allele provides a
balance in the immune response against pathogens, which
might add to its selective advantage.
In the case of non-infectious diseases (diabetes, coronary
artery disease, obesity), endogenous danger signals arising
from disturbed metabolic pathways and tissue damage may
favour a less pro-oxidant cytokine profile as engendered by
the HP1 allele, thus making the HP2 allele a risk factor.
This scenario could similarly apply in HIV and pulmonary
tuberculosis infections, where increased iron retention and
reduced antioxidant factors lead to poor prognosis in subjects with the Hp2-2 phenotype (Delanghe et al., 1998;
Kasvosve et al., 2000). The Hp0 phenotype is associated with
anaphylactic transfusion reactions from IgG and IgE Hp antibodies (Gilstad, 2003; Shimada et al., 2002). Hp0 individuals
are also at risk for iron loading in kidney proximal tubules
due to glomerular filtration of Hb (Fagoonee et al., 2005).
740
Based on the collective phenotype-dependent activities of
Hp described here, one might propose that eventually, routine screening for Hp phenotype could impact the treatment
of diseases with inflammatory etiologies.
6. Conclusions
Hp gene polymorphism has featured prominently in diseases of parasitic, viral and bacterial origin. Additionally, it
has been associated with non-infectious diseases involving
inflammation. The unique and peculiar functional activities
defined by the phenotypes make consideration of Hp phenotypes in the clinical setting during treatment important.
It also calls for intensified research to determine the precise activity of the phenotypes in regulating the pro-oxidant
and antioxidant environments at injury sites that lead to:
inhibition or promotion of pathogen growth through antigen
processing; mitigation or promotion of disease risk and/or
outcome; and tissue damage or wound healing and repair.
Clearly, more studies of Hp and disease associations are
required, particularly with respect to its immunomodulatory function. Studies involving Hp and parasitic diseases,
as well as prospective studies with Hp knockout mice in
non-infectious disease models will be valuable.
Acknowledgement: The author wishes to thank Dr Eleanor
G. Hankins for critically reading the manuscript.
Funding: None.
Conflicts of interest: None declared.
Ethical approval: Not required.
References
Alayash, A.I., 2004. Redox biology of blood. Antioxid. Redox Signal.
6, 941—943.
Arredouani, M., Matthijs, P., Van Hoeyveld, E., Kasran, A., Baumann,
H., Ceuppens, J.L., Stevens, E., 2003. Haptoglobin directly
affects T cells and suppresses T helper cell type 2 cytokine
release. Immunology 108, 144—151.
Atkinson, S.H., Rockett, K., Sirugo, G., Bejon, P.A., Fulford, A.,
O’Connell, M.A., Bailey, R., Kwiatkowski, D.P., Prentice, A.M.,
2006. Seasonal childhood anaemia in West Africa is associated
with the haptoglobin 2-2 genotype. PLoS Med. 3, e172.
Atkinson, S.H., Mwangi, T.W., Uyoga, S.M., Ogada, E., Macharia,
A.W., Marsh, K., Prentice, A.M., Williams, T.N., 2007. The haptoglobin 2-2 genotype is associated with a reduced incidence
of Plasmodium falciparum malaria in children on the coast of
Kenya. Clin. Infect. Dis. 44, 802—809.
Aucan, C., Walley, A.J., Greenwood, B.M., Hill, A.V., 2002. Haptoglobin genotypes are not associated with resistance to severe
malaria in the Gambia. Trans. R. Soc. Trop. Med. Hyg. 96,
327—328.
Baumann, H., Morella, K.K., Jahreis, G.P., Marinkovic, S., 1990. Distinct regulation of the interleukin-1 and interleukin-6 response
elements of the rat haptoglobin gene in rat and human hepatoma
cells. Mol. Cell. Biol. 10, 5967—5976.
Berkova, N., Lemay, A., Dresser, D.W., Fontaine, J.Y., Kerizit, J.,
Goupil, S., 2001. Haptoglobin is present in human endometrium
and shows elevated levels in the decidua during pregnancy. Mol.
Hum. Reprod. 7, 747—754.
I.K. Quaye
Bianchi, M.E., 2007. DAMPs, PAMPs and alarmins: All we need to
know about danger. J. Leukoc. Biol. 81, 1—5.
Bienzle, U., Eggelte, T.A., Adjei, L.A., Dietz, E., Ehrhardt, S.,
Cramer, J.P., Otchwemah, R.N., Mockenhaupt, F.P., 2005. Limited influence of haptoglobin genotypes on severe malaria in
Ghanaian children. Trop. Med. Int. Health 10, 668—671.
Blum, S., Asaf, R., Guetta, J., Miller-Lotan, R., Asleh, R., Kremer, R., Levy, N.S., Berger, F.G., Aronson, D., Fu, X., Zhang, R.,
Hazen, S.L., Levy, A.P., 2007. Haptoglobin genotype determines
myocardial infarct size in diabetic mice. J. Am. Coll. Cardiol.
49, 82—87.
Bowman, B.H., Kurosky, A., 1982. Haptoglobin: The evolutionary
product of duplication, unequal crossing over, and point mutation. Adv. Hum. Genet. 12, 189—261, 453—454.
Chaplin, D.D., 2006. 1. Overview of the human immune response. J.
Allergy Clin. Immunol. 117 (2 Suppl. Mini-Primer), S430—S435.
Chiellini, C., Santini, F., Marsili, A., Berti, P., Bertacca, A., Pelosini,
C., Scartabelli, G., Pardini, E., Lopez-Soriano, J., Centoni, R.,
Ciccarone, A.M., Benzi, L., Vitti, P., Del Prato, S., Pinchera, A.,
Maffei, M., 2004. Serum haptoglobin: A novel marker of adiposity
in humans. J. Clin. Endocrinol. Metab. 89, 2678—2683.
Cid, M.C., Grant, D.S., Hoffman, G.S., Auerbach, R., Fauci, A.S.,
Kleinman, H.K., 1993. Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis. J.
Clin. Invest. 91, 977—985.
Cox, S.E., Doherty, C., Atkinson, S.H., Nweneka, C.V., Fulford, A.J.,
Ghattas, H., Rockett, K.A., Kwiatkowski, D.P., Prentice, A.M.,
2007. Haplotype association between haptoglobin (Hp2) and hp
promoter SNP (A-61C) may explain previous controversy of haptoglobin and malaria protection. PLoS ONE 2, e362.
de Kleijn, D.P., Smeets, M.B., Kemmeren, P.P., Lim, S.K., Van Middelaar, B.J., Velema, E., Schoneveld, A., Pasterkamp, G., Borst, C.,
2002. Acute-phase protein haptoglobin is a cell migration factor
involved in arterial restructuring. FASEB J. 16, 1123—1125.
Delanghe, J.R., Langlois, M.R., Boelaert, J.R., Van Acker, J., Van
Wanzeele, F., van der Groen, G., Hemmer, R., Verhofstede, C.,
De Buyzere, M., De Bacquer, D., Arendt, V., Plum, J., 1998. Haptoglobin polymorphism, iron metabolism and mortality in HIV
infection. AIDS 12, 1027—1032.
Delanghe, J., Langlois, M., Duprez, D., De Buyzere, M., Clement, D.,
1999. Haptoglobin polymorphism and peripheral arterial occlusive disease. Atherosclerosis 145, 287—292.
Eaton, J.W., Brandt, P., Mahoney, J.R., Lee Jr, J.T., 1982. Haptoglobin: A natural bacteriostat. Science 215, 691—693.
Eisenacher, K., Steinberg, C., Reindl, W., Krug, A., 2008. The role
of viral nucleic acid recognition in dendritic cells for innate and
adaptive antiviral immunity. Immunobiology 212, 701—714.
Elagib, A.A., Kider, A.O., Akerstrom, B., Elbashir, M.I., 1998. Association of the haptoglobin phenotype (1-1) with falciparum
malaria in Sudan. Trans. R. Soc. Trop. Med. Hyg. 92, 309—311.
El-Ghmati, S.M., Van Hoeyveld, E.M., Van Strijp, J.G., Ceuppens, J.L., Stevens, E.A., 1996. Identification of haptoglobin
as an alternative ligand for CD11b/CD18. J. Immunol. 156,
2542—2552.
El-Ghmati, S.M., Arredouani, M., Van Hoeyveld, E.M., Ceuppens,
J.L., Stevens, E.A., 2002. Haptoglobin interacts with the human
mast cell line HMC-1 and inhibits its spontaneous proliferation.
Scand. J. Immunol. 55, 352—358.
Eming, S.A., Brachvogel, B., Odorisio, T., Koch, M., 2007. Regulation
of angiogenesis: Wound healing as a model. Prog. Histochem.
Cytochem. 42, 115—170.
Ettrich, R., Brandt Jr, W., Kopecky, V., Baumruk, V., Hofbauerova,
K., Pavlicek, Z., 2002. Study of chaperone-like activity of human
haptoglobin: Conformational changes under heat shock conditions and localization of interaction sites. Biol. Chem. 383,
1667—1676.
Fagoonee, S., Gburek, J., Hirsch, E., Marro, S., Moestrup, S.K., Laurberg, J.M., Christensen, E.I., Silengo, L., Altruda, F., Tolosano,
Haptoglobin, inflammation and disease
E., 2005. Plasma protein haptoglobin modulates renal iron loading. Am. J. Pathol. 166, 973—983.
Friedrichs, W.E., Navarijo-Ashbaugh, A.L., Bowman, B.H., Yang, F.,
1995. Expression and inflammatory regulation of haptoglobin
gene in adipocytes. Biochem. Biophys. Res. Commun. 209,
250—256.
Gabay, C., 2006. Interleukin-6 and chronic inflammation. Arthritis
Res. Ther. 8 (Suppl. 2), S3.
Gilstad, C.W., 2003. Anaphylactic transfusion reactions. Curr. Opin.
Hematol. 10, 419—423.
Grant, D.J., Maeda, N., 1993. A base substitution in the promoter
associated with the human haptoglobin 2-1 modified phenotype decreases transcriptional activity and responsiveness to
interleukin-6 in human hepatoma cells. Am. J. Hum. Genet. 52,
974—980.
Guetta, J., Strauss, M., Levy, N.S., Fahoum, L., Levy, A.P.,
2007. Haptoglobin genotype modulates the balance of
Th1/Th2 cytokines produced by macrophages exposed to free
hemoglobin. Atherosclerosis 191, 48—53.
Hovingh, G.K., Hutten, B.A., Holleboom, A.G., Petersen, W., Rol,
P., Stalenhoef, A., Zwinderman, A.H., de Groot, E., Kastelein,
J.J., Kuivenhoven, J.A., 2005. Compromised LCAT function is
associated with increased atherosclerosis. Circulation 112, 879—
884.
Kalmovarin, N., Friedrichs, W.E., O’Brien, H.V., Linehan, L.A., Bowman, B.H., Yang, F., 1991. Extrahepatic expression of plasma
protein genes during inflammation. Inflammation 15, 369—379.
Kaplanski, G., Marin, V., Montero-Julian, F., Mantovani, A., Farnarier, C., 2003. IL-6: A regulator of the transition from neutrophil
to monocyte recruitment during inflammation. Trends Immunol.
24, 25—29.
Kasvosve, I., Gomo, Z.A., Mvundura, E., Moyo, V.M., Saungweme, T.,
Khumalo, H., Gordeuk, V.R., Boelaert, J.R., Delanghe, J.R., De
Bacquer, D., Gangaidzo, I.T., 2000. Haptoglobin polymorphism
and mortality in patients with tuberculosis. Int. J. Tuberc. Lung
Dis. 4, 771—775.
Kato, T., Kitagawa, S., 2006. Regulation of neutrophil functions by
proinflammatory cytokines. Int. J. Hematol. 84, 205—209.
Kim, I.K., Lee, J.H., Kim, H.S., Kwon, O.J., Shim, B.S., 1995. A
novel function of haptoglobin: Haptoglobin-haemoglobin complex induces apoptosis of hepatocarcinomatous hep 3B cells.
Scand. J. Clin. Lab. Invest. 55, 529—535.
Koda, Y., Soejima, M., Yoshioka, N., Kimura, H., 1998. The
haptoglobin-gene deletion responsible for anhaptoglobinemia.
Am. J. Hum. Genet. 62, 245—252.
Kristiansen, M., Graversen, J.H., Jacobsen, C., Sonne, O., Hoffman, H.J., Law, S.K., Moestrup, S.K., 2001. Identification of the
haemoglobin scavenger receptor. Nature 409, 198—201.
Kushner, I., 1993. Regulation of the acute phase response by
cytokines. Perspect. Biol. Med. 36, 611—622.
Kwiatkowski, D.P., 2005. How malaria has affected the human
genome and what human genetics can teach us about malaria.
Am. J. Hum. Genet. 77, 171—192.
Langlois, M.R., Delanghe, J.R., 1996. Biological and clinical significance of haptoglobin polymorphism in humans. Clin. Chem. 42,
1589—1600.
Larsen, K., Macleod, D., Nihlberg, K., Gurcan, E., Bjermer,
L., Marko-Varga, G., Westergren-Thorsson, G., 2006. Specific
haptoglobin expression in bronchoalveolar lavage during differentiation of circulating fibroblast progenitor cells in mild
asthma. J. Proteome Res. 5, 1479—1483.
Levy, A.P., 2003. Genetics of diabetic cardiovascular disease: Identification of a major susceptibility gene. Acta Diabetol. 40 (Suppl.
2), S330—S333.
Levy, A.P., 2004. Haptoglobin: A major susceptibility gene for diabetic cardiovascular disease. Isr. Med. Assoc. J. 6, 308—310.
Maeda, N., 1991. DNA polymorphisms in the controlling region of
the human haptoglobin genes: A molecular explanation for the
741
haptoglobin 2-1 modified phenotype. Am. J. Hum. Genet. 49,
158—166.
Maeda, N., Yang, F., Barnett, D.R., Bowman, B.H., Smithies, O.,
1984. Duplication within the haptoglobin Hp2 gene. Nature 309,
131—135.
Matzinger, P., 2002. The danger model: A renewed sense of self.
Science 296, 301—305.
Medzhitov, R., Janeway Jr, C., 2000. Innate immunity. N. Engl. J.
Med. 343, 338—344.
Meneghin, A., Hogaboam, C.M., 2007. Infectious disease, the innate
immune response, and fibrosis. J. Clin. Invest. 117, 530—
538.
Minang, J.T., Gyan, B.A., Anchang, J.K., Troye-Blomberg, M., Perlmann, H., Achidi, E.A., 2004. Haptoglobin phenotypes and
malaria infection in pregnant women at delivery in western
Cameroon. Acta Trop. 90, 107—114.
Minneci, P.C., Deans, K.J., Zhi, H., Yuen, P.S., Star, R.A., Banks,
S.M., Schechter, A.N., Natanson, C., Gladwin, M.T., Solomon,
S.B., 2005. Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized
oxyhemoglobin. J. Clin. Invest. 115, 3409—3417.
Oh, S.K., Pavlotsky, N., Tauber, A.I., 1990. Specific binding of haptoglobin to human neutrophils and its functional consequences.
J. Leukoc. Biol. 47, 142—148.
Oliviero, S.G., Morrone, G., Cortese, R., 1987. The human haptoglobin gene: Transcriptional regulation during development
and acute phase induction. EMBO J. 6, 1905—1912.
Palmer, B.F., Henrich, W.L., 1995. Clinical acute renal failure
with nonsteroidal anti-inflammatory drugs. Semin. Nephrol. 15,
214—227.
Papp, M., Lakatos, P.L., Hungarian IBD Study Group, Palatka, K.,
Foldi, I., Udvardy, M., Harsfalvi, J., Tornai, I., Vitalis, Z.,
Dinya, T., Kovacs, A., Molnar, T., Demeter, P., Papp, J., Lakatos,
L., Altorjay, I., 2007. Haptoglobin polymorphisms are associated with Crohn’s disease, disease behavior, and extraintestinal
manifestations in Hungarian patients. Dig. Dis. Sci. 52, 1279—
1284.
Pillay, J., Hietbrink, F., Koenderman, L., Leenen, L.P., 2007. The
systemic inflammatory response induced by trauma is reflected
by multiple phenotypes of blood neutrophils. Injury 38, 1365—
1372.
Polonovski, M., Jayle, M.F., 1938. Existence dans le plasma
humain d’une sunstance activant l’action peroxydasique de
l’hemoglobine. C. R. Soc. Biol. 129, 457—461.
Quaye, I.K., Ekuban, F.A., Goka, B.Q., Adabayeri, V., Kurtzhals,
J.A., Gyan, B., Ankrah, N.A., Hviid, L., Akanmori, B.D., 2000.
Haptoglobin 1-1 is associated with susceptibility to severe Plasmodium falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 94,
216—219.
Quaye, I.K., Ababio, G., Amoah, A.G., 2006. Haptoglobin 2-2 phenotype is a risk factor for type 2 diabetes in Ghana. J. Atheroscler.
Thromb. 13, 90—94.
Quindry, J.C., Stone, W.L., King, J., Broeder, C.E., 2003. The effects
of acute exercise on neutrophils and plasma oxidative stress.
Med. Sci. Sports Exerc. 35, 1139—1145.
Raberg, L., Sim, D., Read, A.F., 2007. Disentangling genetic variation for resistance and tolerance to infectious diseases in
animals. Science 318, 812—814.
Sadrzadeh, S.M., Graf, E., Panter, S.S., Hallaway, P.E., Eaton, J.W.,
1984. Hemoglobin. A biologic Fenton reagent. J. Biol. Chem.
259, 14354—14356.
Saeed, S.A., Ahmad, N., Ahmed, S., 2007. Dual inhibition of
cyclooxygenase and lipoxygenase by human haptoglobin: Its
polymorphism and relation to hemoglobin binding. Biochem. Biophys. Res. Commun. 353, 915—920.
Salvatore, A., Cigliano, L., Bucci, E.M., Corpillo, D., Velasco, S.,
Carlucci, A., Pedone, C., Abrescia, P., 2007. Haptoglobin binding
to apolipoprotein A-I prevents damage from hydroxyl radicals on
742
its stimulatory activity of the enzyme lecithin-cholesterol acyltransferase. Biochemistry 46, 11158—11168.
Shi, Y., Evans, J.E., Rock, K.L., 2003. Molecular identification of
a danger signal that alerts the immune system to dying cells.
Nature 425, 516—521.
Shimada, E., Tadokoro, K., Watanabe, Y., Ikeda, K., Niihara, H.,
Maeda, I., Isa, K., Moriya, S., Ashida, T., Mitsunaga, S., Nakajima, K., Juji, T., 2002. Anaphylactic transfusion reactions in
haptoglobin-deficient patients with IgE and IgG haptoglobin antibodies. Transfusion 42, 766—773.
Smithies, O., Walker, N.F., 1955. Genetic control of some serum
proteins in normal humans. Nature 176, 1265—1266.
Teye, K., Quaye, I.K., Koda, Y., Soejima, M., Tsuneoka, M., Pang,
H., Ekem, I., Amoah, A.G., Adjei, A., Kimura, H., 2003. A-61C
and C-101G hp gene promoter polymorphisms are, respectively,
associated with ahaptoglobinaemia and hypohaptoglobinaemia
in Ghana. Clin. Genet. 64, 439—443.
Teye, K., Soejima, M., Quaye, I.K., Pang, H., Tsuneoka, M., Koda,
Y., Kimura, H., 2006. Haptoglobin gene promoter polymorphism
and haplotypes are unique in different populations. Hum. Biol.
78, 121—126.
Theilgaard-Monch, K., Jacobsen, L.C., Nielsen, M.J., Rasmussen, T.,
Udby, L., Gharib, M., Arkwright, P.D., Gombart, A.F., Calafat, J.,
Moestrup, S.K., Porse, B.T., Borregaard, N., 2006. Haptoglobin is
synthesized during granulocyte differentiation, stored in specific
granules, and released by neutrophils in response to activation.
Blood 108, 353—361.
I.K. Quaye
Tseng, C.F., Lin, C.C., Huang, H.Y., Liu, H.C., Mao, S.J.,
2004. Antioxidant role of human haptoglobin. Proteomics 4,
2221—2228.
Valko, M., Leibfritz, D., Moncol, J., Cronin, M.T., Mazur, M., Telser,
J., 2007. Free radicals and antioxidants in normal physiological functions and human disease. Int. J. Biochem. Cell Biol. 39,
44—84.
Wada, K., Arita, M., Nakajima, A., Katayama, K., Kudo, C.,
Kamisaki, Y., Serhan, C.N., 2006. Leukotriene B4 and lipoxin
A4 are regulatory signals for neural stem cell proliferation and
differentiation. FASEB J. 20, 1785—1792.
Wen, H., Schaller, M.A., Dou, Y., Hogaboam, C.M., Kunkel, S.L.,
2008. Dendritic cells at the interface of innate and acquired
immunity: The role for epigenetic changes. J. Leukoc. Biol. 83,
439—446.
Yang, F., Brune, J.L., Baldwin, W.D., Barnett, D.R., Bowman, B.H., 1983. Identification and characterization of
human haptoglobin cDNA. Proc. Natl. Acad. Sci. USA. 80,
5875—5879.
Yang, F., Friedrichs, W.E., Navarijo-Ashbaugh, A.L., deGraffenried,
L.A., Bowman, B.H., Coalson, J.J., 1995. Cell type-specific and
inflammatory-induced expression of haptoglobin gene in lung.
Lab. Invest. 73, 433—440.
Yerbury, J.J., Rybchyn, M.S., Easterbrook-Smith, S.B., Henriques,
C., Wilson, M.R., 2005. The acute phase protein haptoglobin is
a mammalian extracellular chaperone with an action similar to
clusterin. Biochemistry 44, 10914—10925.