C-Reactive Protein and its Association with Periodontitis and Atherosclerosis: A Review
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International Journal of Research and Review
Vol.8; Issue: 2; February 2021
Website: www.ijrrjournal.com
Review Article E-ISSN: 2349-9788; P-ISSN: 2454-2237
C-Reactive Protein and its Association with
Periodontitis and Atherosclerosis: A Review
Kamalkishor Mankar1, Pranjali Bawankar2, Dhawal Mody3
1
Associate Professor, Department of Periodontics and Implantology, VSPM Dental College & Research Centre,
Nagpur
2
Senior Lecturer, Department of Periodontics and Implantology, VSPM Dental College & Research Centre,
Nagpur
3
Reader, Department of Periodontics and Implantology, VSPM Dental College & Research Centre, Nagpur
Corresponding Author: Pranjali Bawankar
ABSTRACT viral or parasitic infection, mechanical or
thermal trauma, ischaemic necrosis or
Periodontal disease is a chronic inflammatory malignant growth.1 CRP binds to specific
processes resulting from interaction of specific molecular configuration, or found on the
gram negative bacterial species with the host surfaces of pathogens.2 C-reactive protein
defense in disease susceptible individuals. The
when bound to bacteria promotes the
host responds to the microbial challenge, with
increased levels of pro and anti-inflammatory binding of complement, which facilitates
cytokines like IL-1, IL-10, IL-8, IL-6, TNF-α their uptake by phagocytes. CRP increases
etc. These mediators endorse activation of the 100 to 1000 increase within hours of tissue
acute phase reactants resulting in elevated serum injury. C-reactive protein may be considered
levels of CRP, α1-acid glycoprotein, as a primitive form of antibody specifically
ceruloplasmin, serum amyloid A. CRP thus interacting with cell membrane components
produced due to local periodontal infection has of microorganisms such as bacteria and
negative after effects on systemic health. High fungi as well as for damaged mammalian
serum CRP concentrations can be of high risk cell membranes. When complexed, C-
for future cardiovascular disease and events. Pre reactive protein can activate complement to
assessment of serum C reactive protein in
enhance opsonization and clearance of the
chronic periodontitis can predict the risk of
developing cardiovascular disease in future and bacteria prior to the production of specific
thereby can help in diagnosis at earlier stages IgM or IgG. C-reactive protein bound to
and can aid in providing screening services and bacteria or cells can interact with natural
advice to seek immediate dental care. This killer cells and with monocytes and may
review highlights the bidirectional associations increase the tumoricidal activity of these
between the cardiovascular disease marker CRP cells. Serum CRP concentration closely
and periodontitis. follows the course of the acute- phase
response to inflammation and tissue
Keywords: Periodontitis, Periodontal Therapy, necrosis. Acute phase proteins may provide
atherosclerosis, C -reactive protein. essential pathways for modulating
macrophage activity, since macrophages
INTRODUCTION contain CRP receptors and CRP may
CRP is a pentameric plasma protein effectively upregulate the formation of
which is involved in the systemic response proinflammatory cytokines. Periodontitis is
to inflammation. It is an extremely sensitive a polymicrobial disease and these bacteria
and non-specific acute-phase marker for tend to disrupt host mechanisms involved in
inflammation. CRP is produced in response their clearance by activating a number of
to many forms of injury such as bacterial, host immune-inflammatory processes.
International Journal of Research and Review (ijrrjournal.com) 277
Vol.8; Issue: 2; February 2021Kamalkishor Mankar et.al. Link between CRP, periodontitis and atherosclerosis.
These processes are subject to to specific molecules configuration formed
environmental, genetic and acquired on the surface of pathogen.11Interleukin-6
potential risks. Although periodontitis is (IL- 6), interleukin-1β (IL-1β) and tumor
initiated by microbes, host modifying necrosis factor-α (TNF-α) regulates CRP.
factors play an important role in As it was elevated in people with a variety
determining severity and extent of disease. of illnesses including cancer It was initially
Periodontal disease occurs due to a complex thought that CRP might be a pathogenic
interplay of bacterial infection and host secretion however, discovery of hepatic
response.3 Bacteria interacts with host synthesis demonstrated that it is a native
through there virulence factors and induce protein12,13 It is normally present in ng/ml
an innate and humoral immune response.4, 5 quantities but may increase dramatically to
Immune responses to bacterial challenge hundreds of μg/ml within 72hrs following
shows interindividual variations and leads to tissue injury. Periodontal pathogens affect
release of proinflammatory factors, PGE2, the immune system and promote local and
IL-1β. Inflammatory processes at systemic inflammatory responses. Persistent
periodontium results in increase level of localized infection may influence the
CRP and other mediators such as fibrinogen systemic levels of inflammatory mediators.
leading to systemic response. Annually
CVD accounts for 40% of all deaths Structure:
worldwide, with atherosclerosis as C-reactive protein is a plasma
underlying etiology in majority of cases.6,7 protein which along with serum amyloid P
Atherosclerosis is a disease process in component (SAP), forms the pentraxin
which fatty deposits, inflammation, cells family of proteins, which is a part of lectin
and scar tissue buildup within the walls of fold superfamily.14 Human CRP (Mr
arteries. Inflammation plays a central role in 115,135) consists of five identical
the pathogenesis of atherosclerosis, from its noncovalently associated 23KDa protomers
initial stage to development of clinical signs arranged symmetrically around a central
and symptoms.8 Several factors are defined pole.15
as risk factors for cardiovascular diseases; Each protomer contains "lectin fold,"
however, incidence of atherosclerosis that is composed of a double-layered β sheet
cannot be explained by traditional factors with flattened jellyroll topology. The ligand
alone. American Heart Association (AHA) binding site, contains loops with two
working group concluded that periodontal calcium ions bound 4 Å apart by protein
disease is associated with atherosclerotic side-chains, is located on the concave face.
vascular disease (ASVD) independent of The other face carries a single α helix .14
known confounders. 9 CRP has two different conformational
forms: the native pentameric isoform
C-reactive protein :( CRP): (pCRP) and the monomeric isoform
CRP is plasma protein which was (mCRP), which possess distinct antigenic,
first discovered by Tillet and Francis in electrophoretic, and biological features.
1930, as a protein which could precipitate
“C” Polysaccharide derived from C-Reactive Protein: From Pentameric to
Pneumococcal cell wall.10CRP is not only a Monomeric:
marker of inflammation, but also may pCRP is a stable molecule and is the
directly modify the inflammatory process. main form detected in serum. Many studies
CRP can interact with various ligands, can have confirmed that conformational
activate classical complement pathway, can subunits from pCRP can be dissociated,
stimulate phagocytosis and bind to Fc R both in vitro and in vivo, into individual
immunoglobulin receptors. CRP act as a mCRP units. Although independent mCRP
pattern recongnition molecule which binds synthesis also be an important source of this
International Journal of Research and Review (ijrrjournal.com) 278
Vol.8; Issue: 2; February 2021Kamalkishor Mankar et.al. Link between CRP, periodontitis and atherosclerosis.
form .16 There are two main mechanisms for phosphatidylcholine are located on the
in vivo generation of mCRP. lateral surfaces of each subunit and require
a. Local expression: Presence of mCRP binding of two calcium ions at specific
mRNA in various extrahepatic tissues hydrophobic pockets centred on Phe66, in
has been reported by various studies, an event known as calcium-dependent
which includes adipocytes, smooth ligand binding. Then, CRP is able to interact
muscle cells, and inflammatory cells with C1q, activating the classical pathway
within atheromatous plaques. of the complement system.19CRP can be
Mechanisms for synthesis of subunits recognized by immunoglobulin G (IgG) and
and their assembly into pCRP has not Fc R receptors, expressed in numerous
been understood clearly. some in vitro cells, including macrophages, mast cells,
studies support local expression, with platelets, and leukocytes. Fc R receptors are
the detection of mCRP mRNA in U937 classified either as high-affinity
macrophages of atherosclerotic Fc RI(CD64) or as low-affinity receptors,
17,18
lesions. such Fc RII (CD32) and Fc RIII (CD16).
b. Local dissociation: dissociation of Several studies points towards CRP-binding
pCRP into mCRP has been observed in capacity of lectin-like oxidized low density
membranes of apoptotic cells and lipoprotein receptor-1 (LOX-1).
activated platelets in atherosclerotic
plaques. Properties and functions:
Phosphatidylcholine molecules in 1. C-reactive protein when bound to
the cell membrane of activated platelets bacteria, can activate the complement to
appear to play an important role. enhance opsonisation and clearance of
Initially a hybrid intermediate molecule the bacteria prior to the production of
termed mCRPm is formed, exhibiting specific IgM or IgG. This process of
CRP subunit antigenicity, yet retaining protein coating to enhance phagocytosis
native pentameric conformation. This is similar to opsonization by antibodies.
molecule rapidly detaches from cell 2. CRP induces activation of the classical
membrane and finally dissociates in complement pathway and act as
solution into mCRPs. scavenger for chromatin fragments.
3. C-reactive protein bound to bacteria or
Ligands and Receptors: cells can interact with the natural killer
Volanakis and Kaplan (1971) cells and with the monocytes and may
identified the specific ligand for CRP in the increase the tumoricidal activity of these
pneumococcal C-(capsular) polysaccharide cells.20
as phosphocholine, part of the techoic acid 4. C-reactive protein can induce the
of the pneumococcal cell wall. Human CRP synthesis of IL-1α, IL-1β, TNFα and IL-
also binds to a variety of other autologous 6 in human peripheral blood
and extrinsic ligands. Autologous ligands mononuclear cells and alveolar
include damaged cell membranes, apoptotic macrophages.
cells, native and modified plasma 5. CRP modulates macrophage function.
lipoproteins, small nuclear 6. Bound CRP may produce secondary
ribonucleoprotein particles, a number of binding sites for factor H and thereby
different phospholipids and other related regulate alternative-pathway
components. Extrinsic ligands include many amplification and C5 convertases.14
phospholipids, glycans and other
constituents of microorganisms, such as Methods of measuring CRP levels
capsular and somatic components of CRP can be measured using
bacteria, parasites, fungi, and other plant immuno-turbidimetric or immuno-
products. The CRP-binding sites for electrophoretic assays or latex slide
International Journal of Research and Review (ijrrjournal.com) 279
Vol.8; Issue: 2; February 2021Kamalkishor Mankar et.al. Link between CRP, periodontitis and atherosclerosis.
agglutination method. In an enzyme-linked destruction but they are also involved in
immunosorbent assay (ELISA) or an systemic increase in inflammatory and
immune-fluorescent assay high-sensitivity immune response. Trang N. Salzberg et al
CRP (hs-CRP) assay uses labeled demonstrated that patients with AgP
monoclonal or polyclonal anti-CRP demonstrate elevated serum concentrations
antibodies. To detect hs-CRP levels Laser of CRP. It was reported that periodontitis
nephelometry can also be used. As CRP is a had an impact on systemic markers of
non-specific marker its value needs to be inflammation in a relatively young subject
correlated with clinical and laboratory group.23 Boucher et al. reported that CRP
findings. Clinically, CRP can be measured appears in the serum of patients with some
in serum in 2 ways i) routine CRP which forms of inflammatory oral disease. The
measures level above 3mg/L in adults and highest incidence of positive CRP tests and
ii) High sensitivity (hs-CRP) measuring the strongest CRP test reactions were
range up to 3mg/L. Routine CRP level observed in patients with acute alveolar
measurement can be done for a) Screening abscesses.24 Recent study have shown that
for organic disease, b) Monitoring of extent patients with severe periodontitis have
and activity of disease: infection, increased serum levels of CRP, when
inflammation, malignancy and necrosis,c) compared with unaffected control
Detection and management of recurrent population. Various studies have proved a
infection. positive association between the presence of
chronic periodontitis and high serum CRP
C-reactive protein and Periodontitis: levels.25,26,27
Periodontal disease is a chronic
inflammatory processes resulting from Role of C - reactive protein in the
interaction of selected gram negative Pathophysiology of Atherosclerosis:
bacterial species with the host defense in Atherosclerosis is a chronic
disease susceptible individuals, leading to inflammatory disease; inflammatory
progressive destruction of the periodontal processes are the vital part of
ligament and alveolar bone with pocket pathophysiology of atherosclerosis and are
formation, recession or both .21. This supposed to be involved from initiation to
condition occurs in response to a final stages of infarction. Three different
predominantly gram-negative bacterial risk categories based on serum CRP levels
infection originating from dental plaque. have been identified in a consensus
The host responds to the microbial conference of the American Heart
challenge, with a high inflammatory Association (AHA) and the Center for
response with increased levels of cytokines Diseases Control (CDC). CRP
like IL-1, IL-6, TNF-α. These mediators concentrations less than 1 mg/l are
promote activation of the acute phase considered to be at low risk, concentrations
reactants resulting in elevated serum levels in the 1–3 mg/l range are assigned a
of CRP, α1-acid glycoprotein, medium risk level and those with more than
ceruloplasmin, serum amyloid A.22 In 3 mg/l in serum CRP are considered to be at
healthy young adult volunteer blood donors, high risk for future cardiovascular disease
the median concentration of CRP is 0.8 and events.28 High-sensitivity CRP (hsCRP)
mg/l, the 90th centile is 3.0 mg/l, and the has been identified to be a key marker of
99th centile is 10 mg/l, but, following an atherosclerosis, and elevated levels
acute-phase stimulus values may increase constitute a risk factor for ACVD.28, 29
from less than 50 mg/l to more than 500 Expression of adhesion molecules,
mg/l, that is, 10,000-fold. This effect is chemokines, and cytokines by endothelial
mainly seen as periodontal pathogens do not cells can directly be activated by CRP.30
induce only local inflammation and tissue CRP can directly influence atherogenesis by
International Journal of Research and Review (ijrrjournal.com) 280
Vol.8; Issue: 2; February 2021Kamalkishor Mankar et.al. Link between CRP, periodontitis and atherosclerosis.
activation of the complement system, CONCLUSION
apoptosis, vascular cell activation, C-reactive protein is a nonspecific
monocyte recruitment, lipid accumulation, marker of inflammation. Elevated levels of
and thrombosis. pCRP can generate serum C-reactive protein are found in
inflammatory responses, binding to the subjects with cardiovascular diseases.
phosphatidylcholine on the exterior of Chronic periodontitis results in higher
LDLox and the surface of apoptotic cells31, systemic levels of CRP. The elevated
while mCRP is able to modulate platelet inflammatory factors may increase
function inducing aggregation and inflammatory activity in atherosclerotic
contributes to atherothrombotic lesions, thereby increasing the risk for
complications by promoting thrombosis.32 cardiovascular events. CRP plays an
important role in activation of complement
Effect of periodontal therapy on serum system, metalloproteinases and recruitment
CRP level: and activation of inflammatory cells. Many
Periodontal therapy includes studies have shown that periodontal therapy
mechanical disruption of the dental biofilm can lower the levels of CRP in serum of
of the diseased dentition. After periodontal patients with periodontitis. Further research
therapy reduction of serum levels of CRP is needed to find out whether the changes in
and an improvement of measures of cellular and molecular markers in peripheral
endothelial function has been observed. blood in periodontitis are indeed causally
Treatment of periodontal infections, related to cardiovascular events and whether
whether by intensive mechanical therapy, periodontal therapy and maintenance of
drug therapy or extraction, can significantly periodontal health will reduce the risk for
lower serum levels of CRP. Median such events.
decrease in serum CRP level after
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