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Biochemical Pharmacology
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Review
University of Louisville School of Dentistry, Oral Health and Systemic Disease, Loueisville, KY 40292, USA
University of Louisville School of Medicine, Dept. of Microbiology and Immunology, Louisville, KY 40292, USA
A R T I C L E I N F O
A B S T R A C T
Article history:
Received 24 April 2010
Accepted 8 June 2010
Although the complement system is centrally involved in host defense, its overactivation or deregulation
(e.g., due to inherent host genetic defects or due to pathogen subversion) may excessively amplify
inammation and contribute to immunopathology. Periodontitis is an oral infection-driven chronic
inammatory disease which exerts a systemic impact on health. This paper reviews evidence linking
complement to periodontal inammation and pathogenesis. Clinical and histological observations show
a correlation between periodontal inammatory activity and local complement activation. Certain
genetic polymorphisms or deciencies in specic complement components appear to predispose to
increased susceptibility to periodontitis. Animal model studies and in vitro experiments indicate that
periodontal bacteria can either inhibit or activate distinct components of the complement cascade.
Porphyromonas gingivalis, a keystone species in periodontitis, subverts complement receptor 3 and C5a
anaphylatoxin receptor signaling in ways that promote its adaptive tness in the presence of nonproductive inammation. Overall, available evidence suggests that complement activation or subversion
contributes to periodontal pathogenesis, although not all complement pathways or functions are
necessarily destructive. Effective complement-targeted therapeutic intervention in periodontitis would
require determining the precise roles of the various inductive or effector complement pathways. This
information is essential as it may reveal which specic pathways need to be blocked to counteract
microbial evasion and inammatory pathology or, conversely, kept intact to promote host immunity.
2010 Elsevier Inc. All rights reserved.
Keywords:
Complement
C5a
Inammation
Innate immunity
Periodontitis
Contents
1.
2.
3.
4.
5.
6.
7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Periodontal inammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Complement and its role in periodontal pathogenesis. . . . . . . . . . . . . . . . . . . . .
Inammatory diseases and potential for complement-ary therapy. . . . . . . . . . .
CR3 in periodontal pathogenesis and implications for therapeutic intervention
Rationale for targeting the C5aC5aR axis in periodontitis . . . . . . . . . . . . . . . . .
Conclusions and future directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Host defense and inammation is fundamentally dependent on
the complement system, which orchestrates critical events in this
regard. These include recruitment and activation of inammatory
cells, microbial opsonization, phagocytosis, and lysis, as well as
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1992
1993
1993
1996
1996
1998
1998
1999
1999
1993
Fig. 1. Activation and regulation of the complement system. All three pathways converge at the third component of complement (C3) which is activated by pathway-specic
C3 convertases [1]. The classical pathway is initiated by antigenantibody (AgAb) complexes and requires the participation of C1, C2, and C4. The lectin pathway is triggered
through interaction of the mannose-binding lectin (MBL) with specic microbial carbohydrate groups, followed by activation of MBL-associated serine proteases (MASPs) and
cleavage of C2 and C4. The alternative pathway is initiated by spontaneously hydrolyzed C3 [C3(H2O)] which can thereby form a complex with factor B (fB), followed by fB
cleavage by factor D (fD) and formation of the initial alternative pathway C3 convertase [1]. Moreover, the alternative pathway can be induced by bacterial lipopolysaccharide
and lipooligosaccharide in a properdin-dependent way [38]. Proteolytic cleavage of a series of proteins downstream of C3 leads to the generation of potent effector molecules.
These include the inammatory anaphylatoxins C3a and C5a, which activate specic receptors (C3aR and C5aR, respectively), although C5a also interacts with the so-called
C5a receptor-like 2 (C5L2), which appears to mediate both regulatory and proinammatory effects [4044]. In the terminal pathway, C5b initiates the assembly of the C5b-9
membrane attack complex (MAC), which in turn induces microbial cell lysis [1] or host cell signaling at sublytic concentrations [78,168]. Complement activation is regulated
at multiple steps by various regulatory proteins, as indicated by the characteristic inhibitory symbols. C1NH, C1 inhibitor; C4BP, C4b-binding protein; CR1; complement
receptor 1; DAF, decay accelerating factor; fH, factor H; FHR-1, fH-related protein 1.
1994
Table 1
Complement-related clinical associations in periodontitis.
Observations
Refs.
[5458,63,67,69,73,166]
[54,62,6467]
[58]
[68]
[69,167]
[75]
[66]
[82]
[77]
[(Fig._2)TD$IG]
1995
Table 2
Interactions of periodontal pathogens with complement.
Interaction
Refs.
[60,84]
P. gingivalis (HRgpA)
T. denticola (11.4-kDa lipoprotein)
[86,91]
Proteolytic shedding of complement regulatory proteins (CD46) from host cell surface
P. gingivalis (Kgp)
[93]
[84,87,92,150]
P. gingivalis (mbriae)
[119,120]
1996
[(Fig._3)TD$IG]
resting cells is of low afnity, a rapid and transient shift to a highafnity binding state can be triggered by inside-out signals
generated by other receptors, such as chemokine receptors or TLRs
[112,113].
P. gingivalis is particularly strong in activating CR3. Specically,
the mbriae of P. gingivalis bind CD14 and activate TLR2- and
phosphatidylinositol 3-kinase (PI3K)-mediated inside-out signaling leading to activation of the ligand-binding capacity of CR3
[113]. Activated CR3 can in turn interact directly with this
bacterium [114] (Fig. 3). The interactions of CR3 on monocytes or
macrophages with P. gingivalis lead to inammatory responses,
such as induction of certain cytokines (TNF-a, IL-1b, and IL-6)
[106,110,115] and stimulation of monocyte adhesion to endothelial ICAM-1, leading to transmigration across endothelial cell
monolayers [116].
These P. gingivalis-induced CR3-dependent responses could
potentially contribute to innate host defense. However, it is also
possible that they may have pathophysiological consequences in
periodontal disease. In this regard, CR3-induced cytokines such as
TNF-a, IL-1b, and IL-6 can cause periodontal bone resorption [26],
whereas CR3-dependent migration of inammatory cells could
amplify periodontal inammation. Neutrophils, which are implicated as major effectors of inammation-induced tissue damage in
periodontitis [72], express high levels of CR3 which facilitates their
trafcking to sites of extravascular inammation [117,118]. It is
thus plausible that P. gingivalis may promote periodontal tissue
recruitment of neutrophils or other inammatory phagocytes
through activation of CR3, thereby exacerbating periodontal
inammation.
Although the above mechanistic scenario for CR3-mediated
inammation and tissue destruction in periodontitis is hypotheti-
1997
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